Copyright (c) 2009 University of Massachusetts Medical School All rights reserved. http://escholarship.umassmed.edu/ssp Recent documents in Senior Scholars Program en-us Mon, 17 Aug 2009 12:46:18 PDT 3600 http://escholarship.umassmed.edu/ssp/72 http://escholarship.umassmed.edu/ssp/72 Tue, 12 May 2009 14:52:26 PDT Background: Half of all patients who suffer aneurysmal subarachnoid hemorrhage die within the first 30 days. Recent evidence implicates acute local intramural inflammation in intracranial aneurysm instability and rupture. Objectives: The purpose of this pilot study was to demonstrate the feasibility of using a myeloperoxidase (MPO)-specific paramagnetic MR contrast agent to identify active inflammation in an animal model of carotid artery aneurysm not yet described in the literature. Methods: All animal experiments were approved by our Institutional Animal Care and Use Committee. Elastase-induced saccular aneurysms were created at the root of the right common carotid artery in New Zealand white rabbits (n=16). Intramural and perivascular injection of E. coli lipopolysaccharide (LPS) was delivered via endovascular approach to induce aneurysm inflammation. Following intra-arterial injection of 0.1mmol/kg di-5-HT-GdDTPA, animals were subjected to 3T MRI. Intramural presence of MPO in LPS-injected aneurysms was confirmed immunohistologically. Active MPO activity was verified by measuring the spectophotometric oxidation of guaiacol. Results: Endovascular injection of LPS resulted in inflammatory cell infiltration into the aneurysm wall and there was a difference of expression of active MPO compared to control aneurysms (20.3 ngMPO/mg tissue versus 0.12 ngMPO/mg tissue, p<0.002). 3T MR imaging of inflamed aneurysms demonstrated a difference in enhancement ratio compared to control aneurysms (1.55±0.05 for LPS versus 1.16±0.10 for control, p<0.02). Conclusion: This pilot study establishes the feasibility of an animal model of saccular aneurysm inflammation that can be visualized with clinical field strength MRI using the enzyme-sensitive MR contrast agent di-5-hydroxytryptamide of GdDTPA, a paramagnetic MPO substrate that specifically enhances MR signal. Michael J. DeLeo Intracranial Aneurysm Carotid Artery Injuries Arteritis Contrast Media Magnetic Resonance Imaging Peroxidase Models, Animal http://escholarship.umassmed.edu/ssp/71 http://escholarship.umassmed.edu/ssp/71 Tue, 12 May 2009 14:52:25 PDT Background: Postpartum hemorrhage (PPH) is an obstetrical emergency traditionally defined as the loss of >500 ml of blood following vaginal delivery (VD) or >1000 ml of blood following cesarean delivery (CD). PPH affects approximately 5% of all deliveries in the U.S. and is a leading cause of maternal morbidity and mortality worldwide. There have been no studies quantifying the exact amount of experience that training physicians receive nor suggesting how much is required to achieve competence in the management of PPH. Objectives: To evaluate the experience obtained by residents in managing PPH. We hypothesize that the exposure to PPH and experience managing this complication of childbirth is inadequate and requires curriculum supplementation. Methods: A retrospective chart review was conducted of women who delivered at UMass Memorial Hospital between the dates of 7/31/07 and 6/30/08. Subjects were identified and included if they met one or more of the following inclusion criteria: CD with >1000 ml blood loss, VD with >500ml blood loss, postpartum hematocrit <26, transfusion, PPH documented in delivery summary. Charts were reviewed for age, ethnicity, obstetric history, history of PPH, etiology of current PPH, intervening resident postgraduate status, and interventions attempted for PPH treatment/management. Results: During the study period there were 273 women identified with PPH out of the approximately 4500 deliveries per year, accounting for ~6% of deliveries at this institution. PGY-1 residents managed 72 women with uterotonics, 11 women with vaginal approach, 0 women with uterine sparing approaches, 0 women with peripartum hysterectomy, 6 women with transfusion, and 1 woman with interventional radiology as the primary caretaker. PGY-2 residents managed 129 women with uterotonics, 13 women with vaginal approach, 2 women with uterine sparing approaches, 0 women with peripartum hysterectomy, 11 women with transfusion, and 1 woman with interventional radiology as the primary caretaker. PGY-3 residents managed 83 women with uterotonics, 13 women with vaginal approach, 3 women with uterine sparing approaches, 2 women with peripartum hysterectomy, 9 women with transfusion, and 0 women with interventional radiology as the primary caretaker. PGY-4 residents managed 68 women with uterotonics, 3 women with vaginal approach, 3 women with uterine sparing approaches, 0 women with peripartum hysterectomy, 8 women with transfusion, and 0 women with interventional radiology as the primary caretaker. Conclusions: The number of women with PPH at UMass Memorial is concordant with the accepted average in the US. Although there are no evidence-based guidelines, our results suggest that resident exposure to and management of PPH is insufficient. Residents across all postgraduate years receive substantial training in the use of uterotonics to treat PPH. However, the exposure to other treatment modalities, specifically surgical procedures, are not well distributed across the resident groups, nor are they sufficient to support the proficiency of any one particular resident class. We conclude that it is necessary to implement a supplemental curriculum using other means than actual clinical settings to support the clinical skills required of OB/Gyn physicians in training for the treatment of PPH. Erin E. Eppsteiner Postpartum Hemorrhage Education, Medical, Graduate Internship and Residency http://escholarship.umassmed.edu/ssp/70 http://escholarship.umassmed.edu/ssp/70 Tue, 12 May 2009 14:52:24 PDT Background: Much research has focused on the prescribing habits of physicians. The Canadian Agency for Drugs and Technologies in Health (CADTH) created a database of research on drug prescribing called Rx for Change. This database focuses both on interventions directed to professionals as well as interventions directed to consumers in relation to evidence-based prescribing/ drug use. The consumer arm of the Rx for Change database has been created and maintained by the Cochrane Consumers and Communication Review Group (CC&CRG, Australia). The database was first populated in 2006 with Cochrane and DARE (Database of Abstracts and Reviews of Effects) systematic review articles collected after standard literature searches as well as extensive hand-searching of both databases. This database was scheduled for an update in 2008. An important question that arises is whether the new reviews screened and identified broaden the scope of the field and expand the definition of evidence-based prescribing for and drug use by consumers. Objectives: This study sought to identify new reviews appropriate for addition to the CADTH Rx for Change database. Following this, the body of new literature was assessed for scope and contribution to the field. Methods: A search was performed by hand of the Cochrane Library from Issue 3, 2006 until the present--Issue 1, 2008. Criteria developed by the CC&CRG during the initial population of the database were used to identify and to sort reviews relevant to prescribing and drug use, a task performed independently by two researchers, with any discrepancies in selection discussed. A third researcher was available to resolve disputes where these arose. Detailed data was extracted from each high and moderate relevance review identified, and the data was summarized in a format acceptable for input into the Rx for Change database. Data extracted included detailed descriptions of the interventions evaluated by each review. The quality of each review was assessed using the AMSTAR tool. Statistical and methodological data were re-expressed as absolute risk differences or in standard narrative formats where suitable numerical data was not available. The themes of the relevant reviews were mapped to a consumer intervention taxonomy developed by the CC&CRG, in order to begin to organize the evidence relating to consumer prescribing/ drug use. A consumer outcome taxonomy for prescribing and drug use was also adapted from the outcome taxonomy developed by the CC&CRG and utilized in data extraction in order to standardize the language used in this field. Finally, the effectiveness of the intervention under study was mapped to standardized effectiveness statements also developed by the CC&CRG. The number of new reviews was quantified and the scope of the new data now included in the database was evaluated and compared to the pool of data originally included in the database in 2006. Results: After screening several hundred reviews, five new Cochrane reviews published in the period between Cochrane Library Issue 3, 2006 and Issue 1, 2008 inclusive were deemed to be high relevance for the Rx for Change database. However, two of these had significant errors requiring clarification by the authors and are therefore excluded from this analysis. A further five reviews were graded as moderate relevance and eleven were low or very low relevance. This is a total of 21 new Cochrane reviews for inclusion in the consumer category of the Rx for Change database. Conclusions: The field of evidence-based prescribing for and drug use by consumers has continued to be an area of growth in new research. Several new highly relevant Cochrane systematic reviews have been published between 2006 and 2008 that expand the populations and diagnoses specifically covered in the Rx for Change database. In addition, they add to and expand the literature that looks at consumers as decision-makers rather than merely recipients of medical interventions. The consumer intervention taxonomy developed by the Cochrane Consumers and Communication Review Group has been used to help establish a framework for the field and allows accurate assessment of the gaps and advances in the literature. This is an exciting and highly relevant field in the climate of patient autonomy and evidence-based medicine, and both the literature and the Rx for Change database will continue to grow. Caroline A. Kaufman Evidence-Based Medicine Review Literature as Topic Databases as Topic Drug Prescriptions Drug Therapy Decision Making http://escholarship.umassmed.edu/ssp/69 http://escholarship.umassmed.edu/ssp/69 Tue, 12 May 2009 14:52:23 PDT Objectives: To explore the experience of reproductive-age women in the French population with premenstrual syndrome (PMS) by estimating perceived symptom prevalence, identifying risk factors, and quantifying the burden of symptoms. This study also assesses the stability of the PMS diagnosis over a one-year period of follow-up. Methods: The prevalence of reported PMS was estimated from a population-based cohort of 2863 French women interviewed in 2003 and 2004. Multivariate logistic regressions were used to identify risk factors associated with PMS. PMS fluctuation was studied by comparing women's responses in 2003 and 2004. Results: Results show that 4.1% of women qualified for severe PMS (six symptoms) and 8.1% qualified for moderate PMS (one to five symptoms), resulting in 12.2% of women who reported PMS symptoms that impacted their daily lives. Risk factors for PMS fell into three categories: hormonal, psychosocial, and physiological, with life stressors and exogenous hormonal exposure exerting the most substantial impact. Results also indicate a high level of intra-individual variation in PMS status over time; among women who qualified for PMS during one or both years of the study, 72% demonstrated fluctuation in their PMS status. Conclusions: More women report suffering from distressing premenstrual symptoms than are captured by strict premenstrual dysphoric disorder (PMDD) diagnostic criteria. The impact of PMS symptoms on women appears to fluctuate over time, however, producing greater variability in the syndrome than previously recognized. Clinicians should be mindful of high intra-individual variability in the syndrome when advising patients about long-term management. Julia Potter Premenstrual Syndrome France Epidemiologic Studies Women's Health http://escholarship.umassmed.edu/ssp/68 http://escholarship.umassmed.edu/ssp/68 Mon, 21 Jul 2008 18:30:02 PDT Background: While current research has demonstrated significant health and societal benefits of breastfeeding, the national breastfeeding rate remains below the Healthy People 2010 goal of 75% initiation and 50% continuation at 6 months (while 73.8% initiated, at 6 months only 41.5%, were breastfeeding and 11.3% were exclusively breastfeeding). A 1997 chart review of Family Health Center of Worcester (FHCW) patients also found low initiation and high attrition rates within the diverse, low-income population served by the FHCW; 56% were breastfeeding at 4 days or less post-partum (42% exclusively), while 42 % were still breastfeeding at 15 days post-partum (15% exclusively). Previous studies have found that predictors of breastfeeding initiation and attrition include the woman's knowledge about benefits of breastfeeding, messages received about breastfeeding, and availability of breastfeeding support. In order to improve breastfeeding rates at the FHCW, this study investigated postpartum women's perceptions of how the FHCW counseled and supported them around breastfeeding. Objectives: This study lays the groundwork for identifying ways in which the Family Health Center of Worcester can improve breastfeeding initiation and duration among its patients. By directly interviewing postpartum women, the study seeks to determine what messages FHCW patients receive about breastfeeding, as well as to assess how the FHCW prepares pregnant and post-partum women for breastfeeding and supports those who choose to breastfeed. Methods: This cross-sectional analysis involved voluntary interviews of postpartum women who came to the FHCW for a previously scheduled appointment during a three-week period in March, 2008. Eligible patients had received all their prenatal and post-partum care through the FHCW and had delivered a live baby within the past 6 months. The surveys were administered, either immediately before or after the patients' appointments, by a medical student investigator in English or Spanish. Questions addressed participants' attitudes about breastfeeding, the messages and information they were given about breastfeeding, and their personal experiences with breastfeeding. The study was exempted by the UMass IRB and approved by the FHCW Board. Results: (Preliminary data) Of the fifty-one women who were interviewed, forty-nine were included in the data analysis. The mean age of women who participated in the survey was 25, 53% were born outside the U.S., and 59% identified themselves as Hispanic. Twenty-four of the women had more than one child, and 20 of these women had attempted to breastfeed a previous baby. ¾ of the women interviewed agreed with the statement "breast milk is the best food for babies" while 20% agreed that "formula and breast milk together is the best". Women who thought that breast milk is best were the most likely to breastfeed. Fifty-nine percent of women (29 of 49) had made a feeding decision before the end of their first trimester. Women who made a feeding choice either before they got pregnant or in their first or second trimester were more likely to plan on breastfeeding than women who decided during their third trimester or after they left the hospital. Forty-two women (86%) reported that when they left the hospital they had planned to mostly breastfeed, while 7 women (14%) reported that they had planned to mostly formula feed. The most common reasons for choosing formula over breast milk included "I was sick or on medicine", "I didn't want to breastfeed in public", "I went back to work or school", and "I was worried breastfeeding would be painful". Of the 42 women who planned to mostly breastfeed, 52% (22 women) were still breastfeeding or pumping breast milk at the time of the interview. Of the women who had stopped, 4 (10%) stopped within the first 2 weeks post-partum, 9 (21%) had stopped by 4 weeks, and 14 (33%) had stopped by 6 weeks. The most common reasons to stop included "I did not produce enough milk", "Breast milk alone did not satisfy my baby", "My baby had difficulty nursing", "I had trouble breastfeeding", and "My milk dried up". When asked how well the FHCW prepared breastfeeding women for the challenges of breastfeeding, 66% of women (27 of 40) rated the FHCW either "well" or "very well". When asked about their experience in the hospital where their baby was born, 55% of women (23 of 42) reported that staff had encouraged them to supplement their breast milk with formula. Upon discharge, greater than 90% (38 of 42) felt confident that they would have the breastfeeding support that they needed. Women were asked whether they remembered anyone telling them particular facts about infant feeding. Fifteen women (33%) remembered being told that "giving a baby formula can affect how much milk a breastfeeding woman makes", 22 (50%) remembered "some women have pain or get infections with breastfeeding", and 18 (41%) remembered "breastfeeding can reduce a woman's risk of some cancers". Discussion: The results of this study support that women are deciding whether or not to attempt breastfeeding very early in their pregnancies, and that those who decide earlier are more likely to breastfeed. Such early decisions highlight the importance of counseling women early in their pregnancies (or pre-conception) about the benefits of breastfeeding. The large number of women who stopped breastfeeding within the first 6 weeks post-partum is representative of trends nationwide. Such results support the need for improved interventions for breastfeeding women during the first few weeks post-partum. In particular, since many women stopped because of concerns about their milk supply or breastfeeding technique, these results suggest that breastfeeding women should receive more counseling around these specific issues. The data suggest that patients did not remember being told some of the benefits, challenges, and facts of breastfeeding. Since our study was based on participant recall, we cannot distinguish between providers not giving this information to pregnant women, the women not understanding this information, or women not recalling that they were ever told this information. Our study is limited by its small sample size and not knowing for how long the "still breastfeeding" women would continue to breastfeed. Conclusion: These results suggest that women who receive care through the FHCW are making decisions about whether or not to breastfeed early in their pregnancies, and that there is a significant breastfeeding attrition rate in the first few weeks post-partum. This study lays the groundwork for future studies that will help the FHCW identify ways to improve breastfeeding initiation and duration among its patient population. Ellen Green Breast Feeding Cross-Sectional Studies Interview Outcome Assessment (Health Care) Worcester (Mass.) http://escholarship.umassmed.edu/ssp/67 http://escholarship.umassmed.edu/ssp/67 Mon, 21 Jul 2008 18:29:58 PDT Background: Current guidelines strongly recommend the measurement of ejection fraction (EF) in all patients hospitalized with acute myocardial infarction (AMI). Over the past decade, the modalities and timing of tests used to evaluate EF in patients hospitalized with AMI have changed significantly, though there are little data available describing evolving trends in the use of these diagnostic modalities. Purpose: The purpose of this study was to evaluate changing trends in the use of left ventriculography and echocardiography to measure EF in patients hospitalized with AMI. Methods: The study sample consisted of 5,385 residents of the Worcester, MA metropolitan area hospitalized with AMI in 5 annual periods between 1997 and 2005. Patients were classified into 4 mutually exclusive categories based on the tests that they received to determine EF: Echocardiography only, ventriculography only, neither, or both. Univariate and multivariate methods were used to characterize differences between the groups. Results: Between 1997 and 2005, the proportion of patients hospitalized with AMI undergoing measurement of EF by both ventriculography and echocardiography increased from 11% to 18%, while the percentage of patients who did not receive an evaluation of EF by either modality decreased from 37% to 27%. The percentage of patients undergoing measurement of EF by ventriculography alone increased from 15% to 20%, while the percentage of patients undergoing measurement of EF by echocardiography alone was stable at approximately 37%. In 1997, echocardiography was performed prior to ventriculography in approximately two-thirds of patients, while in 2005 ventriculography was performed prior to echocardiography in approximately two-thirds of patients. Conclusions: Our results suggest that the use of ventriculography, and the duplicative use of both ventriculography and echocardiography, to assess EF in patients hospitalized with AMI are increasing. While the proportion of AMI patients who do not have their EF assessed has declined significantly during recent years, approximately one-quarter of all AMI patients still do not receive this important test. Samuel W. Joffe Myocardial Infarction Stroke Volume Echocardiography Radionuclide Ventriculography Worcester (Mass.) http://escholarship.umassmed.edu/ssp/66 http://escholarship.umassmed.edu/ssp/66 Mon, 21 Jul 2008 18:29:30 PDT Background: Autopsies of Egyptian and Chinese mummies have demonstrated the existence of gallstones for at least 3,500 years. Today, gallstones occur commonly, especially in the West and in westernized societies. Gallstone complications include biliary colic, acute cholecystitis, choledocholithiasis, cholangitis, gallstone pancreatitis, and gallstone ileus. Gallstone disease exacts a considerable amount of financial and social burden worldwide. Gallstones lead to frequent physician visits and hospitalizations. In 2000, more than 750,000 outpatient visits in the United States were due to gallstones. In the same year, gallstone disease (defined as cholelithiasis with acute cholecystitis) was the most common inpatient diagnosis among gastrointestinal disorders, with more than 250,000 hospitalizations, a median inpatient charge of $11,584 (Russo, 2004) and an estimated annual cost of almost $6.5 billion. Notably, cholecystectomy is the most common elective abdominal operation performed in the United States, with more than 700,000 performed annually. Prevalence of gallstones: It has been estimated that in the United States approximately 20 million persons harbor gallstones. Gallstones, cholecystectomies, and gallbladder disease are more prevalent in women than in men at all ages (Everhart, 1999). The prevalence of gallstones varies widely in different countries and among different ethnic groups living in the same country. The highest rates occur among American Indians (Everhart, 1998), especially the Pima Indians of North America, Scandinavians, and Mexican-American women (Maurer, 1989, Everhart, 1999). The lowest rates are seen among African Americans. Although rarer in the non-westernized world, the prevalence of cholelithiasis increased in African (Adedeji, 1986) and Asian countries (Su, 1992) during the 20th century. For example, the prevalence of gallstones in Tokyo has more than doubled since the 1940s; a shift from pigment to cholesterol gallstones has also been observed. It has been theorized that this increase is due to nutritional and environmental changes, i.e. the westernization of the diet (increased consumption of imported food, decreased fiber and protein intake, increased fat intake) and the decreased rate of chronic biliary infections. The type of gallstone also varies among populations. For example, cholesterol stones (found primarily in the gallbladder) are more prevalent in developed countries, whereas pigment gallstones (found primarily in the bile ducts) are more common in developing countries of Africa and Asia. Composition of gallstones: All gallstones consist of poorly soluble components of bile that precipitate on a 3-dimensional matrix of mucins and proteins. Precipitants include cholesterol, calcium bilirubinates, and calcium salts of phosphate, carbonate or palmitate. The matrix consists of large, polymeric mucin glycoproteins and small, amphipathic polypeptides. Based on their composition, gallstones are categorized as cholesterol, black pigment, and brown pigment, with each category having a unique structural, epidemiologic and risk factor profile. The pathogenesis of each type of stone is defined based on the physical-chemical properties of each stone and their differences result mainly from changes in the lipid and lipopigment composition of gallbladder bile. Bile metabolism: In order to understand the pathogenesis of gallstones, one must be familiar with the role of bile, bile acids and the importance of enterohepatic circulation. Bile is formed in hepatic lobules and is an isotonic fluid whose electrolyte composition resembles that of blood plasma. It is then secreted into a complex network of canaliculi, small bile ductules, and larger bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored for future use. The composition of bile in the gallbladder differs from that of hepatic bile because water and inorganic anions (chloride, bicarbonate) are reabsorbed across the gallbladder epithelium. The solute composition of bile in the gallbladder includes approximately 80% bile acids, 16% phospholipids (mostly lecithin), 4% unesterified cholesterol, and other compounds (conjugated bilirubin, proteins, electrolytes, mucus, rarely drugs and their metabolites). In lithogenic states, the percentage of unesterified cholesterol can reach 8-10% of the total solute composition. Bile acids are the end products of cholesterol metabolism. Bile acid synthesis is the major mechanism of bodily excretion of excess cholesterol. Since hepatic synthesis can increase only 4-5 times its normal synthetic rate, this mechanism is not sufficient for the excretion of excess dietary cholesterol. Bile acids are detergent-like molecules that can form micelles (molecular aggregates) in aqueous solutions if they are above a critical concentration of 2mM. As a result, they are able to solubilize hydrophobic molecules, such as cholesterol, or emulsify digested fats in the intestine. Regulation of bile salt synthesis is determined by multiple factors, such as the viability of hepatocytes, the availability of cholesterol (the precursor molecule), and the amount of bile salts returning to the liver via the enterohepatic circulation (feedback inhibition by dihydroxy bile salts). Some genetic factors might contribute as well, but they are poorly understood at this point. As mentioned above, the ultimate fate of bile acids is secretion into the intestine where they aid in the emulsification of dietary lipids, promote the absorption of fat-soluble vitamins, and allow the fecal excretion of excess cholesterol. A small percentage of bile acids is excreted fecally, while the majority is reabsorbed by the intestine and returned to the liver via the portal venous system. This process whereby bile is secreted from the liver, concentrated in the gallbladder, released into the duodenum and finally reabsorbed in the ileum is termed the enterohepatic circulation. Cholesterol stones: Cholesterol stones are the most common type of gallstones, representing around 80% of gallstones in developed countries. They are mainly composed of cholesterol monohydrate crystals (>50%), as well as calcium salts, bile pigments, proteins, and fatty acids. Grossly, they are often large (up to 4.5 cm in size) and yellowish-white in color. Microscopically, they appear as long, thin crystals that are bound together by a matrix of mucin glycoproteins. Cholesterol stones are typically found in the gallbladder in a bacterially sterile environment. Cholesterol is essentially insoluble in aqueous solution, such as bile. As a result, cholesterol in bile is transported either in unilamellar bilayered vesicles (cholesterol complexed with phospholipids, mostly lecithin) or in mixed multilamellar micelles (cholesterol complexed with phospholipids and bile acids). The total and relative proportions of cholesterol to phospholipids and bile salts determine the solubility of free cholesterol in bile. When cholesterol concentration exceeds its solubility, cholesterol crystals can precipitate in bile, eventually giving rise to gallstones. Cholesterol crystal formation requires the presence of one or more of the following factors: a) cholesterol supersaturation, b) accelerated nucleation, and c) gallbladder hypomotility/bile stasis. Many risk factors for the formation of gallstones have been identified and studied. These myriad risk factors underscore the multifactorial genesis of gallstone formation. These risk factors include: age, gender, obesity, weight loss, total parenteral nutrition, genetics (first degree family member), pregnancy, diet, ileal disease (Crohn's disease), hypertriglyceremia, low HDL, diabetes, and drugs (estrogen, progesterone, ceftriaxone, and octreotide). Pigment stones overview: In the United States, pigment stones comprise around 20% of the total gallstones, but this percentage is much higher in Asian populations. Pigment stones are subclassified into black and brown types, each with unique morphology, pathogenesis and clinical associations. Generally, the prevalence of pigment stones increases with age and is higher in women. As their name implies, pigment stones are formed by the precipitation of bilirubin in bile. This can occur as a consequence of an increase in ionized calcium concentration (as in hyperparathyroidism) or an increase in unbound bilirubinate anions in bile. Bilirubin metabolism: One cannot comprehend the pathogenesis of pigment stones without understanding the role of bilirubin and its subsequent metabolism in the liver. Bilirubin is the breakdown product of normal heme catabolism from destroyed erythrocytes. Like cholesterol, it is insoluble in water. In the liver, it is conjugated with glucuronic acid producing diglucuronides (75-80%) and monoglucuronides (20%), which are soluble in water and can be secreted into bile. Normally, the remainder of the bilirubin that reaches the liver (around 3%) is hydrolyzed by beta-glucuronidases and becomes unconjugated. Unconjugated bilirubin and its calcium salts are poorly soluble in water. In a healthy individual, pigment stones are not formed because the amount of unconjugated, and thus insoluble, bilirubin is not enough to promote stone formation. In abnormal states, though, the excessive amount of unconjugated bilirubin becomes an important factor in pigment gallstone pathogenesis. Black pigment stones: Black pigment stones are composed primarily of pure calcium bilirubinate, but they also contain calcium carbonate and calcium phosphate (in polymer-like complexes with mucin glycoproteins). They are formed in the gallbladder in a bacterially sterile environment. Black stones are found in people with chronic hemolytic states (i.e. sickle cell disease, hereditary spherocytosis), liver cirrhosis, Gilbert's syndrome, or cystic fibrosis. Patients with ileal disease (i.e. Crohn's disease) or ileal resections are also predisposed to pigment stones. The pathogenesis of black stones involves two mechanisms: the hypersecretion of bilirubin conjugates and a defect in the acidification of bile. In the presence of chronic hemolysis, the concentration of bilirubin conjugates (especially monoglucuronides) increases ten-fold from the action of the endogenous enzyme beta-glucuronidase. The bilirubin conjugates are then unconjugated, form salts with calcium or phosphate, and eventually precipitate. The inability of an inflamed gallbladder mucosa to acidify bile may be an additional factor in pigment gallstone formation. By increasing the solubility of calcium carbonate, an acidic bile pH promotes the supersaturation of bile with calcium cations and allows the precipitation of calcium salts. To date, no defects in gallbladder motility have been found in patients with black stones (Behar, 1989). Brown pigment stones: Brown pigment stones are composed of calcium salts of unconjugated bilirubin with varying amounts of cholesterol and protein. They are formed as the result of chronic bacterial infection of the bile and are almost always associated with colonization of bile by enteric organisms. The most common bacteria found in brown stones are Escherichia coli, Bacteroides, and Clostridium. In populations that are prone to pigment stones, a clear shift to cholesterol gallstones has been observed. This shift has been attributed to the decrease in chronic biliary infections. For example, the percentage of pigment stones in the Japanese population decreased from 60% to 24% since 1940. Unlike the other two types of stones, they are primarily found in the intrahepatic or extrahepatic bile ducts. Rarely, they are formed in the gallbladder as a consequence of acute cholecystitis. Brown pigment stones are caused by an excess of unconjugated, insoluble bilirubin in bile that eventually forms stones. The pathogenesis of these stones is thought to involve both stasis in the bile ducts as well as chronic anaerobic infection of bile (Cahalane, 1988). Stasis facilitates the bacterial infection, which in turn promotes the accumulation of both mucin and bacterial cytoskeletons in the bile ducts. The hydrogen ions in the bile are buffered by the mucus, resulting in a less acidic environment where calcium carbonate, phosphate, and bilirubin precipitate easily. The three bacterial compounds that play a key role in brown stone formation are beta-glucuronidase (which produces unconjugated bilirubin), phospholipase A (which produces palmitic and stearic acids), and bile acid hydrolases (which produce unconjugated bile acids). The anionic counterparts of all three products form insoluble complexes with calcium and precipitate to form stones. The enlarging stone causes further ductal obstruction, which promotes more stasis and bacterial infection, thus perpetuating the cycle. Also, the association of certain parasitic infections and biliary stone formation has been well documented in the literature (ex. Opisthorchis veverrini, Clonorchis sinensis - liver flukes prevalent in Thailand and China respectively). Although the exact mechanism of how parasite infections enhance pigment stone formation is not clearly understood, it is thought that the parasitic worm or egg directly stimulates stone formation. The calcified overcoat of the parasitic egg, for example, may serve as a nidus and may enhance the precipitation of calcium bilirubinate (Sripa, 2004). Stephanie Lambou-Gianoukos Cholelithiasis Gallstones Bile http://escholarship.umassmed.edu/ssp/65 http://escholarship.umassmed.edu/ssp/65 Mon, 21 Jul 2008 18:29:25 PDT Background: Total knee arthroplasty (TKA) effectively relieves arthritis pain in 98% of patients but improvement in physical function varies after TKA. Research has identified demographic and clinical predictors of high and low function after TKA. Variation in patients' physical activity levels prior to TKA may contribute to variable functional gains but this has never been quantified. Objectives: The purpose of this study was to determine if pre-operative physical activity measurement improves the ability to predict post-operative functional outcome. Methods: Seventy-nine (79) primary, unilateral TKA patients enrolled in a prospective study between 2006 and 2007 had complete data. The mean age was 68 years, and 71% of the patients were female. All patients who were scheduled for a TKA by one of three high-volume arthroplasty surgeons at a single total joint replacement center were invited to participate in this study. Exclusion criteria included surgery that would interfere with physical activity improvement during the 6-month post-operative period (i.e., TKA of the contralateral knee). Descriptive and multivariate statistics (mixture models) evaluated associations between pre-operative home physical activity level and 6-month post-operative function. Pre-operative physical activity was measured using a step activity monitor, an accelerometer that measures the frequency, intensity and duration of steps. Average steps per day (general activity), average maximum steps in a 5-minute period (a measure of intensity) and average maximum steps in a 30-minute period (a measure of endurance) were calculated. Global post-operative function was assessed using the Short-Form 12 (SF-12) Physical Component Score (PCS) and knee function using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC). Results: After adjusting for age, gender, BMI, and emotional health (SF12/MCS), pre-operative average steps per day was significantly correlated with post-operative WOMAC score (p = 0.003). The greater the average steps per day, the better the post operative knee function (WOMAC). However, no significant relationship was detected with global physical function (SF12/PCS). There were no statistically significant associations observed between the 5 and 30 minute rates and the post-operative knee or global function. Conclusion: These data suggest that pre-operative average steps per day measurement is predictive of knee function after TKA. Pedometer measures may be adequate in clinical use as step rates data did not add significantly to these analyses. Future accelerometer studies should test maximal rates in a controlled condition and in larger patient samples before its value in pre-operative assessment can be determined. Craig Lareau Arthroplasty, Replacement, Knee Recovery of Function Exercise Physical Fitness http://escholarship.umassmed.edu/ssp/64 http://escholarship.umassmed.edu/ssp/64 Mon, 21 Jul 2008 18:29:09 PDT Abstract: Optimal treatment for clinically localized rectal cancer continues to evolve. Preoperative chemoradiotherapy (CRT) may diminish radiation (XRT) toxicity and preserve the anal sphincter. In this prospective, phase 2, single institution trial, we studied preoperative neoadjuvant weekly paclitaxel (P), concurrent XRT, and oral glutamine in patients with rectal cancer and either transmural or nodal (N+) disease. Patients received intravenous weekly P concurrent with XRT and oral glutamine. Patients were restaged 4 weeks following the end of CRT, and then underwent resection. Patients were then offered 4 months of postoperative 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Twenty-five of 25 planned patients were enrolled. The median age was 58 years (range 40-83). At initial enrollment: there were 15 distal and 9 mid-upper primary rectal tumors initial clinical stage: T2 5%, T3 90%, T4 5%; N- 59%, N+ 41% all were M0 Ninety-six percent of planned doses of paclitaxel were administered and 96% of patients received the full dose of XRT. GI/local toxicity was graded per SWOG criteria. Most severe toxicity during preoperative chemoradiotherapy included grade 3 anemia and grade 3 neutropenia; grade 3 and grade 4 diarrhea; grade 2 dysuria and grade 4 perianal desquamation. Ninety-two percent of patients were surgically resected. Low anterior resection (LAR) was accomplished in 77% and 23% patients required abdominoperineal resection (APR). final pathologic stage: Tis/T1 18%, T2 23%, T3 59%; N- 68%, N+ 32% there was 13% progression to metastatic disease prior to surgery Eighty-three percent of patients received postoperative 5-FU-based chemotherapy. Fourteen (64%) of patients remained disease-free after surgery and completion of adjuvant chemotherapy; 12 are still living. Five year disease-free survival is 64% and 5 yr overall survival is 76%. We conclude that this therapy is a tolerable alternative to current standard neoadjuvant regimens, does not lead to an increase in postoperative complications and demonstrates down staging of primary rectal tumors allowing preservation of anal sphincter function. Introduction: Nearly 42,000 patients are diagnosed with rectal cancer each year1. There has been constant evolution regarding optimal treatment for clinically localized rectal cancer. The current standard of care for the majority of T2-T4 tumors is preoperative neoadjuvant chemoradiotherapy followed by potentially curative surgery2,3. The main goals of treatment aside from cure are to minimize toxicity and optimize patients' quality of life during and after treatment. Definitive management of low-lying rectal cancers has a greater likelihood of impacting patients' quality of life. Continued research to optimize treatment options will most benefit this population of patients with regard to quality of life after surgery. The leading concept behind preoperative neoadjuvant therapy is reduction in tumor burden and down staging. The goal is to minimize the resection field, preserve satisfactory sphincter function and leave as few patients as possible with permanent colostomies. Current standard of care also includes post operative 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Paclitaxel, an antineoplastic agent, has been widely used as a solitary agent or in combination with other chemotherapeutic agents and radiation therapy against a number of neoplastic diseases including breast,4 pancreatic,5 lung,6 ovarian,7 and gastric cancers8. No studies have examined the role of this agent against rectal cancer. Paclitaxel is an attractive agent in preoperative chemoradiation given its role as a radiation sensitizer9. Paclitaxel blocks cells in the G2/M phase of the cycle by blocking mitotic spindle function and holding cells in a state known to be up to 4-fold more sensitive to radiation than other cell cycle phases10. Thus, the ability of paclitaxel to block cells in the G2/M phase of the cell cycle appears to directly cause its radiation sensitizing ability11,12. Recent research has also provided insight to the role of paclitaxel as a mediator of reactive oxygen species and subsequent damage to bystander cancer cells13. In either case, paclitaxel is an appropriate choice for preoperative chemotherapy with concurrent radiation therapy. While the current trend is towards oral chemotherapeutics to optimize patient quality of life, we believe paclitaxel may be a highly useful alternative in patients who cannot tolerate the current standard of care or these newer oral therapies14,15,16,17. Therefore we studied preoperative neoadjuvant weekly paclitaxel, concurrent radiation (XRT), and oral glutamine in patients with rectal cancer and either transmural or nodal (N+) disease as suggested by rectal exam, pelvic MRI, CT scan, or transrectal ultrasound.18 Methods: Twenty-five patients were enrolled in a prospective, phase 2, single institution trial evaluating the role of preoperative paclitaxel and radiation in rectal cancer. Patients with rectal cancer and either transmural or nodal (N+) disease as suggested by rectal exam, pelvic MRI, CT scan, or transrectal ultrasound were consented to receive intravenous weekly paclitaxel at 50mg/m2/dose concurrent with XRT (5040 cGy in 28 fractions) and oral glutamine 10g three times daily. Patients were re-evaluated following the completion of combined modality treatment (CMT), restaged, and then underwent resection. Patients with initial clinical stage T3 or N+ tumors were offered adjuvant chemotherapy. Clinical data was collected during the treatment regimens preoperatively and postoperatively to evaluate for tumor response, toxicity of treatment as well as to compare variations and/or complications of the surgical procedure. Patients were followed after therapy for evaluation of recurrence or cure, toxicity symptoms and quality of life. Results: Enrollment goal was met with 25 patients (9 female and 16 male) and data are presented here. Of the 25 patients enrolled in this study, we report the findings on 24 evaluable patients. The median age was 58 years (range 40-83). There were 15 distal rectal (≤ 5 cm above anal verge) and 9 mid-upper rectal lesions. These included 7 well differentiated, 8 moderately differentiated and 3 poor or undifferentiated adenocarcinomas. Differentiation of the remaining 6/24 (25%) was not stated in pathology record. Initial staging information was missing from 2/24 evaluable patient records. Initial T stage was T2 in 1 (4.5%), T3 in 20 (91%) and T4 in 1 (4.5%) of 22 patients. Initial imaging used for staging could not assess nodal status in 5/22 patients. Initial N stage was N- in 10/17 (59%), N+ in 7/17 (41%). All patients were M0. Twenty-three of 24 (96%) planned doses of paclitaxel were administered and 23/24 (96%) patients received the full dose of XRT. Toxicity was graded per SWOG criteria. Adverse effects during preoperative chemoradiotherapy included hematologic toxicity: 11 patients with grade 1 or 2 anemia, 1 patient with grade 3 anemia, 3 patients with grade 1 or 2 neutropenia, 1 patient with grade 3 neutropenia (these included 1 patient with both grade 1 anemia and grade 2 neutropenia). Fourteen patients had grade 1 or 2 diarrhea, 2 had grade 3 and 2 had grade 4. Grade 1 or 2 dysuria occurred in 8 patients. Perianal erythema/desquamation was grade 1 or 2 in 14 patients and grade 3 in 4. Twenty-two of 24 (92%) patients were surgically resected. One patient had distant metastases found on presurgical imaging and another died from his disease prior to completing the neoadjuvant regimen. Two surgically resected patients had microscopic (+) margins. Low anterior resection was accomplished in 17/22 (77%) and 5/22 (23%) patients required abdominoperineal resection. Two patients experienced postoperative fever and 8 experienced wound complications including infection, hernia or fistula. One patient experienced a postoperative small bowel obstruction requiring surgical intervention. While in the immediate postoperative recovery period, 5 patients experienced mild to moderate fecal incontinence, tenesmus and/or diarrhea all of which eventually resolved. Final pathologic stage was Tis/T1 in 4 (18%), T2 in 5 (23%) and T3 in 13 (59%) of 22 patients; N- in 15/22 (68%), N+ in 7/22 (32%). Three of 23 (13%) progressed to metastatic disease prior to surgery. Of 15 patients with evaluable T and N staging at both enrollment and at surgery there was 1 (7%) pathologic complete response (CR). Of 20 patients with evaluable T staging at both enrollment and at surgery, there were 2 (10%) T stage CRs; of 15 patients with evaluable N staging there were 2 (13%) N stage CRs. Twenty of 24 (83%) patients received postoperative 5-FU-based chemotherapy. One patient with a down-staged T2N0M0 tumor elected not to proceed with postoperative adjuvant therapy. With a median follow-up of 89 months (7.5 yrs), 14/22 (64%) patients remained disease-free after treatment. Two patients died of intercurrent disease and 12 are still living. Eleven of those still living have exceeded their 5-year mark disease-free. Five year disease-free survival is 64% and 5 year overall survival is 76%. Median current disease-free survival is 5.0 years and median overall survival is 6.4 years. One patient who experienced pathologic recurrence of their disease is also still living with overall survival of more than 9 years. Conclusions: This study offers the benefit of a prospective, phase 2 trial of paclitaxel as a preoperative neoadjuvant chemotherapeutic agent in the setting of primary rectal cancer. Results show paclitaxel to be tolerable when compared to the current neoadjuvant regimen of infusional 5-FU delivered concurrently with XRT. Paclitaxel does not lead to an increase in postoperative complications compared to current standard of care regimens. With regard to potential preservation of anal sphincter function, paclitaxel showed 7/19 (37%) overall down-staging and 3/14 (21%) pathologic down-grading. There was a 9/20 (45%) reduction in T stage and 1/15 (7%) pathologic CR (T and N stage) of the primary tumor. We believe that this data is sufficient to support the use of paclitaxel as a safe alternative to either 5-FU or oral chemotherapeutic agents in patients who cannot tolerate them. We hope to update this analysis with comparison of paclitaxel to the current standard of care in neoadjuvant chemoradiotherapy and also to currently acceptable alternative therapies. In addition we hope to provide descriptive information with respect to the treatment, complications and outcomes of these patients so that overall management and patient quality of life may be optimized. Additionally, there is ongoing evaluation of other clinical data from this trial including a quality of life questionnaire as well as the presence or absence of the p53 mutation from initial biopsies and surgical resection specimens. We believe these analyses will aid in the current knowledge and consideration of alternative therapeutic options as well as understanding the possible treatment outcomes of patients with clinically localized rectal cancer. References: 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. 2. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004 Oct 21;351(17):1731-40. 3. Willett CG. Sphincter preservation in rectal cancer. Local excision followed by postoperative radiation therapy. Semin Radiat Oncol 1998 Jan;8(1):24-9. 4. Miller K, Molin W, Gralow, J, et al. Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. N Eng J Med 2007;357:2666-76. 5. Safran H, Moore T, Iannitti D, et al. Paclitaxel and Concurrent Radiation for locally Advanced Pancreatic Cancer. Int. J. Radiation Oncology Biol. Phys., 2001; Vol. 49, No. 5, pp. 1275-1279 6. Sandler A, Gray R, Perry M, et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer. N Eng J Med 2006; 355:2542-50. 7. Armstrong D, Bundy B, Wenzel L, et al. Intraperitoneal Cisplatic and Paclitaxel in Ovarian Cancer. N Eng J Med 2006;354:34-43. 8. Kawabata R, Fujiwara Y, Doki Y, et al. Phase I/II Study of a Combination of S-1 and Weekly Paclitaxel in Patients with Advanced or Recurrent Gastric Cancer. Oncology 2007;72:219-225. 9. Choy H, Rodriguez FF, Koester S, et al. Investigation of Taxol as a potential radiation sensitizer. Cancer 1993; 71(11):3774-8. 10. Sinclair WK, Morton RA. X-ray sensitivity during the cell generation cycle of cultured Chinese Hamster cells. Radiat Res 1966; 29:450-474. 11. Geard CR, Jones JM, Schiff PB. Taxol and radiation. J Natl Cancer Inst Monogr 1993; 15:89-94. 12. Tishler R, Schiff, Geard CR, et al. Taxol: a novel radiation sensitizer. Int J Radiat Oncol Biol Phys 1992; 22:613-7. 13. Alexandre J, Hu Y, Lu W, et al. Novel Action of Paclitaxel against Cancer Cells: Bystander Effect Mediated by Reactive Oxygen Species. Cancer Res 2007; 67(8):3512-7. 14. Fernandez-Martos C, Aparicio J, Bosch C et al. Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years follow-Up. J Clin Oncol 2004 Aug 1;22(15):3016-22. Epub 2004 Jun 21. 15. Das P, Lin EH, Bhatia S, et al. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis. Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1378-83. Epub 2006 Oct 23. 16. Kopec JA, Yothers G, Ganz PA, et al. Quality of life in operable colon cancer patients receiving oral compared with intravenous chemotherapy: results from National Surgical Adjuvant Breast and Bowel Project Trial C-06. J Clin Oncol. 2007 Feb 1;25(4):424-30. 17. Borner MM, Schoffski P, de Wit R, et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer. 2002 Feb;38(3):349-58. 18. Savarese D, Smyczynski M, Counihan T, et al. Preoperative Radiation Therapy in Combination with Weekly Paclitaxel and Oral Glutamine for Clinically Localized Rectal Cancer. Proc Am Soc Clin Oncol 19: 2000 (abstr 1095) Leah Burnett Rectal Neoplasms Neoadjuvant Therapy Radiotherapy Paclitaxel Glutamine http://escholarship.umassmed.edu/ssp/63 http://escholarship.umassmed.edu/ssp/63 Wed, 16 Jul 2008 07:56:06 PDT Introduction: Cardiopulmonary exercise testing (CPX) has been used to identify elderly patients at high risk for major surgery; Older demonstrated that postoperative cardiovascular-related deaths were predicted by an anaerobic threshold (AT) < 11 ml/min/kg1. This methodology is limited by the uncomfortable and claustrophobic facemask used for standard CPX. During cycling, pulmonary oxygen consumption (VO2) is equivalent to twice muscle VO22. Our research group has developed novel methods of using near infrared spectroscopy (NIRS) to determine muscle oxygen saturation (SmO2), muscle pH and hematocrit. Hypothesis: NIRS, in combination with heart rate (HR) monitoring, may be used to determine VO2. Methods: Ten healthy subjects (5M/5F) performed CPX. Pulmonary VO2 was determined with a metabolic cart simultaneously with NIR spectra from the thigh. Muscle VO2 was calculated using the Fick equation (VO2 = SV x HR x C(a-v)O2) where stroke volume was estimated from HR. Oxygen content difference was calculated from hematocrit and SmO2 obtained with NIRS. Pulmonary and NIRS VO2 were compared by Bland-Altman analysis. AT was identified from spectrally determined pH3. Results: SV was gender specific and a mathematical equation was developed to calculate SV from HR during exercise. Our data showed that NIRS VO2 closely approximated pulmonary VO2 up to the AT. The bias between pulmonary and NIRS-measured VO2 was -0.05 L/min and the limits of agreement were -0.6 and +0.5 L/min; R2 = 0.89. Larger errors were observed for VO2 > AT. Conclusion: Our results demonstrate the feasibility of using NIRS to determine VO2 for preoperative risk assessment. References: 1. Older P, et al. Chest. 1999, 116:355-362. 2. Grassi et al. J Appl Physiol. 1996, 80:988-998. 3. Soller BR, et al. J Appl Physiol. 2008, 104:837-844. Funded by FAER and NSBRI through NASA NCC9-58. Nathan Marengi Spectroscopy, Near-Infrared Exercise Test Oxygen Consumption Surgical Procedures, Operative Preoperative Care Risk Assessment