BLEEDING RISK IN TRANSBRONCHIAL LUNG BIOPSY IN PATIENTS TAKING ANTIPLATELET MEDICATIONS

Li Ding, MD (Associate). Department of Internal Medicine, Sinai-Grace Hospital/Detroit Medical Center, Wayne State University, Detroit, Michigan.

INTRODUCTION: Antiplatelet agents (APA) are wildly used in primary and secondary prevention for coronary heart disease, cerebral vascular accident and peripheral artery diseases. Evidence has shown that perioperative withdrawal of aspirin will precede acute cardiovascular syndromes. The aim of this project is to study the safety of patients taking APA while undergoing transbronchial lung biopsy (TBLB).

METHODS: A comprehensive literature review was done using PubMed, Ovid Medline and Cochrane library databases. Keywords used were bronchoscopy, transbronchial lung biopsy, aspirin, clopidogrel, antiplatelet therapy, bleeding, invasive procedure and surgery. The results of relevant articles were then compared.

STUDY SELECTION CRITERIA: Prospecitve or retrospective cohort study, meta-analysis and randomized controlled trials published during the past ten years were selected.

SEARCH RESULTS: Of the few relevant studies, this project reviews mainly three studies, two of which are prospective cohort studies and the third one is a meta-analysis.

RESULTS: The first study showed that there was no significant difference in post TBLB bleeding rate between aspirin group (3.5%) and control group (5%). The second study compared the bleeding events in TBLB among the patient taking clopidogrel or without taking clopidogrel. They found that bleeding rate is 3.4% in control group, 88% in clopidogrel alone group and 100% in clopidogrel + aspirin group (P<0.001). This result indicated that clopidogrel use greatly increases the risk of bleeding in TBLB, and aspirin exacerbates this bleeding effect. The meta-analysis compared all the studies on bleeding risk of patients who taking aspirin and undergoing different invasive procedures or non-cardiac surgeries. This study showed that aspirin increased the rate of bleeding complication by a factor of 1.5. However, aspirin did not lead to a high level of the severity of bleeding complications.

CONCLUSION: TBLB can be safely performed on patients taking aspirin on standard doses. However, clopidogrel increases the bleeding rate of TBLB and aspirin exacerbates this risk. Controlled clinical studies are urgently needed to further determine the safety of patients who taking antiplatelet agents and undergoing invasive procedures.

A RARE CASE OF DUODENAL MALTOMA PRESENTING WITH OBSTRUCTIVE JAUNDICE

Li Ding, MD (Associate), Saad Usmani, MD (Associate), Husain Saleh, MD, Mohammed Siddique MD FACP. Department of Internal Medicine, Sinai Grace Hospital/Detroit Medical Center, Wayne State University, Detroit, Michigan.

INTRODUCTION

Mucosa-associated lymphoid tissue (MALT) makes up to 8% of all NHL cases. The most common site for MALT lymphomas is stomach. Primary duodenal MALT lymphoma represents a very rare neoplasm. There are only 29 cases reported on English literature to date. Obstructive jaundice has only been documented in one patient. Lethal case has not yet been reported. We are reporting the first case of primary duodenal MALT lymphoma causing the death of the patient, it is also the second case of MALT lymphoma presented with obstructive jaundice.

CASE REPORT

A 57-year-old male presented with complaint of nausea, vomiting and right upper quadrant abdominal pain for 2 weeks. Physical examination revealed scleral icterus and right upper quadrant tenderness. Laboratory studies showed normocytic anemia, direct bilirubinemia, elevated alkaline phosphatase and aminotransferases. Complete blood count revealed hemoglobin 9.6. CT of abdomen and pelvis showed a large mass in the right anterior para-renal space. EGD revealed evidence of mucosal abnormality around the second portion of duodenum. Biopsy histopathology was consistent with MALT lymphoma and Helicobacter pylori was not seen. A common bile duct stent was placed under endoscopic retrograde cholangiopancreatography (ERCP). However, patient developed contrast-induced nephropathy, acute pancreatitis, aspiration pneumonia, and ARDS. Patient was admitted to the ICU but his condition continuously deteriorated. The patient expired on the 47th day of admission while in the ICU.

DISCUSSION AND CONCLUSION

A thorough literature search revealed only 29 reported cases of duodenal MALT with average age of presentation being 56 years old. The symptoms of duodenal MALT lymphoma are insidious and non-specific, obstructive jaundice is one of the rare presenting symptoms. Unlike gastric MALT, there is not sufficient evidence of chronic Helicobacter pylori infection being associated with duodenal disease, and the response to H. pylori eradication therapy in the reported patients has been variable. Primary duodenal MALT lymphoma progresses very slowly. However, it can lead to a poor prognosis. Further investigation is needed to establish the strategy for the therapeutic approach.

Treatment Of Venous Tromboembolism In Patients With Cancer.

Ganna Doronina, MD( Associate), Joel Appel, MD FACP,

Department of Internal Medicine, Sinai-Grace Hospital, Wayne State University

Introduction: Association between cancer and venous thromboembolism (VTE) is well established. Challenges of VTE in cancer patients compared to non-cancer patients include increased recurrence and bleeding rates during warfarin therapy.

Methods: I performed literature search for clinical evidence in support of therapy alternative to warfarin. I used Pubmed, Ovid Medline and Cochrane as search engines. My key words were: cancer, tromboembolism, and warfarin.

Results: The CLOT trial was a randomized, open-label trial comparing dalteparin and warfarin in the prevention of recurrent VTE in 672 patients with acute VTE and cancer. The cumulative rate of recurrent VTE at 6 months was significantly higher, at 17, 4%, in the warfarin group than in the dalteparin group (8.8%). There was no statistically significant difference in the rate of bleeding between two groups.

The post-hoc analysis of the CLOT data showed that the survival in the dalteparin group at 1 year was higher than in warfarin group in patients without metastasis (P=0.03). There was no statistically significant difference in 1-year survival in patient with advanced cancer.

In randomized, open-label, French trial enoxaparin at fixed dose and warfarin were compared in 146 patients with acute VTE and cancer. Major bleeding and/or recurrent VTE was the measured outcome. During the 3-months treatment period, 21.1% of patients receiving warfarin and 10, 5% receiving enoxaparin experienced recurrent VTE and/or major bleeding. The difference was not statistically significant (P=0.09).

Conclusion: Low-molecular-weight heparin is more effective than warfarin in reduction of the risk of recurrent thromboembolism without increasing risk of bleeding. Use of low-molecular-weight heparin associated with higher rate of survival in patients with cancer without metastasis.

New Face Of Chronic Myeloid Leukemia.

Ganna Doronina, MD, Saad Usmani, MD, Joel Appel, MD FACP, Yasir Zaidi, MD, Department of Medicine, Wayne State University, Sinai-Grace Hospital, Detroit, MI.

Introduction: Chronic myeloid leukemia is a clonal myeloproliferative disorder characterized at the molecular level by the BCR-ABL gene fusion. The use of cytogenetics and fluorescent in-situ hybridization (FISH) analysis in CML patients have identified atypical inversions/translocations of the Philadelphia chromosome in less than 5% of cases. Their role in prognosis is still controversial. We present a case of CML that presented with unique pericentric inversion of chromosome 9.

Case Report: 67 year old woman with past medical history of gastro-esophageal reflux disease and mitral valve replacement was admitted to hospital with acute onset of left-sided chest discomfort and recent history of recurrent epistaxis. Physical exam revealed hepatomegaly and abdominal bruit. Laboratory work-up showed elevated white cell count. Myocardial ischemic and septic work-up was negative. Peripheral smear showed marked leucocytosis with increased bands, myelocytes and metamyelocytes, basophillia and eosinophillia with no increase in blast count. CT of the abdomen showed hepatomegaly and mediastinal lymphadenoapthy. Bone marrow aspiration showed myeloid hyperplasia with left shift, increased megakaryocytes consistent with chronic myelogenous leukemia. Cytogenic analysis was positive for Ph chromosome. FISH analysis revealed the presence of single fusion pattern of BCR-ABL along with pericentric inversion of chromosome 9. Patient was started on imatinib mesylate (Gleevac) and has reached complete hematological remission.

Discussion and Conclusion: Our understanding of hematological malignancies in general and CML specifically has evolved with the insight into cancer genomics. It is still controversial whether CML patients with variant translocations have significantly deferent response to therapy and prognosis. Our patient has shown excellent response to standard CML therapy, achieving complete hematological remission. We are presenting this case to highlight the emerging role of molecular genetics in CML therapy and good response to therapy in our patient.

UNILATERAL EXUDATIVE PLEURAL EFFUSION DUE TO PULMONARY TOXICITY FROM AMIODARONE

Salah Fares , MD (Associate), Rajika L. Munasinghe, MD, Fellow,

Sinai-Grace Hospital/Wayne State University, Detroit, Michigan

INTRODUCTION:

Amiodarone is a very effective antiarrhythmic drug that has been associated with multi –organ toxicity. Pulmonary toxicity is reported in approximately 5-7% of patients treated with amiodarone. We present an unusual case of unilateral exudative pleural effusion induced by amiodarone.

CASE REPORT: A 88-year-old Caucasian woman with a known history of atrial fibrillation treated with 200 mg of amiodarone since 2004, presented with shortness of breath since June-2005. Chest X-ray showed a right pleural effusion and air space disease that was confirmed by chest CT. The patient underwent a diagnostic thoracentesis, and pleural fluid analysis demonstrated an exudative effusion with no evidence of infection or malignancy. The patient had been treated empirically with multiple courses of antibiotics without a significant improvement in her condition. In October-2005 a follow up chest X-ray showed a persistent moderate right-sided pleural effusion with basilar pulmonary infiltrates. High resolution chest CT scan showed a small right pleural effusion with calcification within the inner and outer aspect of the pleura in the right lower chest. Atelectasis and infiltrate in the right lower lobe was also present. Drug induced lung disease was suspected and Amiodarone was discontinued. The patient was followed with serial chest X-rays that showed a gradual decrease in the amount of pleural effusion and the most recent chest X-ray in August-2006 showed no evidence of pleural or pulmonary pathology.

DISCUSSION & CONCLUSION:

Although pulmonary toxicity induced by amiodarone has been well described in the medical literature, our case is unique from other cases because pulmonary toxicity was associated with a relatively lower dose of amiodarone (200 mg) and the co-existence of an exudative plural effusion. Previous case reports of pulmonary toxicity have been associated with amiodarone doses between 400mg-1600mg. Amiodarone-induced pleural effusion is rare with only seven prior cases reported in the literature. Unless this diagnosis is entertained early, patients may be subjected to unnecessary interventions and a reversible cause of exudative pleural effusion overlooked.

Association of FLT-3 ITD Mutations with AML arising from MDS.

S Jindani M.D, Z Gul M.D, N Galili PhD, A Raza M.D

Department of Medicine Hematology section

University of Massachusetts, Worcester Massachusetts.

Sinai Grace Hospital Detroit Medical Center Wayne State University.

Introduction: Receptor-tyrosine kinase genes play an essential role in hematopoiesis. Internal tandem repeats (ITD) of the FLT3 receptor-tyrosine kinase gene have been found in 20-27% of patients with de novo AML and correlates with poor prognosis. ITD mutations are rare in patients with MDS. Those that do harbor the mutation may have a higher risk of evolving to AML. We proposed to look for FLT-3 mutation in AML patients transformed from MDS as a possible contributory cause of this transformation. Methods: Bone marrow samples of 16 patients with AML progressing from MDS were obtained. DNA was extracted ( DNeasy Tissue kit, Qiagen) and exons 11 - 12 and the intervening intron of the FLT3 gene were amplified from isolated DNA by PCR. Amplified products were electrophoresed through 1.8% agarose gels and visualized under UV light with ethidium bromide staining. ITD was recognized as an increase in the size of the PCR product which is normally 328 base pairs.

Results: One out of 16 bone marrow samplesof patients who had secondary AML after MDS was positive for FLT3/ITD mutation as recognized by increase in size of the PCR product

Discussion: The FLT3/ITD mutation has prognostic significance i.e with high risk of transformation to AML, rapid progression of AML, and poor survival in patients with MDS. However, in our cohort, the presence of this mutation is clearly not the major event leading to progression to AML Similar to previous findings this one patient found to have the FLT3 mutation correlated clinically with rapid progression from MDS to AML with a karyotype of triploidy (92,XXYY[13]/46,XY[7]).

Conclusion: The result of the current study demonstrates that in patients with MDS FLT3/ITD is associated with risk of transformation to AML. However for the vast majority of patients with AML arising from MDS, role of other mechanisms should be explored.

Reversal Of Karyotype In Paroxysmal Nocturnal Hemoglobinuria (PNH) With Myelodysplastic Syndromes (MDS): A Case Report.

Shireen Jindani,MD Associate of American College of Physicians, Leopoldo Eisenberg,MD Fellow of American College of Physicians Clinical Associate Professor of Medicine University School of Medicine

Department of Internal Medicine, Sinai-Grace Hospital / Detroit Medical Center, Wayne State University, Detroit, Michigan.

PNH is a consequence of nonmalignant clonal expansion of one or several hematopoitic stem cells that have acquired a somatic mutation of PIGA. Progeny of affected stem cells are deficient in glycosyl phosphatidylinositol- anchored proteins. (GPI-APs). Deficiency of GPI-anchored complement regulatory proteins CD55 and C59 (accounts for the intravascular hemolysis that is the primary clinical manifestation of the disease.

PNH frequently arises in association with disorders of bone marrow failure. Flow cytometric characterization of glycosyl phosphatidylinositol–anchored protein expression on peripheral blood cells and marrow analysis are required for comprehensive disease classification. For optimum management, the contribution of both hemolysis and marrow failure to the complex anemia of PNH should be determined. Complement inhibition by eculizumab is a promising new approach to treating the hemolytic anemia. Stem cell transplantation is potentially curative, but the decision on use is best made

on a case-by-case basis because of the heterogeneous natural history of the disease.1 Bone marrow analysis and cytogenetics are used to determine if PNH arose in association with specified bone marrow disorder.

We Report a case of PNH with MDS with reversal of genetic abnormalities.

Case:

In August 2000, 38 year old Caucasian Lady was referred for the evaluation of anemia and thrombocytopenia with symptoms of dizziness, ringing in ears, headache and fatigue. Patient had history of hypertension for which she took amlodipine. She was otherwise in good health and took no other medication. Work up showed, Hb 5.5 gm/dl, MCV 101.9fl, Peripheral smear marked degree of Macrocytic anemia and megaloblastoid forms. Bone marrow revealed Sideroblastic erythropoises with 80% cellularity while cytogenetics were initially normal. Differential diagnosis at that point was B12, Folate deficiency Vs Myelodysplastic syndrome . Patient was managed with transfusions and supplements, but remained transfusion dependent and two months after presentation cytogenetics showed 13 q deletions by then B12 and folate defieciency was ruled out. She complained of passing dark colored urine her haptoglobin was low with high Lactate dehydrogenase and negative direct and indirect Coomb’s test, CD59 CD 55 assay were negative with 7.3% and 2.1% of type II and III PNH cells respectively on flow cytometric analysis so patient now had PNH with MDS. While awaiting bone marrow transplant she became transfusion independent. Cytogenetics were further changed with addition of 7 q partial deletion but patient was doing fine so she did not get bone marrow transplant and remained transfusion independent for some time with surprisingly reversal of her cytogenetics to normal in 2006. Patient is on Eculizumab, humanized monoclonal antibody against terminal complement protein C5. that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH) and has been found to be an effective therapy in a double blind randomized, Placebo controlled phase 3 trial.This case with follow up for past six years of a patient with Myelodysplasia with Paroxysmal Nocturnal Hematuria and cytogenetic changes with complete reversal provides a unique opportunity to look for dynamic interaction between myelodysplastic and PNH clones

ARE THE NEWER INSULIN DERIVATIVES INSULIN GLARGINE AND LISPRO BETTER THAN PREMIXED NPH/REGULAR(70/30)FOR THE TREATMENT OF TYPE 1 DIABETES?

Gulnaz Khan,MD,Associate, Rajika L.Munasinghe,MD Fellow

Sinai Grace Hospital / Wayne State University, Detroit, Michigan

Background:

DCCT and UKPDS confirmed the value of glycemic control in the prevention of complications of diabetes.This is achieved with regular insulin administered by either as continuous subcutaneous insulin(CSI) by pump or multiple daily injections( MDI ).The chief adverse event with intensive therapy was severe hypoglycemia. Insulin analogues are characterized by action profiles that afford more flexible treatment with a lower risk of the development of hypoglycemia. Objective: To compare glargine + lispro with NPH + regular insulin and to suggest insulin regimen based on blood glucose profiles in patients with Type 1 diabetes.

Methods:

Articles were identified through MEDLINE, PubMed, Cochrane library and Ovid.Five (relevant) randomized Multicenter controlled Trial in type 1 diabetes were identified.

Results:

Three out of the 5 studies showed a statistically significant improvement in HbA1c in patients treated with Insulin Glargine and Lispro compared to NPH and Regular insulin. Fasting blood glucose values were significantly improved in 3 out of 5 trials for patients treated with Insulin Glargine and Lispro.Incidence of nocturnal hypoglycemia was significantly less with Glargine and Lispro in 4 trials.The remainder of the results were non-significant.NPH/Regular insulin was not superior to Glargine/Lispro for the above outcome measures in any one of the trials.

Conclusion:

Insulin analogues allow more accurate replication of the basal and prandial components of insulin replacement.Glycemic control is improved as measured by HbA1c,FBG,nocturnal hypoglycemia and postprandial hyperglycemia with no major differences in safety and efficacy profiles of two groups.New insulin preparations are more expensive and increased cost should be considered in deciding between different insulins.Recent studies have also shown that flexible insulin management can be cost effective and can be associated with an improvement in quality of life.Our literature review supports the use of insulin analogues to achieve recommended goals of glycemic control in patients with diabetes.

Gulnaz Khan,MD (Associate), Kavitha Potluri,MD (Associate), Dr.Krishnamoorthy, MD (Member), Irfan Omar, MD (Member),

Sinai Grace Hospital / Wayne State University, Detroit, MI

IgA Nephropathy: A Common disease with an uncommon presentation.

Introduction:

IgA Nephropathy is known to be the most common form of glomerulonephritis worldwide. In U.S, the incidence is approximately 4% of all renal biopsies and it is six times lower in African Americans than in Caucasians. Lower prevalence in African Americans is unexplained.

Case report:

We are describing a case of 41 year old African American male with past medical history of hypertension and type II diabetes, who presented with worsening shortness of breath and bilateral leg swelling for 3 days. Patient was recently discharged from the hospital after being treated for pneumonia and review of the medical records revealed that he had a right leg DVT during the hospital stay. Physical examination revealed anasarca with prominent facial swelling and diffuse crackles on auscultation.Workup showed nephrotic range proteinuria with spot urine protein of 450mg/dl, serum creatinine of 0.5, hemoglobin of 7.7 and thrombocytosis. Work up for the nephrotic range protienuria including Hepatitis profile, HIV, ASO titers, ANCA levels and protein electrophoresis, were negative. Dilated fundoscopy did not show any evidence of diabetic retinopathy. CT guided renal biopsy was performed which showed immune complex mediated, IgA predominate; diffuse mesangial and segmental endocapillary proliferative glomerulonephritis. Patient’s symptoms improved with aggressive diuresis and he was discharged home on ACE inhibitors.

Discussion:

IgA Nephropathy is an immune complex mediated glomerulonephritis, occurring in all age groups. It is often progressive with 25% of the patients going to end stage renal disease over the course of 25 years. Asymptomatic microscopic hematuria is the most common presentation and less than 30% present with nephrotic range proteinuria. Although proteinuria at the time of biopsy is a well known indicator of progressive renal disease in patients with IgA Nephropathy, our patient has stable renal function even after 2 years of follow up.

Conclusion:

IgA nephropathy shows regional and racial variation which may reflect different clinical policies for diagnostic test. These facts and the rarity in African American may suggest genetic and environmental role in IgA nephropathy. When clinical picture such as diabetes does not explain nephropathy, renal biopsy should be contemplated as a diagnostic test.

An Unusual progression of Cardiac Amyloidosis

Saba Khokar.MD(Associate),Sabeeh A Siddiqui.MD(Associate), Salah Fares.MD(Associate), Randy Liebermann.MD.FACC

Sinai Grace Hospital/Detroit Medical Center/Wayne State University.

Cardiac amyloidosis can result from any of the systemic amyloidoses. The disease is often characterized by a restrictive cardiomyopathy although the particular signs and symptoms depend on the underlying cause. In addition to managing the symptoms of heart failure, treatment options vary depending on the etiology of amyloid deposition.

We present a case report of a 79yo African American female who had been diagnosed with Multiple Myeloma one and a half years ago and had been on chemotherapy. For the last 6 months, she had been feeling short of breath and had been to ER multiple times, and treated for heart failure. Cardiac catheterization done six months ago did not reveal any coronary lesions but moderate pulmonary hypertension, and EF was 60%. Echocardiogram one year also had shown preserved cardiac function and she was started on treatment for diastolic heart failure. She presented to the hospital this time with dyspnea, and was diagnosed with CHF exacerbation, EKG revealed low-amplitude but no ST-changed and troponin was negative, By next day, her condition deteriorated with a drop in blood pressure. A repeat echocardiogram showed an ejection fraction of 25%, her condition slowly improved with CHF management,. However, she went into cardiac arrest , she was resuscitated and transferred to ICU. Again she recovered enough to be transferred to general floor and had a right heart cath with cardiac biopsy which showed cardiac amyloidosis; a decision was made not to implant an ICD and treatment was geared to comfort care. Two weeks later the patient expired.

Limited data is available about the rate of progression or decline in cardiac functioning in Patients with cardiac amyloidosis but studies do indicate the improvement of cardiac functioning with successful treatment of multiple myeloma.However our patient Having completed her chemotherapy continued to show decline in cardiac functioning with EF dropping from 55-60 % to 25% in 3 months. Although the prognosis is very poor in these cases with life expectancy less than 6 months, it warrants further studies to better understand the modality of progression and to improve therapeutic interventions.

Impact of baseline glycemic control on longitudinal blood pressure responses in drug-treated hypertensives ?

Krithi Ramesh 1, MD; Zongshan Lai, MS; Xuefeng Liu, PhD; Anupam Goel, MD; John Flack, MD, MPH.

Department Of Internal Medicine,Wayne State University and 1 Sinai-Grace Hospital, Detroit, MI.

Background: Most persons with diabetes have hypertension. Glycemia, per se, has physiological effects such as vascular stiffening that might interfere with longitudinal blood pressure (BP) lowering in drug-treated hypertensive patients.

Objective: To determine the BP response to antihypertensive drugs in a pharmacologically treated in a largely African American hypertensive cohort.

Methods: We performed a retrospective review in the Wayne State University Hypertension Clinic (WSUHC) between May 2001 and May 2006 of patients with at least two visits and one glycosylated hemoglobin (A1C) determination. The outcome of interest was last available SBP. We recorded age, sex, race, weight, A1C, chronic kidney disease staging and albuminuria. A therapeutic intensity score (TIS), the patient’s daily medication dose over the maximum FDA approved dose of that medication for each drug, was calculated to determine therapeutic intensity of treatment. We compared the fitting of two linear mixed models on last available SBP: a) Hemoglobin A1C alone versus b) Hemoglobin A1C with other covariates.

Results: The average age in our cohort [N=146] was 61.0 years. Most of the patients were female (101 [69.2%]) and 136 (93.2%) were African American. The average weight (lbs), hemoglobin A1C (%), and baseline SBP (mm Hg) were 213.3 pounds, 7.3, and 175.8 mm Hg, respectively. Average baseline antihypertensive TIS was 2.0 (SD 1.2). The average follow-up period was 18.1 months. The average final antihypertensive TIS was 2.8 (SD 1.2) and the ending mean SBP was 145.3 mm Hg. In the model including hemoglobin A1C alone, each 1% higher baseline hemoglobin A1C was associated with a 2.6 higher exit SBP (P=0.009). In the multivariate mixed model for predicting final SBP including all baseline variables and time-dependent covariates such as antihypertensive TIS, the each 1% higher baseline hemoglobin A1C was linked to 2.9 mm Hg higher SBP (P=0.004).

Conclusions: Baseline glycemic control has a very significant and negative impact on longitudinal SBP levels in a drug-treated hypertensive cohort with diabetes. These data imply, though do not prove, that better glycemic control will improve BP control in drug-treated hypertensive patients with diabetes.

Effectiveness of Exenatide Therapy In The Treatment of Type 2 Diabetes In Ambulatory Practice.

K.Ramesh, M.D, R.Munasinghe, M.D, O. Alzohaili, M.D, G.W.Edelson, M.D, Sinai-Grace Hospital, Detroit Medical Center, Wayne State University.

Introduction: Exenatide, an incretin mimetic and GLP-1 agonist improves glucose homeostasis and promotes weight loss by glucose dependent insulin release, regulation of glucogan secretion, delaying gastric emptying, and decreasing appetite. It is approved as adjunctive therapy for type 2 diabetes in conjunction with Metformin and/or sulfonylurea to improve glycemic control. Principal side effects are gastrointestinal manifestations such as nausea, vomiting and diarrhea. This study was conducted to evaluate the effectiveness of exenatide in two private endocrinology practices.

Method: Medical records of 30 poorly controlled type 2 diabetic patients seen in office practice between Oct 2005 and August 2006 were reviewed. Exenatide was initiated at 5mcg twice daily and increased to 10mcg twice daily in 4 weeks. The change in HbA1c, lipid profile and body weight before and after initiation of exenatide were evaluated using paired Student’s t-Test. The prevalence of hypoglycemia and other major adverse effects of exenatide were also recorded.

Result: The mean age of the study subjects was 54.7 years, 53.3% were female and 93% were white. Treatment prior to initiation of exenatide included oral hypoglycemic drugs [Metformin (22) +/- Sulfonylurea (18) +/- Thiazolidinedione (13)] with or without insulin (9). The mean duration of follow up was 15 weeks (range 8 to 28 weeks). The mean HbA1c of the study subjects declined from 7.80% to 7.32% (p <.0008) and the mean body weight decreased from 244.3 to 238.6 lbs (p <0.0002), an average loss of 5.7 lbs. There was no statistically significant change in total cholesterol, triglycerides, HDL, LDL, or in the cholesterol/HDL ratio. The majority (90%) of patients continued exenatide after the first follow up visit. Hypoglycemia was noted in 10% of patients while nausea and vomiting was reported by 31% of patients. Other gastrointestinal side effects were reported by 23% of patients.

Conclusion: In typical ambulatory practice, exenatide is effective in improving glycemic control and promoting weight loss in poorly controlled type 2 diabetic patients on oral hypoglycemic therapy. Although a substantial number of patients reported gastrointestinal side effects, the majority of patients managed to remain on exenatide therapy.

Effectiveness of Exenatide Therapy In The Treatment of Type 2 Diabetes In Ambulatory Practice.

K.Ramesh, M.D, R.Munasinghe, M.D, O. Alzohaili, M.D, G.W.Edelson, M.D, Sinai-Grace Hospital, Detroit Medical Center, Wayne State University.

Oxaliplatin associated anaphylactic shock, immunological neutropenia and thrombocytopenia.

Syed Raza, MD, Saad Usmani, MD, Joel Appel, DO FACP

Department of Internal Medicine, Detroit Medical Center/Wayne State

University, Sinai Grace Hospital, Detroit MI.

Introduction:

Oxaliplatin is a platinum salt that has been used as a chemotherapeutic agent, specifically for gastrointestinal malignancies. We present a case of a patient who developed an uncommon but life-threatening anaphylactic reaction to this agent.

Case Report:

A 63 year old Caucasian female with past medical history of hypertension and hypothyroidism was diagnosed with Stage III A sigmoid cancer. She underwent colectomy and was started on adjuvant therapy with FOLFOX 4 regimen containing oxaliplatin, 5-flourouracil (5-FU) and leucovorin. She was asymptomatic after Cycle#1. On the second day of Cycle#2, she presented with fevers and chills at home. On physical examination, she was found to be hypotensive and had a generalized non-pruritic rash. Laboratory evaluation revealed neutropenia. She was treated for febrile neutropenia and was discharged after 6 days. While receiving oxaliplatin for the Cycle#3 a week later, she became diaphoretic, developed the same rash and went into shock. She was admitted to the ICU and treated for suspected septic shock with fluids, antibiotics and required vasopressor agents. Physical examination did not reveal a focus of infection and the septic work-up was negative. Blood counts, which were normal before Cycle#3, now showed profound neutropenia and thrombocytopenia. Patient made a quick recovery and was transferred to the general medical floor on day 2 of her second admission. She was later discharged on day 5 of her admission in a stable condition. Her shock was attributed to anaphylaxis to oxaliplatin.

Discussion and Conclusion:

Oxaliplatin induced anaphylactic shock is an unusual presentation with only three prior reported case. It is a Type 1 hypersensitivity reaction, possibly IgE mediated. Our patient developed shock while on oxaliplatin infusion and also developed immunological neutropenia and thrombocytopenia. A thorough review of the literature showed that three patients had type 2 hypersensitivity reactions with immunological thrombocytopenia. Three cases of 5-FU anaphylaxis have been reported in the literature but the timeline in our case leads us away from incriminating this agent. We report this case to alert physicians to consider oxaliplatin anaphylaxis in the differential for patients on this agent who present with shock when other etiologies have been ruled out.

Biology, clinical relevance and pharmacology of Lipoprotein associated phospholipase A2 as a marker of vascular inflammation and a promising therapeutic target in atherosclerosis.

A Clinical Review

Sabeeh A Siddiqui,MD,Associate; Arshad Jahangir,MD,FACC;Syed A Mahmood,MD,FACC

Department of Medicine,Sinai Grace Hospital/Detroit Medical Center,Detroit,MI

Mayo Clinic,Rochester,MN

Atherosclerosis is a chronic, progressive vascular disease, that can lead to cardiovascular events such as myocardial infarction and stroke and is the fundamental pathology behind most cardiovascular disease, the leading cause of death in the Western population, resulting in the estimated cost of $142.5 billion. Interest in potential therapies for this disease is correspondingly great, but until recently most strategies have aimed to address the dyslipidaemias frequently observed in high-risk populations by statins, however, this strategy is effective in preventing outcome such as myocardial infarction in only 30–40% of the patient population.

Thus, despite substantial progress in preventing adverse cardiovascular events with current therapeutic strategies, there remains an extensive residual risk of clinical events, and focal rupture of vulnerable plaques being responsible for most of these. Evidence is accumulating that inflammation plays a role in the pathophysiology of atherosclerosis, thus identifying and targeting inflammatory pathways could help further reduce cardiovascular risk. Lipoprotein-associated phospholipase A2(Lp-PLA2) is emerging as a novel biomarker of vascular inflammation and accumulating evidence from pathology, biology and epidemiological studies favor a pro-atherogenic role of this enzyme and thus the idea that inhibition of this enzyme would promote anti-thrombotic effect. The past few years have seen numerous advances in this context with numerous compounds with anti-Lp-PLA2 activity being in advanced stages of development. In addition if this target truly does reduce vascular inflammation, it may extend the therapeutic spectrum for atherosclerosis beyond statins. An LP-PLA2 inhibitor, if approved could be used as a single agent, or combined with others, in the same way that antihypertensive therapy has evolved, to ultimately more effectively reduce the risk of myocardial infarction and stroke in patients at risk.

Despite these findings, unanswered questions still exist with respect to this enzyme and its biological role in atherosclerosis. Addressing these questions will help clarify the clinical utility of measuring Lp-PLA2 in routine clinical practice in the context of other approaches for identifying and treating at-risk patients. Thus, this review will focus on this enzyme’s association with coronary heart disease, stroke, diabetes and heart failure; and the possible benefits of its therapeutic inhibition.

CENTRAL NERVOUS SYSTEM LEUKEMIA AFTER IMATINIB MESYLATE THERAPY FOR CHRONIC MYELOGENOUS LEUKEMIA

Solh M1, Kantarjian H2, O’Brien S2, Cortes J2, Ravandi F2

1 Wayne State University/Detroit Medical Center-Sinai-Grace- Detroit/Michigan

2 Department of Leukemia – The University of Texas – M D Anderson Cancer Center

Background - Imatinib mesylate is now established as the standard for the first line treatment of patients with chronic myelogenous Leukemia (CML). A complete cytogenetic response (CGCR) rate of approximately 90% and a major molecular response rate of about 60% is expected at 5 years using the standard dose of imatinib in patients with chronic phase CML. Imatinib penetrates the cerebrospinal fluid (CSF) poorly; as such CSF may act as a disease reservoir with a potential for central nervous system (CNS) disease. In this article, we examine the incidence and outcome of CNS disease in patients with chronic or accelerated phase CML treated with imatinib mesylate at the University of Texas - MD Anderson Cancer center (UT-MDACC).

Methods - Patients with chronic and accelerated phase CML treated with imatinib between 1999 and 2006 at UT-MDACC. Patients had regular monitoring of blood counts, bone marrow aspiration with cytogenetic analysis every three month for the first 12 month, and then every six month. Data were collected regarding age, gender, initial laboratory results, response, occurrence of extramedullay disease, CNS disease and overall survival. Patients with documented CNS disease were compared with the rest of imatinib resistant group.

Results - Among 910 patients with early or late chronic or accelerated phase CML treated with imatinib, 83 patients developed resistance during the follow up period and progressed to blastic phase. Fifteen patients had evidence of CNS disease either by CSF alone or by radiological evidence of leptomeningeal or parenchymal disease. Patients developing CNS leukemia had a lower platelet count on presentation, younger age and a worse overall survival. They had a similar rate of CGCR and CHR before progressing to blast phase as the rest of the patients. The CNS disease group had a worse survival than patients with extramedullay disease in sites other than the central nervous system.

Conclusion - Imatinib has a documented poor CNS penetration in humans and mice. The concern of a high residual CNS disease in patients treated with imatinib is valid as evident by several case reports of CNS leukemic infiltrates. The low incidence of such disease (15 out of 910 patients) may not be a sufficient reason to consider changing treatment strategies to include intrathecal chemoprophylaxis as is the case with other leukemia. However; special concern should be given to any neurological symptoms presented by CML patients as it can represent CNS leukemia. Further studies with the new tyrosine kinase inhibitors should examine the CSF penetration of these drugs.

Synchronous Versus Metachronous Breast Cancer: Characteristics of The Second Tumor

Melhem Solh, MD1 ,Hanadi Bu-Ali, MD2, Vijay Mittal, MD, FACS2

1-Wayne State University/Detroit Medical Center;Sinai-Grace Hospital. Detroit-Michigan

2-Providence Hospital and Clinincs. Southfield-Mi

Introduction: Synchronous breast cancer is a tumor diagnosed within three months from the diagnosis of the first tumor. There is, currently, no consensus as to it being a totally independent second primary or having the same disease entity as the primary tumor. Our study describes the clinical, histopathologic and prognostic factors of synchronous breast cancer and compares them with metachronous breast cancer.

Methods: A retrospective analysis of all patients with synchronous and or metachronous breast cancer treated between January 1991 and March 2004 was done through chart review. Further follow up data was obtained from the patients’ oncologist’s database.

Results: Out of a total of 114 patients, 63% had metachronous breast cancer and 37% synchronous. 77.8% of the metachronous group documented a first degree relative with breast cancer compared with 22.2% in the synchronous group (p<0.05). 84% of metachronous tumors and 87% of synchronous tumors involved the contralateral breast. Infiltrating ductal carcinoma was the most common histologic type of the first tumor in both groups. Synchronous breast cancers had a higher incidence of LCIS (16% vs. 4%; p<0.01). This was observed in the second tumor as well (p>0.05). Both first and second tumors of the synchronous group were histologically more aggressive than the metachronous tumors (p<0.05). Both groups were similar regarding the expression of estrogen and progesterone receptors. Both groups were also similar regarding the distribution of tumor stage with 64% of first diagnosed tumors as stage I-II. Synchronous cancer metastasis involved more than one organ (p<0.05). The average lifetime survival from the day of diagnosis for the synchronous group was 4.7 years compared with 12.5 in the metachronous group (p<0.005).

Conclusions: Our series shows synchronous breast cancer to be more aggressive than metachronous breast cancer with a poorer outcome. Moreover, the concordance between different tumors within the same patient, in particular for histology, grade, stage and receptor status support the hypothesis of monoclonal origin of synchronous breast cancer.

CASEATING GRANULOMA CAUSING VERTEBRAL CORD COMPRESSION

Shironda Stewart, MD (Associate) Cortney Jones, MD (Associate) Jennifer Holt, MD ( Member) Department of Medicine, Sinai-Grace Hospital, Detroit, Michigan

Introduction:

Acute compressive myelopathies are true medical emergencies. The most common etiology in adults is metastatic disease. We present a case of acute spinal cord compression caused by a caseating granuloma.

Case Report:

A fifty-eight-year-old female with a history of asthma, hypertension, and chronic back pain presented with lower extremity weakness. A review of systems was positive for a non-productive cough, pleuritic chest pain, night sweats, and weight loss. There was no travel history. A neurological exam revealed distal lower extremity weakness, decreased pinprick sensation at T4-T6 dermatome regions, depressed reflexes of the lower extremities, and decreased rectal tone. Labs were normal. An MRI of the spine revealed a compression fracture at the level of T5 with epidural, vertebral body, and soft tissue enhancement at the level of T4-T6. The patient underwent a T4-T6 laminectomy with excision of the epidural mass. The mass was placed in formalin. A pathologic diagnosis of the bone and soft tissue revealed multiple caseating granulomas. There was no evidence of malignancy. AFB and gram stains for fungus were negative. The patient received antituberculosis therapy. HIV serology was recommended.

Discussion:

The differential diagnosis of caseating granulomas includes tuberculosis, fungi, and necrotizing tumors. In the United States, skeletal tuberculosis is rare and tends to occur among the immigrant population and immunocompromised. Nevertheless, it is more likely to cause vertebral cord compression when compared to fungal infections. A positive AFB stain and culture confirm a diagnosis; however, the sensitivity of these tests may be decreased if the tissue specimen is fixed in formalin. This has been described in literature. Skeletal tuberculosis was the most accurate diagnosis in this patient. She completed three months of antituberculosis therapy and her neurological symptoms significantly improved. She will require close follow-up and a minimum of twelve months of antituberculosis therapy.

Conclusion:

Vertebral cord compression is a medical emergency that requires a multidisciplinary approach. This entails proper imaging, a tissue biopsy with proper storage techniques, and the correct interpretation of test results.

A COMPARISION OF MRI AND MAMMOGRAPHY FOR BREAST CANCER SCREENING

Shironda Stewart, MD (Associate) Department of Medicine, Sinai-Grace Hospital, Detroit, Michigan

Suppose a forty-year-old woman with a strong family history of breast cancer requests an MRI of the breast despite recent negative mammography. Is there evidence supporting that an MRI is more useful than mammography in this setting?

The incidence of breast cancer has risen over the past two decades. In 2006, it is approximated to be 200,000. 41,000 deaths are predicted. Despite an increase in mammography, breast cancer is the second leading cause of cancer deaths in females. Perhaps one explanation is that the false negative rate of screening mammography, 10-30%, prevents detection of slow growing tumors. Moreover, mammography is not a useful tool in women with radiologically dense breast tissue. However, yearly screening mammography has been proven to decrease breast cancer mortality in women forty and older. Contrast enhanced MRI is able to distinguish benign from malignant breast lesions. It is not limited by radiologically dense breast tissue; but may miss microcalcifications.

The objectives of this literature search are to compare the sensitivity and specificity of mammography with contrast enhanced MRI for breast cancer screening. Inclusion criteria require both modalities to be used on a patient. All studies must be prospective. Search engines Ovid Medline, Pub Med, and Cochrane Library were used. One hundred ninety two (192) studies were identified. Five (5) studies qualified for this evidence based research. Overall, the sensitivity of MRI was higher than mammography; however the specificity of MRI was less than mammography.

The amount of studies pertaining to this literature search was inadequate. Furthermore, the inclusion criteria varied among different studies. At this point in time, there is insufficient evidence to conclude that MRI is a superior screening modality when compared to mammography.

Racial Disparities In A Five Year Outcome Follow Up After Percutaneous Coronary Intervention.

Vikas Veeranna, Jyotiranjan Pradhan, Ashutosh Niraj, Krithi Ramesh, Luis C.Afonso, Theodore L. Schrieber, Wayne State University/Detroit Medical Center, Detroit, MI.

Background: Percutaneous Coronary Intervention (PCI) is an effective form of revascularization being routinely performed in acute ST elevation myocardial infarction (STEMI) and high risk acute coronary syndromes (ACS) as part of early invasive strategy. Limited data exists in literature regarding racial differences in outcomes after percutaneous coronary intervention (PCI).

Methods: 416 consecutive patients undergoing PCI from January 1999 to January 2000 at Harper University Hospital, a tertiary care center in Detroit, Michigan, were followed up. End points studied were either all cause mortality collected from Social security Death Index or first hospital admission after index procedure due to myocardial infarction (MI), congestive heart failure (CHF), target vessel revascularization [PCI or CABG(coronary artery bypass surgery)].Statistical tests used were Kaplan-Meier survival analysis (log-rank test) and Cox regression( hazard model propensity score adjustment) analysis. Two sided test with p < 0.05 was considered statistically significant.

Results: Among the initial cohort of patients(n=416) at the baseline, African American(AA) were more likely than Whites to be women, have hypertension and CHF but less likely to have hypercholesterolemia, prior MI or revascularization.

In a five year follow up, 202 out of 416(48.6%) patients were event free. Among the patients in whom end points were identified (n=214; AA=144; Caucascians=70), African Americans were more likely than whites to present with MI or CHF (18.7% vs 5.7%; OR =2.50, 95% CI 1.47-7.20; p<0.05). No racial difference was observed in death or revascularization rates. On gender subanalysis, African American men were less likely than Caucasian men to present to the hospital for revascularization(47.9% vs. 62.2%; OR=0.62, CI 0.37-0.92, p<0.05). This trend was not evident among women.

Conclusions: In a five year outcome followup of patients post PCI, African Americans were more likely to present with MI or CHF after the index procedure and in men a lower rate of revascularization compared to their Caucasian comparators. There was no apparent racial difference in survival after PCI during this period.

Cryoplasty for Superficial Femoral Artery Stenosis : An Effective Strategy?

Vikas Veeranna, Rashad H. Khazi-Syed, Sabeeh A. Siddiqui, Geetha Krishnamoorthy, Rajika Munasinghe, Syed A. Mahmood, Sinai-Grace Hospital, Wayne State University/Detroit Medical Center, Detroit, MI

Background

Peripheral arterial disease [PAD] affects about 8 million Americans and is associated with significant morbidity and mortality. Femoropopliteal arteries are common sites of occlusion. We present a retrospective study on the efficacy of cryoplasty as a technique for superficial femoral artery stenosis revascularization.

Method

A retrospective study was done which involved 8 patients (10 arterial segments). Each patient had undergone cryoplasty of the superficial femoral artery [SFA]. A baseline Duplex ultrasound and ABI measurement was done. A follow-up Duplex ultrasound and ABI was done at less than a month and at > 6 months post procedure. The mean pre-procedural and follow-up ABI’s were compared using paired t-test.

Result

Of the 8 patients, 12.5% had diabetes mellitus, 62.5% had coronary artery disease, 62.5% had dyslipidemia and 50% were smokers. The mean age was 70.25 years. All patients were Rutherford classification stage 3 or 4. 70% of the patients had total occlusion. The mean lesion length was < or = 10 cm. Technical success was 100% defined by residual stenosis of <30% and no flow limiting dissection. The mean ABI pre-procedure was 0.62 with standard deviation of 0.02. The mean ABI at follow up was 0.71 with standard deviation of 0.09. The mean duration at follow-up was 238.3 days. The change in ABI at > 6 months follow up was statistically significant with P value of 0.0065 indicating improved arterial patency. Two patients (2 segments) needed revascularization procedure for restenosis [20%].

Conclusion and Discussion

Cryoplasty is an effective method of intervention for SFA as evidenced by a significant change in ABI at > 6 months of follow-up with low restenosis rates. However, larger prospective and retrospective studies need to be done.

Bailout Cryoplasty in Iatrogenic Superficial Femoral Artery Dissection.

Vikas Veeranna, Rashad H. Khazi-Syed, Sabeeh A. Siddiqui, Geetha Krishnamoorthy, Thomas Matthys, Syed A. Mahmood, Sinai-Grace Hospital, Wayne State University/Detroit Medical Center, Detroit, MI

Background

Superficial Femoral Artery [SFA] occlusion presents as difficult management problem to interventional cardiolovascular specialist because of several major technical challenges which include long lesions, significant calcifications, high rate of restenosis, and incidence of stent fractures. We present an observational study introducing the potential role of cryoplasty as a bailout strategy in wire induced vessel dissection during attempts at crossing the SFA occlusion.

Method and Procedure

We report an observational study comprising 5 patients who underwent cryoplasty to the SFA. In all of these cases there was iatrogenic wire induced dissection of the SFA ranging from linear non flow limiting dissection to more complex dissection including one case of extravasation of radiocontrast dye. In all of these cases we were eventually able to cross the lesion and the distal intraluminal placement of the guide wire was confirmed by injecting radiocontrast dye in the distal SFA beyond the occluded segment using a 4 french angled glide catheter. A cryoplasty Polar Catheter was successfully used to seal this dissection and obtain good angiographic results.

Result

Of the five patients 20% had diabetes mellitus, 60% had coronary artery disease, 60% had hyperlipidemia and 60% were smokers. The lesions were long segments of severely calcified chronic occlusions. The lesion length ranged from 6 to 10 cm. Technical success was 100%, defined by < 30% residual stenosis and no flow limiting dissection.

Conclusion

We conclude that in cases of iatrogenic dissection of SFA, cryoplasty may be a viable bailout strategy. The mechanism behind this process needs to be further evaluated and merits a larger study.

Paradoxical Embolism in A Young Male.

Vikas Veeranna, Rashad H Khazi-Syed, Preeti Misra, Christopher Schooley.

Department Of Internal Medicine, Sinai Grace Hospital, Detroit Medical Center, Wayne State University, Detroit, Michigan.

Introduction:

Paradoxical embolism (PDE) is a well know cause of systemic thromboembolism. We report a young patient who developed acute arterial occlusion from a presumed paradoxical embolism of a venous thrombosis through a patent foramen ovale (PFO).

Case report:

A 34 year old male was being evaluated for suspected bacterial endocarditis with a TEE, which showed a PFO with no vegetations or a thrombus. During his stay in the hospital he developed acute left lower limb ischemia. He underwent an angiogram which showed an acute thrombus in left common and the left external iliac arteries and complete occlusion of the left superficial femoral artery. Since the suspicion for PDE was high , venous duplex was performed which showed acute deep vein thrombosis of the right common femoral, right popliteal vein, the left popliteal and the left posterior tibial vein. The patient was treated with thrombolytics followed by stenting of the left common and the external iliac was performed with an inferior venacava filer placement. Subsequently, due to deterioration in the limb ischemia and gangrenous changes he underwent left above knee amputation. Hypercoagulable state was ruled out.

Discussion:

Paradoxical embolism is the passage of venous thrombus into arterial circulation. Most common cause for this is an intracardiac defect at the level of atria. A presumptive diagnosis of PDE is made if there is a systemic arterial embolism in the presence of right to left shunt at any level, venous thrombosis and / or pulmonary embolism, and with out any evidence of a left heart or proximal arterial thrombus. Literature review showed that the PFO is present in about 35% of the population. PDE should be suspected in the young and middle aged patients presenting with acute systemic thromboembolic events especially in the presence of simultaneous deep vein thrombosis.

Mitogen-activated protein kinase (MAPK) inhibition via MAP Kinase, epidermal growth factor receptor, or erbB-2 leads to return of estrogen-dependence and anti-estrogen response in ERα- breast cancer

Prakash Vishnu, MD (associate) 1, Jill Bayliss 2, Amy Hilger 2, Dorayya El-Ashry, PhD 2

1 Department of Internal Medicine, Sinai Grace Hospital/Detroit Medical Center, Wayne State University, Detroit, Michigan

2 Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan

Background/hypothesis:

Breast cancer presents as estrogen receptor alpha (ERα) positive or negative. ERα- tumors have a poor prognosis and are resistant to anti-hormonal therapy. ERα- tumors frequently show overexpression, amplification, and/or hyperactivation of growth factor signaling, especially of the erb-B family, resulting in hyperactivation of MAPK pathway. Previously, we have shown that hyperactive MAPK causes reversible down regulation of ERα. In this study, we sought to determine if the inhibition of MAPK activity in ERα- breast cancer cell lines and tumor specimens could restore ERα expression and anti-estrogen response.

Methods:

Three ERα- cell lines were used in this in-vitro study - SUM229 (ERα-/PR-/Her2/neu-/EGFR+), DT13 (ERα-/PR-/Her2/neu+) and DT16 (ERα-/PR-/Her2/neu-). SUM229 is an established ERα- human breast cancer cell line with over expression of EGFR; DT13 and DT16 are dissociated tumor cells from human ERα- breast cancers. Inhibition of MAPK was achieved by MEK1/MEK2 inhibitor, U0126 (10mM). Western blotting and immuno-staining was performed to visualize the re-expression of ERα. A colorimetric growth assay for cell proliferation and viability was performed using WST-1 to assess anti-estrogen sensitivity in these cells by treating them with 4-hydroxy-tamoxifen (selective estrogen receptor modulator) and fulvestrant (estrogen receptor antagonist) in combination with U0126.

Results:

Inhibition of MAPK resulted in re-expression of ERα protein in all three ERα- cell lines and tumor cell cultures. While having no growth inhibitory effects on its own, U0126 restored the growth inhibitory effects of both 4-hydroxy-tamoxifen and fulvestrant.

Conclusions:

These results support our hypothesis that there exists a population of ERα- tumors where up-regulated growth factor signaling is directly involved in the generation of ERα- phenotype by repressing ERα expression; and further, this reversible down-regulation may be targeted clinically such that this repression can be reversed by inhibiting MAPK, resulting in re-expression of ERα and restoration of tamoxifen sensitivity.

The role of Tissue Doppler Assessment of Right Ventricular Function in Inferior Wall Myocardial Infarction using Tricuspid annular motion &tricuspid annular velocity.

Malini Venkatram MD, Associate, Dept of Internal Medicine, Wayne state university/Sinai Grace hospital, Detroit, MI

Venkataramu N. Krishnamurthy MD, Asst professor, Dept of Radiology, University of Michigan, Ann Arbor, MI

INTRODUCTION: Tissue Doppler (TD) imaging is a novel echocardiographic technique that measures myocardial velocities. However, there are sparse data on TD imaging of the right ventricular (RV) free wall in the diagnosis of RV myocardial infarction (RVMI) in inferior wall MI (IWMI).This has application in detecting RV failure in inferior wall MI which would have therapeutic implications like volume expansion since the echocardiographic assessment of RV failure is technically difficult.

METHODS: Forty-seven patients with first IWMI were studied and were prospectively compared with 25 age-matched healthy controls. They were categorized into those with RVMI and those without RVMI based on standard EKG criteria. From the echocardiographic apical 4-chamber view, the systolic motion of the tricuspid annulus (TAM) was recorded at the RV free wall with the use of 2-dimensional guided M-mode recordings. Tricuspid annular systolic velocity (TAV[S]), tricuspid annular early diastolic velocity (TAV [E]) and late diastolic velocity (TAV [L]) at the RV free wall were also recorded with the use of tissue Doppler imaging.

RESULTS: TAM of IWMI patients (19±4.6 mm) was significantly reduced as compared to controls (26.5±2 mm) (p<0.001). Tricuspid annular systolic velocity (TAV[S]), tricuspid annular early diastolic velocity (TAV [E] of IWMI was also reduced, being 12.7±2.5 cm/s and 13±3.1 cm/s versus 22.7±3.1 cm/s and 20.6±4.1 cm/s in controls, respectively (p<0.001). Patients with inferior MI were divided into 2 subgroups: those with and without EKG signs of RV infarction. TAM in patients of IWMI with RVMI (16±1.7 mm) showed a significant reduction as compared to those without RVMI (21±2.8 mm p<0.001).Also tricuspid annular systolic velocity (TAV[S]) & tricuspid annular early diastolic velocity (TAV[E] in patients of IWMI with RVMI (10.7±1.5 cm/s and 9.6±1.4 cm/s, respectively) (p<0.001) was significantly reduced compared to those without RVMI (14±2.2 cm/s and 15.5±10.5 cm/s, respectively, p<0.001). However, there was no significant reduction in late diastolic velocity (TAV [L]).

CONCLUSION: These results suggest that tricuspid annular motion and tricuspid annular velocity are simple and sensitive parameters to assess RV function in patients with inferior MI.

Amyloid beta peptide-related angiitis of CNS - a rare case of primary angiitis of central nervous system with cerebral amyloid angiopathy

Prakash Vishnu, MD (Associate) 1, Pratik Bhattacharya, MD (Associate) 1, Scott Glitman, DO, PhD 2, Sarmad Al-Mansour, MD, FACP 3, William Kupsky, MD 4

1 Department of Internal Medicine, 2 Division of Neurosurgery, 3 Division of Rheumatology, 4 Department of Pathology,

Detroit Medical Center / Wayne State University, Detroit, Michigan

Introduction

Cerebral amyloid angiopathy (CAA), seen in 30% of otherwise normal elderly subjects rarely evoke an inflammatory response in cerebral microcirculation. Very few cases of CAA-associated CNS vasculitis, also known as amyloid (b) peptide-related cerebral angiitis (ABRA) has been reported to-date. Diagnosing angiitis limited to CNS is particularly difficult because of nonspecific nature of cerebral angiography. Brain biopsy is, hence, considered the gold standard for diagnosis of primary angiitis of CNS (PACNS). We present a biopsy-proven case of ABRA, who showed a remarkable clinical improvement with immunosuppressive therapy.

Case report

LK, a 68 year old female with a past medical history of hypertension presented to our institute with sudden deterioration of pre-existing left-sided weakness. She had developed left hemi-paresis and encephalopathy two months earlier, which was provisionally diagnosed elsewhere as viral encephalitis and treated with acyclovir and steroids. CT scan of the brain showed low-attenuation area in right temporo-parieto-occipital lobe with significant edema and midline shift. Magnetic resonance (MR) imaging/angiography revealed intense signaling in the same area, with a normal intracranial vasculature. The distribution did not correspond to a major vascular territory. Allergy to dye precluded conventional cerebral angiography. Patient had no evidence of extra-cranial organ involvement. ESR was 76 mm/hr. Serology revealed IgG against measles and varicella. Anti-nuclear antibodies were absent. Histopathology of stealth-MRI assisted brain biopsy revealed extensive amyloid (b) peptide deposits with granulomatous and lymphocytic inflammation affecting small vessels, establishing the diagnosis of PACNS with CAA. AFB-stain was negative. She was started on oral Cyclophosphamide and Prednisone. Patient showed a complete resolution of left-sided weakness in six weeks following initiation of immunosuppressive therapy and physiotherapy. Repeat CT scan of the brain at six weeks showed resolution of edema and midline shift with decrease in ‘low-attenuation’ areas.

Discussion

Primary angiitis of CNS with CAA is a rare disease entity with varied neurological presentation and is quite challenging to diagnose. Given a low specificity of cerebral angiography, biopsy is the key step in making a firm diagnosis. Combined cortical and lepto-meningeal biopsy is most likely to be diagnostic, with results from angiography or MRI identifying the involved area.

Mitogen-activated protein kinase (MAPK) inhibition via MAP Kinase, epidermal growth factor receptor, or erbB-2 leads to return of estrogen-dependence and anti-estrogen response in ERα- breast cancer

Prakash Vishnu, MD (associate) 1, Jill Bayliss 2, Amy Hilger 2, Dorayya El-Ashry, PhD 2

1 Department of Internal Medicine, Sinai Grace Hospital/Detroit Medical Center, Wayne State University, Detroit, Michigan

2 Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan

Background/hypothesis:

Methods:

Results:

Conclusions:

RADIATION PNEUMONITIS IN LUNG CANCER PATIENTS TREATED WITH CHEMOTHERAPY AND THORACIC RADIATION: RETROSPECTIVE ANALYSES OF PATIENTS TREATED AT A COMPREHENSIVE CANCER CENTER

Prakash Vishnu, MD, Sridhar Srinivasan, MD, Lance K. Heilbrun, PhD, Raghu Venkat, MS Antoinette Wozniak, MD, Ayman Soubani, MD, Shirish M. Gadgeel, MD

Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan

Background

Combined chemotherapy and thoracic radiation (TR) is the current standard for locally advanced non-small cell lung cancer (NSCLC) and SCLC. Severe RP, an important adverse effect of TR, is reported in clinical trials to occur in 10% of patients receiving chemotherapy and TR. The rate in routine care may be higher as patients are not selected based on pulmonary function. We conducted a retrospective study to assess the incidence of RP in lung cancer patients treated with chemotherapy and TR.

Methods

Retrospective identification of patients who underwent combined modality therapy (concurrent or sequential chemotherapy and TR) for lung cancer (NSCLC & SCLC) at our cancer center between January 2001 and December 2004. Demographic features, RP incidence and grade (RTOG criteria), hospitalization rate and overall survival (OS) were assessed.

Results

51 patients who met the selection criteria were analyzed. The demographic features were - males 61%; Caucasians - 53%; African Americans - 39%; history of pulmonary disorder - 45%; NSCLC - 82%; CT - 62% received Cisplatin/Etoposide, while 24% received Carboplatin/Paclitaxel; 92% received concurrent CT and TR. The median dose of TR was 5940 cGy. 20 patients (39%) developed RP; 13 (25%) had grade > 3 RP. Median time to development of RP was 4.4 months. Rate of RP in females and males was 50% vs. 32% (p=0.25). Rate of RP in patients with pulmonary disorder at baseline was 52% vs. 29% in others (p=0.15). 1 year hospitalization rate was 75% and 42% in RP and non-RP patients (p=0.025). For all 51 patients, the median overall survival (OS) was 16.4 months (95% CI 11.8 - 23.3). Length of OS did not differ significantly (p = 0.36) between the 20 patients who had RP vs. the 31 who had no RP (median OS: 22.2 vs. 14.5 months, respectively).

Conclusion

RP rate in lung cancer patients treated off-protocol with chemotherapy and TR is higher than that reported in clinical trials. The rate was higher in patients with history of pulmonary disorder. Despite higher morbidity (i.e. increased hospitalization) in patients with RP, overall survival did not differ significantly based on RP status.

EWS-CREB 1: A Novel Variant Gene Fusion Transcript in Clear Cell Sarcoma of the Gastrointestinal Tract

Venkata Yalamanchili, MD, Associate, Melhem Solh, MD, Associate,

Doina David, MD, Geetha Krishnamoorthy, MD, Member

Department of Medicine and Department of Pathology

Wayne State University/Detroit Medical Center (Sinai Grace Hospital) Detroit, MI

Introduction: Clear cell sarcoma (CCS) is a rare malignant soft tissue neoplasm that commonly afflicts tendons and aponeuroses in young adults. Primary CCS of digestive tract is exceedingly rare and only three cases of ileal involvement are reported thus far. We hereby report a patient with CCS of the ileum presenting with abdominal pain and fever.

Case Report: A 40 year old African American woman with a history of appendectomy and cholecystectomy, presented with a two day history of lower quadrant abdominal pain and fever. No nausea, vomiting, change in bowel movements, burning micturition or vaginal discharge was reported. Physical exam revealed a fever of 100.7 F, bilateral lower abdominal and cervical motion tenderness. Laboratory data revealed leucocytosis, a negative urinalysis and pregnancy tests. Pelvic ultrasound showed a 7x7x4 cm mixed echogenic complex mass in the left adnexa. After 72 hours of empiric antibiotics for pelvic inflammatory disease, abdominal pain worsened and fever persisted. CT scan of the abdomen showed a 6 cm soft tissue mass engulfing the ileum. The patient underwent exploratory laparotomy with small bowel resection and anastomosis. Surgery revealed a 9.5 X 9.0 X 5.0 cm mass arising from the terminal ileum. The mass was focally ulcerated and infiltrating into the mesentery and the bladder. Pathology reported an epithelioid neoplasm, with small, oval nuclei surrounded by abundant clear cytoplasm and well defined cell membranes. On immunohistochemical examination, tumor cells were strongly and diffusely immunoreactive for S-100 while are negative for melanocytic markers (HMB45, A103) and gastro intestinal stromal tumor (GIST) markers (CD117and CD34). Reverse transcription polymerase chain reaction analysis performed on paraffin embedded tissue showed EWS-CREB 1 rearrangement, indicating presence of variant t (12; 22) translocation of clear cell sarcoma. Follow up CT scan of the abdomen showed hepatic lesions, histologically consistent with CCS. The patient was started on palliative chemotherapy.

Discussion: Cytogenetics and KIT tyrosine kinase stains have a central role in the diagnosis of this highly malignant tumor which can be mistakenly diagnosed as GIST or a melanoma. The outcome of metastatic CCS is dismal despite aggressive surgery and adjuvant therapy.

LAMBDA II IMMUNOGLOBULIN LIGHT CHAIN A PRECURSOR PROTEIN OF PRIMARY LOCALIZED RECTAL AMYLOIDOSIS

Ziad S. Zaky, M.D. (Associate, Juris J. Liepnieks, Ph.D., Douglas K. Rex, MD, F.A.C.G.3, Oscar W. Cummings, M.D., Merrill D. Benson, M.D

Introduction

Localized amyloidosis is limited to the involved organ and does not become systemic. Localized rectal amyloidosis is a rare entity, and, to the best of our knowledge, there were less than ten cases reported in the literature.

Case description

A 61-year-old Caucasian male, with no significant past medical history, was admitted to hospital for screening colonoscopy. The patient was asymptomatic. Physical examination was non impressive with no evidence of systemic amyloidosis. Colonoscopy revealed a 3 cm sessile smooth mass 10 cm from the anal verge and two small polyps. Biopsy of the mass revealed amyloidosis and the polyps were hyperplastic but without evidence of malignancy.Workup to exclude systemic amyloidosis was done and found to be negative.

Amyloid fibrils were isolated from amyloid laden tissue and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The isolated protein was transferred to Polyvinylidine Difluoride (PVDF) for sequence analysis. Edman sequence analysis was applied before and after Tryptic digestion showed that the protein belongs to immunoglobulin light chain (Ig LC) λII subgroup

Discussion/Conclusion

Rectal involvement is usually a part of systemic amyloidosis. However, localized rectal amyloidosis is a rare entity. We present a case of asymptomatic localized rectal amyloidoma. To our knowledge, this is the first reported case to isolate the amyloid fibrils and analyze using SDS-PAGE and amino acid sequence from a localized rectal amyloidoma.

In our case the isolated fibril subunit protein proved to be derived from a λ II immunoglobulin light chain. There were a few cases of localized amyloidosis of the rectum and colon reported in the literature, amyloid fibrils identified by immunohistochemistry in the described cases was AL type.

In contrast to systemic amyloidosis, local resection is the preferred treatment and this small subset of patients does not need chemotherapy for a plasma cell dyscrasia

Currently, the type of amyloid often can be determined by immunohistochemical analyses or immunologic assays. However, the results may be inaccurate and ambiguous, due to failure to react with the specific antiserum. Thus, extraction and unequivocal biochemical characterization of the amyloid protein will add to the management of amyloid patients.

LAMBDA II IMMUNOGLOBULIN LIGHT CHAIN A PRECURSOR PROTEIN OF PRIMARY LOCALIZED RECTAL AMYLOIDOSIS

Ziad S. Zaky, M.D. (Associate), Juris J. Liepnieks, Ph.D., Douglas K. Rex, MD, F.A.C.G., Oscar W. Cummings, M.D. , Merrill D. Benson, M.D

Introduction

Case description

Workup to exclude systemic amyloidosis was done and found to be negative.

Discussion/Conclusion

In contrast to systemic amyloidosis, local resection is the preferred treatment and this small subset of patients does not need chemotherapy for a plasma cell dyscrasia

LAMBDA II IMMUNOGLOBULIN LIGHT CHAIN A PRECURSOR PROTEIN OF PRIMARY LOCALIZED RECTAL AMYLOIDOSIS

Ziad S. Zaky, M.D. (Associate) Juris J. Liepnieks, Ph.D., Douglas K. Rex, MD, F.A.C.G., Oscar W. Cummings, M.D., Merrill D. Benson, M.D.

Introduction

Case description

Workup to exclude systemic amyloidosis was done and found to be negative.

Discussion/Conclusion

In contrast to systemic amyloidosis, local resection is the preferred treatment and this small subset of patients does not need chemotherapy for a plasma cell dyscrasia

LAMBDA II IMMUNOGLOBULIN LIGHT CHAIN A PRECURSOR PROTEIN OF PRIMARY LOCALIZED RECTAL AMYLOIDOSIS

Ziad S. Zaky, M.D. (Associate) Juris J. Liepnieks, Ph.D., Douglas K. Rex, MD, F.A.C.G., Oscar W. Cummings, M.D., Merrill D. Benson, M.D.

Introduction

The amyloidoses are a group of at least 20 different protein deposition diseases with characteristic fibrillar nature and common tinctorial properties. These diseases vary in pattern of organ involvement association with other conditions, prognosis and therapeutic options. Thus it is crucial for the clinicians to recognize the type of amyloidogenic protein.

Case description

Workup to exclude systemic amyloidosis was done and found to be negative.

Discussion/Conclusion

While most patients with amyloidosis involving the colon have systemic amyloidosis, it is important to recognize the rare patient who has localized amyloidosis of the colon. In contrast to systemic amyloidosis, local resection is the preferred treatment and this small subset of patients does not need chemotherapy for a plasma cell dyscrasia

Currently, the type of amyloid often can be determined by immunohistochemical analyses or immunologic assays. However, the results may be inaccurate and ambiguous, due to failure to react with the specific antiserum. In addition, AL fibrils most often consist of light chain fragments. Thus, extraction and unequivocal biochemical characterization of the amyloid protein will add to the management of amyloid patient

LAMBDA II IMMUNOGLOBULIN LIGHT CHAIN A PRECURSOR PROTEIN OF PRIMARY LOCALIZED RECTAL AMYLOIDOSIS

Ziad S. Zaky, M.D. (Associate), Juris J. Liepnieks, Ph.D., Douglas K. Rex, MD, F.A.C.G., Oscar W. Cummings, M.D., Merrill D. Benson, M.D.

Introduction

Case description

Workup to exclude systemic amyloidosis was done and found to be negative.

Discussion/Conclusion

Currently, the type of amyloid often can be determined by immunohistochemical analyses or immunologic assays. However, the results may be inaccurate and ambiguous, due to failure to react with the specific antiserum. In addition, AL fibrils most often consist of light chain fragments. Thus, extraction and unequivocal biochemical characterization of the amyloid protein will add to the management of amyloid patients.

BIOCHEMICAL ANALYSIS OF AMYLOID PROTEIN OF PERCUTANEOUS RENAL BIOPSIES

Ziad Zaky M.D. (Associate), Juris J. Liepnieks PhD, Merrill D. Benson M.D.

Department of Internal Medicine Sinai-Grace hospital/Wayne State University, Detroit, Michigan. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana

Introduction

Amyloidosis is characterized by the pathologic deposition of at least 20 different precursor proteins. Despite the differing chemical nature of these molecules, all forms of amyloid have identical tinctorial and ultrastructural features and, as a result, cannot be differentiated microscopically. Because the cause, treatment, and prognoses of these illnesses differ, it is essential that the exact nature of the fibrillar deposits be identified.

Objective

To determine if sufficient tissue amyloid can be obtained by percutaneous renal biopsy to differentiate the type of amyloid protein. If successful, it would be recommended to do biochemical analysis for all renal biopsies with diagnosis of amyloid.

Methods

Amyloid protein was isolated from sixteen percutaneous renal biopsies using microextraction techniques. Samples were analyzed on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Separated proteins were transferred to Polyvinylidine Difluoride (PVDF) membrane for sequence analysis. A portion of isolated protein was digested with trypsin and fractionated by reverse phase high pressure liquid chromatography (HPLC). Samples were analyzed by Edman degradation technique.

Results

Analysis of the pool on SDS PAGE of six patients showed bands at 14 and 20 KDa. One patient showed bands 14, 18, 20, 25, 30 and 40 KDa. The type of amyloid protein was as follows: λVI light chain was identified in three patients, қ light chain in two patients and AA was identified in one patient. The results are still pending.

Discussion/Conclusion

The type of amyloid can be inferred from immunohistochemical analyses or immunologic assays, but, the results may be inconclusive owing to the lack of appropriate antisera or loss of protein-specific epitopes. Thus, to establish the nature of the amyloid protein, it is essential that the material be extracted and analyzed chemically. The ability to diagnose precisely the type of amyloid protein has become increasingly important given the development of specific therapies. These include high-dose chemotherapy and organ transplantation for AL and transthyretin (ATTR), respectively, as well as the use of inhibitors of fibril formation, amyloidolytic drugs. Thus, to provide optimal patient care, we recommend that pathologists to ascertain the specific type of protein that is deposited as amyloid.

LAMBDA II IMMUNOGLOBULIN LIGHT CHAIN A PRECURSOR PROTEIN OF PRIMARY LOCALIZED RECTAL AMYLOIDOSIS

Ziad S. Zaky, M.D. (Associate)1 Juris J. Liepnieks, Ph.D.2, Douglas K. Rex, MD, F.A.C.G.3, Oscar W. Cummings, M.D. 4 , Merrill D. Benson, M.D.2

1-Department of Internal Medicine, Sinai-Grace Hospital (Wayne State University) Detroit, Michigan.

2-Department of pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN

3- Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN

4- Department of pathology, Indiana University School of Medicine, Indianapolis, IN

Introduction

The amyloidoses are a group of at least 20 different protein deposition diseases with characteristic fibrillar nature. These diseases vary in pattern of organ involvement association with other conditions, prognosis and therapeutic options.

Case description

A 61-year-old male, with no significant past medical history, was admitted to hospital for screening colonoscopy. The patient was asymptomatic. Physical examination was non impressive with no evidence of systemic amyloidosis. Colonoscopy revealed a mass 10 cm from the anal verge. Biopsy of the mass revealed amyloidosis.

Workup to exclude systemic amyloidosis was done and found to be negative.

Amyloid fibrils were isolated and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The isolated protein was transferred to Polyvinylidine Difluoride (PVDF) for sequence analysis. Edman sequence analysis was applied before and after Tryptic digestion showed that the protein belongs to immunoglobulin light chain.

Discussion/Conclusion

Localized rectal amyloidosis is a rare entity. We present a case of asymptomatic localized rectal amyloidoma. To our knowledge, this is the first reported case to isolate the amyloid fibrils and analyze using SDS-PAGE and amino acid sequence from a localized rectal amyloidoma.

In our case the isolated fibril subunit protein proved to be derived from a λ II immunoglobulin light chain. A few cases of localized amyloidosis of the rectum and colon were reported in the literature, amyloid fibrils identified by immunohistochemistry in the described cases were AL type.

While most patients with amyloidosis involving the colon have systemic amyloidosis, it is important to recognize the rare patient who has localized amyloidosis of the colon. In contrast to systemic amyloidosis, local resection is the preferred treatment and these patients do not need chemotherapy for a plasma cell dyscrasia

Currently, the type of amyloid can be determined by immunohistochemical or immunologic assays. However, the results may be ambiguous. Thus, biochemical characterization of the amyloid protein will add to the management of amyloid patients.