Mitchell A. Cahan

Cytotoxicity of taxol in vitro against human and rat malignant brain tumors.

Taxol is a novel antitumor alkaloid that has shown clinical activity against several tumors, including ovarian and breast carcinoma and melanoma. To evaluate taxols potential as a therapy for malignant brain tumors, we measured the sensitivity of four human (U87, U373, H80, and D324) and two rat (9L, F98) brain-tumor cell lines to taxol. The cells were exposed to taxol in vitro using a clonogenic assay. Log cell kill (LD90) occurred at concentrations of 42 (9L), 25 (F98), 19 (H80), 7.2 (U373), 9.1 (U87), and 3.9 nM (D324) when cells were continuously exposed to taxol for 6–8 days. The human cell lines were uniformly more sensitive to taxol than were the rat lines. The duration of exposure had a significant effect on taxols cytotoxicity. When cells were exposed to taxol for 1 h the LD90 increased to 890 nM for the 9L rat line and 280 nM for the human U373 line. On the basis of these results, we conclude that taxol has significant potency in vitro against malignant brain tumors and that the activity occurs at concentrations of taxol that have previously been shown to be effective for several tumors against which the drug is currently being evaluated clinically.

Surgical management of acute cholecystitis at a tertiary care center in the modern era.

HYPOTHESIS The advent of laparoscopy has changed the paradigm of surgical training and care delivery for the treatment of patients with acute cholecystitis (AC). DESIGN Retrospective data collection and analysis. SETTING Hospital admissions with a primary diagnosis of AC at a tertiary care center from January 1, 2002, to January 1, 2007. PATIENTS During the study period, 923 patients were admitted with a primary diagnosis of AC. One hundred fourteen patients were excluded from the study because of missing data, medical management, incomplete operative notes or documents, or metastatic gastrointestinal cancer. MAIN OUTCOME MEASURES Patient demographics, preoperative morbidity, procedures (medical and surgical), and postoperative outcomes were statistically analyzed using chi(2) test, t test, and analysis of variance. RESULTS Eight hundred nine patients (87.6%) with a primary diagnosis of AC underwent surgery by 44 surgeons. Procedures included 663 laparoscopic cholecystectomies (LCs) (82.0%), 9 open cholecystectomies (1.1%), 51 conversions from LC to open cholecystectomy (6.3%), and 86 cholecystostomy tube placements (10.6%). During the study period, cholecystostomy tube placements increased, while open cholecystectomies and conversions from LC to open cholecystectomy decreased (P < .05). Laparoscopic cholecystectomy was associated with significantly better outcomes, including shorter postsurgical stay (2.2 vs 6.3 days for other modalities) and fewer complications (8.5% vs 17.0%). CONCLUSIONS Based on 5-year results from a tertiary care center, LC was performed with a low conversion rate to open surgery and was associated with decreased morbidity and mortality compared with other surgical modalities to treat AC. Our data confirm the benefits and widespread use of LC in the modern era, reflecting changes in the training paradigm and learning curve for laparoscopy.

Duplex ultrasound insertion of inferior vena cava filters in multitrauma patients

BACKGROUND Techniques for placement of inferior vena cava (IVC) filters have undergone continued evolution from open surgical exposure of the venous insertion site to percutaneous insertion in most cases today. However, the required transport either to an operating room or interventional suite can be complex and potentially hazardous for the multiply injured trauma patient who may require ventilator support, controlled intravenous infusions, or skeletal immobilization. Increased experience with color-flow duplex scanning for routine IVC imaging and portability of ultrasound equipment have suggested the usefulness of duplex-guided IVC filter insertion (DGFI) in critically ill trauma and intensive care unit (ICU) patients. METHODS A total of 25 multitrauma/ICU patients were considered for DGIF. Screening color-flow duplex scans were performed on all patients, and obesity or bowel gas prevented ultrasound imaging in 2 cases, leaving 23 patients suitable for DGFI. In each case, the IVC was imaged in the transverse and longitudinal planes. The right renal artery was identified as it passed posterior to the IVC and was used as a landmark of the infrarenal segment of the IVC. All procedures were performed at the bedside in a monitored ICU setting using percutaneous placement of titanium Greenfield filters. Duplex scanning after insertion was used to document proper placement, and circumferential engagement of the filter struts in the IVC wall. An abdominal radiograph was also obtained in each case to confirm proper filter location. Duplex ultrasound imaging was repeated within 1 week of insertion to assess IVC and insertion site patency. RESULTS DGFI was successful in all cases. The filter was deployed at a suprarenal level in one case, as was recognized at the time of postprocedural scanning. Three patients died as a result of their injuries but there were no pulmonary embolism deaths. Repeat duplex scanning was obtained in 17 patients, and revealed no case of IVC or insertion site thrombosis. CONCLUSIONS Vena caval interruption can be safely performed under ultrasound guidance in a monitored, ICU environment. In selected multiply injured trauma patients, this will reduce the risk, complexity and cost of transport for these critically ill patients. DGFI also reduces procedural costs compared with an operating room or interventional suite, and eliminates intravenous contrast exposure. Preprocedural scanning is essential to identify patients suitable for DGFI, and careful attention must be paid to the known ultrasonographic anatomical landmarks.

Use of Cholecystostomy Tubes in the Management of Patients with Primary Diagnosis of Acute Cholecystitis

BACKGROUND Management of patients with severe acute cholecystitis (AC) remains controversial. In settings where laparoscopic cholecystectomy (LC) can be technically challenging or medical risks are exceedingly high, surgeons can choose between different options, including LC conversion to open cholecystectomy or surgical cholecystostomy tube (CCT) placement, or initial percutaneous CCT. We reviewed our experience treating complicated AC with CCT at a tertiary-care academic medical center. STUDY DESIGN All adult patients (n = 185) admitted with a primary diagnosis of AC and who received CCT from 2002 to 2010 were identified retrospectively through billing and diagnosis codes. RESULTS Mean patient age was 71 years and 80% had ≥1 comorbidity (mean 2.6). Seventy-eight percent of CCTs were percutaneous CCT placement and 22% were surgical CCT placement. Median length of stay from CCT insertion to discharge was 4 days. The majority (57%) of patients eventually underwent cholecystectomy performed by 20 different surgeons in a median of 63 days post-CCT (range 3 to 1,055 days); of these, 86% underwent LC and 13% underwent open conversion or open cholecystectomy. In the radiology and surgical group, 50% and 80% underwent subsequent cholecystectomy, respectively, at a median of 63 and 60 days post-CCT. Whether surgical or percutaneous CCT placement, approximately the same proportion of patients (85% to 86%) underwent LC as definitive treatment. CONCLUSIONS This 9-year experience shows that use of CCT in complicated AC can be a desirable alternative to open cholecystectomy that allows most patients to subsequently undergo LC. Additional studies are underway to determine the differences in cost, training paradigms, and quality of life in this increasingly high-risk surgical population.

Risk-group targeted inferior vena cava filter placement in gastric bypass patients.

BackgroundDespite a growing body of evidence guiding appropriate perioperative thromboprophylaxis in the general population, few data direct strategies to reduce deep venous thrombosis (DVT) and pulmonary embolism (PE) in the morbidly obese. We have implemented a novel protocol for venous thromboembolism (VTE) risk stratification in Roux-en-Y gastric bypass (RYGB) candidates at our institution, which augments clinical assessment with screening for thrombophilias, to guide retrievable inferior vena cava (IVC) filter utilization.MethodsA retrospective review of prospectively collected data from patients who underwent primary RYGB between 2001 and 2008 at the University of North Carolina at Chapel Hill was completed. During that time, clinical assessment of VTE risk was amplified by focused plasma screening for common thrombophilias (factors VIII, IX, and XI, d-dimer, fibrinogen). Preoperative prophylactic IVC filters were offered to high-risk patients. The database was reviewed for perioperative DVTs, PEs, and filter-related complications.ResultsOf 330 patients, in 162 attempts, 160 had prophylactic IVC filters placed with four complications overall (2.47%). No patient had symptoms of PE during the planned 6-week filter period, though one had a PE occur immediately after filter removal (0.63%); in contrast, five of 170 patients (2.94%) without prophylactic IVC filters presented with symptomatic PE (p = 0.216). In total, 147 (91.88%) prophylactic filters were removed.ConclusionsRisk-group targeted prophylactic inferior vena cava filter placement prior to RYGB is safe with a trend towards reduced occurrence of PE.

Development of endogenous beta-galactosidase and autofluorescence in rat brain microvessels: implications for cell tracking and gene transfer studies.

Cell transplantation is commonly used in studies of CNS development, tumor biology, and gene therapy. Fluorescent dyes and the E. coli lacZ reporter gene are used to identify transplanted cells in host tissues. The usefulness of these methods depends on host autofluorescence and beta-galactosidase (beta-Gal) activity. Our interest in the CNS vasculature led us to examine vascular autofluorescence and beta-Gal activity in postnatal and adult rat brains. Brains were perfusion-fixed (3.7% paraformaldehyde), cryoprotected, and cryostat-sectioned (12 microns). Autofluorescent vessel profiles were quantitated in sections using rhodamine filter sets and beta-Gal-positive vessels were quantitated under bright-field after incubation of sections with X-Gal chromogenic substrate for 1-18 hr at 37 degrees C. Multifocal vessel autofluorescence appeared in postnatal Day (PND) 18 Lewis rats (0.6 +/- 0.4 vessels/field) and increased tenfold in adults (6.8 +/- 0.3/field). The numbers of beta-Gal-positive vessels in PND 18 and adult sections incubated with X-Gal for 18 hr were 21.1 +/- 1.7 and 119 +/- 17, respectively. Host beta-Gal staining was similar to that produced by implanted endothelial cells expressing the bacterial lacZ reporter gene. Reducing incubation times in X-Gal to less than 4 hr eliminated endogenous staining and retained lacZ-specific staining. The presence of vascular autofluorescence and endogenous beta-Gal activity must be considered when either fluorescence- or lacZ-dependent cell markers are used in rat brain.

Prevalence of Thrombophilias in Patients Presenting for Bariatric Surgery

BackgroundThe rise in bariatric surgery has driven an increased number of complications from venous thromboembolism (VTE). Evidence supports obesity as an independent risk factor for VTE, but the specific derangements underlying the hypercoagulability of obesity are not well defined. To better characterize VTE risk for the purpose of tailoring prophylactic strategies, we developed a protocol for thrombophilia screening in patients presenting for bariatric surgery at our institution.MethodsBetween April 2004 and April 2006, 180 bariatric surgery candidates underwent serologic screening for inherited thrombophilias (Factor V-Leiden mutation, low Protein C activity, low Protein S activity, Free Protein S deficiency) and acquired thrombophilias (D-Dimer elevation, Fibrinogen elevation, elevation of coagulation factors VIII, IX, and XI, elevation of Lupus anticoagulants and homocysteine level, and Antithrombin III deficiency). Prevalence rate of each thrombophilia in the subject group was compared to the actual prevalence rate of the general population.ResultsMost plasma markers of both inherited and acquired thrombophilias were identified in higher than expected proportions, including D-Dimer elevation in 31%, Fibrinogen elevation in 40%, Factor VIII elevation in 50%, Factor IX elevation in 64%, Factor XI elevation in 50%, and Lupus anticoagulant in 13%.ConclusionsObesity is a well-described demographic risk factor for VTE. In bariatric surgery candidates routinely screened for serologic markers, both inherited and acquired thrombophilias occurred more frequently than in the general population, and may therefore prove to be useful for individualized VTE risk assessment and prophylaxis.

The Effect of Cigarette Smoking Status on Six-Minute Walk Distance in Patients with Intermittent Claudication

The purposes of the study were threefold: (1) to compare 6-minute walk performance as a measure of exercise tolerance among three different groups of peripheral arterial occlusive disease (PAOD) patients with intermittent claudication—current smokers, former smokers, and patients who have never smoked; (2) to identify important covari ates that might affect the relationship between smoking and exercise in the PAOD popu lation ; (3) to determine whether differences among the three groups in 6-minute walk performance persist after statistically controlling for the significant covariates. Recruited into the study were 415 PAOD patients with intermittent claudication between the ages of 42 and 88 years. The self-reported smoking status consisted of 182 current smokers, 196 former smokers, and 37 patients who had never smoked. The authors recorded 6- minute walk distance, a reliable measurement of exercise tolerance in PAOD patients, as well as age, body composition, self-reported ambulatory function, self-reported physical activity, and standard peripheral hemodynamics. Nonsmokers walked significantly farther (413 ± 14 m; mean ±standard error) and took more steps (665 ± 14 steps) than either current (352 ±7 m; 563 ±9 steps) or former smokers 370 ±7 m; 600 ±8 steps) (p<0.05). The nonsmokers had a higher ankle-brachial index (ABI) value (0.70 ±0.03) than patients who actively smoked 0.62 ± 0.01 (p<0.03); the authors observed an inverse relationship between smoking history and self-reported physical activity (WIQ Distance Score: nonsmokers 51 ±6%, former smokers 38 ±3%, and smokers 32 ±2%) (p<0.01). From a multivariate perspective, ABI, physical activity, and perceived walking ability were the only independent predictors of 6-minute walk distance. Differences in the adjusted 6-minute walk distance among the nonsmokers (388 ± 13 m), current smokers (359 ±6 m), and former smokers (368 ±6 m) no longer remained after controlling statis tically for these covariates. The findings suggest that 6-minute walk distance is a sensitive measure to detect differences in submaximal exercise performance between smoking and nonsmoking PAOD patients with intermittent claudication. Moreover, the group differ ence in the 6-minute walk distance is explained by group differences in walking percep tion, PAOD severity, and physical activity level.

A Human Factors Curriculum for Surgical Clerkship Students

HYPOTHESIS Early introduction of a full-day human factors training experience into the surgical clerkship curriculum will teach effective communication skills and strategies to gain professional satisfaction from a career in surgery. DESIGN In pilot 1, which took place between July 1, 2007, and December 31, 2008, 50 students received training and 50 did not; all received testing at the end of the rotation for comparison of control vs intervention group performance. In pilot 2, a total of 50 students were trained and received testing before and after rotation to examine individual change over time. SETTING University of Massachusetts Medical School. PARTICIPANTS A total of 148 third-year medical students in required 12-week surgical clerkship rotations. INTERVENTIONS Full-day training with lecture and small-group exercises, cotaught by surgeons and educators, with focus on empathetic communication, time management, and teamwork skills. MAIN OUTCOME MEASURES Empathetic communication skill, teamwork, and patient safety attitudes and self-reported use of time management strategies. RESULTS Empathy scores were not higher for trained vs untrained groups in pilot 1 but improved from 2.32 to 3.45 on a 5-point scale (P < .001) in pilot 2. Students also were more likely to ask for the nurses perspective and to seek agreement on an action plan after team communication training (pilot 1, f = 7.52, P = .007; pilot 2, t = 2.65, P = .01). Results were mixed for work-life balance, with some trained groups scoring significantly lower than untrained groups in pilot 1 and no significant improvement shown in pilot 2. CONCLUSIONS The significant increase in student-patient communication scores suggests that a brief focused presentation followed by simulation of difficult patient encounters can be successful. A video demonstration can improve interdisciplinary teamwork.

Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy

IMPORTANCE The role of interval appendectomy after conservative management of perforated appendicitis remains controversial. Determining the etiology of perforated appendicitis is one reason to perform interval appendectomies. OBJECTIVE To determine whether adult patients undergoing interval appendectomy experience an increased rate of neoplasms. DESIGN Retrospective study. SETTING A single tertiary care institution. PARTICIPANTS All patients 18 years or older who underwent appendectomy for presumed appendicitis from January 1, 2006, through December 31, 2010. EXPOSURES Appendectomy for presumed appendicitis. MAIN OUTCOMES AND MEASURES Underlying neoplasm as the cause of presentation for presumed appendicitis. Demographic data, clinicopathologic characteristics, interval resection rate, and complication data were collected and analyzed. RESULTS During the study period, 376 patients underwent appendectomies. Interval appendectomy was performed in 17 patients (4.5%). Neoplasms were identified in 14 patients (3.7%); 5 of those tumors occurred in patients who had undergone interval appendectomy (29.4%). Nine neoplasms were mucinous tumors (64.3%), including all neoplasms associated with interval appendectomies. The mean age of all patients with appendiceal tumors was 49 years (range, 35-74 years). CONCLUSIONS AND RELEVANCE Mucinous neoplasms of the appendix were found in 5 of 17 patients (29.4%) undergoing interval appendectomy. Interval appendectomies should be considered in all adult patients, especially those 40 years or older, to determine the underlying cause of appendicitis. A multi-institutional study to determine the generalizability of these findings is warranted.