David McAneny

Results of a phase I trial of a recombinant vaccinia virus that expresses carcinoembryonic antigen in patients with advanced colorectal cancer

AbstractBackground: The inadequacy of systemic treatments of advanced colorectal cancer has aroused interest in biologic therapy. Recent animal models have demonstrated the efficacy and safety of a recombinant vaccine that contains vaccinia and the gene for carcinoembryonic antigen (rV-CEA). Methods: A phase I clinical trial of rV-CEA was conducted to assess vaccine toxicities, the maximum tolerated dosage, resulting immune activities, and tumor responses. A dose-escalation protocol was devised for three concentrations. Six patients per dosage were each to receive three vaccinations. Results: Seventeen patients with advanced colorectal cancer received a total of 44 vaccinations. Mild local and systemic reactions—comparable to those seen with vaccinia alone—were observed and were typically associated with the first vaccination. No significant complications or deaths were caused by the rV-CEA. In particular, no autoimmune colitis developed, nor did leukopenia occur, despite some homology between CEA and leukocyte antigens. All three vaccine concentrations were equally well tolerated. Most patients demonstrated tumor progression by clinical and radiographic parameters and by CEA levels. Immune assays are pending. Conclusions: This phase I trial demonstrated the safety of rV-CEA in patients with advanced colorectal cancer. Future clinical studies are warranted and will likely be influenced by investigations of the immune responses to the vaccine.

I COUGH: Reducing Postoperative Pulmonary Complications With a Multidisciplinary Patient Care Program

IMPORTANCE Postoperative pulmonary complications can be a devastating consequence of surgery. Validated strategies to reduce these adverse outcomes are needed. OBJECTIVES To design, implement, and determine the efficacy of a suite of interventions for reducing postoperative pulmonary complications. DESIGN A before-after trial comparing our National Surgical Quality Improvement Program (NSQIP) pulmonary outcomes before and after implementing I COUGH, a multidisciplinary pulmonary care program. SETTING An urban, academic, safety-net hospital. PARTICIPANTS All patients who underwent general or vascular surgery at our institution during a 1-year period before and after implementation of I COUGH. INTERVENTIONS A multidisciplinary team developed a strategy to reduce pulmonary complications based on comprehensive patient and family education and a set of standardized electronic physician orders to specify early postoperative mobilization and pulmonary care. Designated by the acronym I COUGH, the program emphasizes incentive spirometry, coughing and deep breathing, oral care (brushing teeth and using mouthwash twice daily), understanding (patient and family education), getting out of bed at least 3 times daily, and head-of-bed elevation. Nursing and physician education promoted a culture of mobilization and I COUGH interventions. I COUGH was implemented for all general surgery and vascular surgery patients at our institution in August 2010. MAIN OUTCOMES AND MEASURES The NSQIP-reported incidence and risk-adjusted ratios of postoperative pneumonia and unplanned intubation, which NSQIP reports as observed-expected (OE) ratios for the 1-year period before implementing I COUGH and as odds ratios (ORs, statistically comparable to OE ratios) for the period after its implementation. RESULTS Before implementation of I COUGH, our incidence of postoperative pneumonia was 2.6%, falling to 1.6% after its implementation, and risk-adjusted outcomes fell from an OE ratio of 2.13 to an OR of 1.58. The incidence of unplanned intubations was 2.0% before I COUGH and 1.2% after I COUGH, with risk-adjusted outcomes decreasing from an OE ratio of 2.10 to an OR of 1.31. CONCLUSIONS AND RELEVANCE I COUGH, a standardized postoperative care program emphasizing patient education, early mobilization, and pulmonary interventions, reduced the incidence of postoperative pneumonia and unplanned intubation among our patients.

Comparative response to splenectomy in coombs‐positive autoimmune hemolytic anemia with or without associated disease

We reviewed our experience in 30 patients with direct Coombs‐positive (DAT+) autoimmune hemolytic anemia (AHA) who underwent splenectomy. Twelve patients had idiopathic “warm” AHA (group I) and 18 had AHA associated with systemic diseases (group II). Complete response to splenectomy was defined as having normal hemoglobin and reticulocyte count lasting for at least 6 months without subsequent medical therapy. Subnormal but greater than 50% improvement in these parameters with or without medical therapy was considered to be a partial response. Median age was 64 (23–81) in group I and 68 (23–76) in group II. Median follow‐up duration was 18 and 10.9 months, respectively. Nine of 11 (82%) evaluable patients with idiopathic AHA and 3 of 16 (19%) patients with associated disease achieved a complete response. Partial response was obtained in 2 (18%) and 6 (37%) patients in groups I and II, respectively. Both complete‐response and overall‐response rates were statistically different between two groups (P = 0.001 and 0.02). Postoperative courses of group I patients were uneventful except for one who developed a subphrenic abscess. Five patients in group II developed bacterial infections, which were mostly pneumonias. Our findings indicate that splenectomy is an effective treatment approach with low morbidity and mortality in patients with refractory idiopathic AHA. It should, however, be considered cautiously in AHA patients with underlying systemic diseases because of its decreased efficacy and increased surgical morbidity in this subgroup. Am. J. Hematol. 61:98–102, 1999.

Treatment options for Graves disease: a cost-effectiveness analysis.

BACKGROUND First-line treatment for Graves disease is frequently 18 months of antithyroid medication (ATM). Controversy exists concerning the next best line of treatment for patients who have failed to achieve euthyroidism; options include lifelong ATM, radioactive iodine (RAI), or total thyroidectomy (TT). We aim to determine the most cost-effective option. STUDY DESIGN We performed a cost-effectiveness analysis comparing these different strategies. Treatment efficacy and complication data were derived from a literature review. Costs were examined from a health-care system perspective using actual Medicare reimbursement rates to an urban university hospital. Outcomes were measured in quality-adjusted life-years (QALY). Costs and effectiveness were converted to present values; all key variables were subjected to sensitivity analysis. RESULTS TT was the most cost-effective strategy, resulting in a gain of 1.32 QALYs compared with RAI (at an additional cost of 9,594 US dollars) and an incremental cost-effectiveness ratio of 7,240 US dollars/QALY. RAI was the least costly option at 23,600 US dollars but also provided the least QALY (25.08 QALY). Once the cost of TT exceeds 19,300 US dollars, the incremental cost-effectiveness ratio of lifelong ATM and TT reverse and lifelong ATM becomes the more cost-effective strategy at 15,000US dollars/QALY. CONCLUSIONS This is the first formal cost-effectiveness study in the US of the optimal treatment for patients with Graves disease who fail to achieve euthyroidism after 18 months of ATM. Our findings demonstrate that TT is more cost effective than RAI or lifelong ATM in these patients; this continues until the cost of TT becomes > 19,300 US dollars.

Trainee participation is associated with adverse outcomes in emergency general surgery: an analysis of the National Surgical Quality Improvement Program database.

Objective:To identify whether resident involvement affects clinically relevant outcomes in emergency general surgery. Background:Previous research has demonstrated a significant impact of trainee participation on outcomes in a broad surgical patient population. Methods:We identified 141,010 patients who underwent emergency general surgery procedures in the 2005–2010 Surgeons National Surgical Quality Improvement Program database. Because of the nonrandom assignment of complex cases to resident participation, patients were matched (1:1) on known risk factors [age, sex, inpatient status, preexisting comorbidities (obesity, diabetes, smoking, alcohol, steroid use, coronary artery disease, chronic renal failure, pulmonary disease)] and preoperatively calculated probability for morbidity and mortality. Clinically relevant outcomes were compared with a t or &khgr;2 test. The impact of resident participation on outcomes was assessed with multivariable regression modeling, adjusting for risk factors and operative time. Results:The most common procedures in the matched cohort (n = 83,790) were appendectomy (39.9%), exploratory laparotomy (8.8%), and adhesiolysis (6.6%). Trainee participation is independently associated with intra- and postoperative events, wound, pulmonary, and venous thromboembolic complications, and urinary tract infections. Conclusions:Trainee participation is associated with adverse outcomes in emergency general surgery procedures.

Active MMP‐2 effectively identifies the presence of colorectal cancer

Fully active MMP‐2 is expressed at such low levels in human tissues that studies often fail to confirm its value as a cancer marker despite strong associations with malignancy. Our study utilized careful extraction, accurate activity measurements, standardization to purified controls and a new statistical metric to determine whether active MMP‐2 is an effective indicator of colorectal cancer compared to pro‐MMP‐2 or pro‐MMP‐9. MMP‐2 and MMP‐9 activities were analyzed in matched normal and cancer samples from 269 patients by gelatin zymography, computer‐assisted image analysis, serial dilutions of strong samples and standardization to controls. An index of effect size was designed for comparative evaluation of active MMP‐2, pro‐MMP‐2 and pro‐MMP‐9 activities. For each gelatinase, mean activity and protein levels/mg soluble protein in normal mucosa and colorectal cancer were calculated for the first time with respect to commercial standards. Active MMP‐2 activity, detected in 99% of colorectal cancers, was higher in 95% of cancers (on average 10‐fold) than in normal mucosa. Levels of pro‐MMP‐2 and pro‐MMP‐9, but not active MMP‐9, activities were also significantly higher in cancers versus normal. However, active MMP‐2 activity provided the most effective test for the presence of cancer (p < 0.0.0001) with an effect size statistically significantly larger than for either pro‐MMP‐2 or pro‐MMP‐9. Receiver operating characteristic (ROC) curves demonstrated that a cut‐off for active MMP‐2 of >44 SDU activity/mg soluble protein (>180 pg/mg), which is three times mean normal levels, would permit detection of colorectal cancer with an estimated sensitivity of 84% and estimated specificity of 93%.

Caprini venous thromboembolism risk assessment permits selection for postdischarge prophylactic anticoagulation in patients with resectable lung cancer

OBJECTIVE Postoperative venous thromboembolism (VTE) creates an 8-fold increase in mortality after lung resection. About one third of postoperative VTEs occur after discharge. The Caprini risk assessment model has been used by other specialties to calculate the risk of a VTE. Patients deemed high risk by the model are candidates for prophylactic anticoagulation after discharge, reducing the VTE risk by 60%. Our primary aims were to determine the frequency of VTE events and evaluate whether the Caprini model could risk-stratify patients. METHODS Patients undergoing lung cancer resections during 2005 to 2013 were evaluated. Exclusion criteria were preoperative filter and therapeutic anticoagulation. A total of 232 patients were reviewed and Caprini scores calculated. Subjects were risk stratified into groups of low risk (0-4), moderate risk (5-8), and high risk (≥ 9). Occurrence of VTE events (deep vein thrombosis; pulmonary embolism) were identified by imaging. RESULTS The 60-day VTE incidence was 5.2% (12 of 232); 33.3% occurred postdischarge (n = 4). Half (6 of 12) were pulmonary emboli, 1 of which caused a death, in an inpatient with a score of 16. The VTE incidence increased with Caprini score. Scores in the low, moderate, and high risk groups were associated with a VTE incidence of 0%, 1.7%, and 10.3%, respectively. With a high risk score cutoff of 9, the sensitivity, specificity, and accuracy are 83.3%, 60.5%, and 61.6%, respectively. CONCLUSIONS One third of VTE events occurred after discharge. Postoperative VTE incidence was correlated with increasing Caprini scores. Patients in the high risk group had an incidence of 10.3%. Elevated scores may warrant extended chemoprophylaxis for patients after discharge.

Is splenectomy more dangerous for massive spleens

BACKGROUND Reports vary about whether risks are greater for removal of massive (> or = 1500 g) spleens than for smaller (< 1500 g) spleens. We sought to determine the hazards of splenectomy. METHODS We reviewed 223 consecutive adults with elective splenectomies for hematologic diseases. Morbidity and mortality rates were combined with published data to create a meta-analysis. RESULTS Patients with massive spleens are more likely to have postoperative complications (relative risk [RR] 2.1, 95% confidence interval [CI] 1.3 to 3.4; P = 0.003) and death (RR 4.7, 95% CI, 1.5 to 15.1; P = 0.01). However, when the investigation is restricted to comparable diagnoses, patients with massive spleens do not differ from those with smaller spleens regarding complications (RR 1.4, 95% CI, 0.8 to 2.7; P = 0.3) or mortality (RR 2.1, 95% CI, 0.5 to 9.7; P = 0.4). These observations are confirmed by metaanalysis. Furthermore, multivariate analysis indicts age as a critical risk of complications and death. CONCLUSIONS Increased age and underlying illness are the predominant factors associated with morbidity and mortality following splenectomy for hematologic disease. Adjusting for age and diagnosis, spleen size is not a hazard.

Evaluation of the Caprini Model for Venothromboembolism in Esophagectomy Patients.

BACKGROUND Patients undergoing esophagectomy for cancer are in the highest-risk group for venous thromboembolism, with a 7.3% incidence reported by the National Surgical Quality Improvement Program. Venothromboembolism (VTE) doubles esophagectomy mortality. The Caprini risk assessment model (RAM) is a method to stratify postoperative thromboembolism risk for consideration of prolonged preventive anticoagulation in higher-risk patients. Our aim was to examine the potential use of this model for reducing the VTE incidence in esophagectomy patients. METHODS The records of patients who underwent an esophagectomy by the thoracic surgery service at our institution between June 2005 and June 2013 were reviewed. The inclusion criteria were a diagnosis of esophageal cancer treated with esophagectomy (any approach) and with available 60-day postoperative follow-up. Exclusion criteria were the presence of an inferior vena cava filter or chronic anticoagulation therapy. The Caprini risk score and the number of VTE events were recorded retrospectively for each patient. RESULTS Seventy patients satisfied eligibility criteria. The VTE incidence was 14.3%. Patients with esophageal thromboembolism had a higher Caprini score distribution than patients without thromboembolism (p < 0.001). Adjusted logistic regression analysis demonstrated increased odds of VTE with increasing score (p < 0.05), with good discrimination. CONCLUSIONS In this first report examining the Caprini model categories in an esophagectomy population, the VTE incidence in true high-risk patients was high. From this retrospective calculation of risk and events, patients in the highest-risk Caprini group may benefit from an enhanced course of postoperative anticoagulation.

CORRELATING PRE-OPERATIVE VITAMIN D STATUS WITH POST-THYROIDECTOMY HYPOCALCEMIA

OBJECTIVE To examine the relationship between pre-operative vitamin D status and post-thyroidectomy hypocalcemia. METHODS Retrospective study examining 264 total and completion thyroidectomies conducted between 2007 and 2011. Subjects included had a recorded 25-hydroxyvitamin D (25[OH]D) level within 21 days prior to or 1 day following surgery, did not have a primary parathyroid gland disorder, and were not taking 1,25-dihydroxyvitamin D3 (calcitriol) prior to surgery. Some subjects were repleted with vitamin D pre-operatively if a low 25(OH)D level (typically below 20 ng/mL) was identified. Pre-operative 25(OH)D, concurrent neck dissection, integrity of parathyroid glands, final pathology, postoperative parathyroid hormone (PTH), calcium nadir and repletion, and length of stay were examined. RESULTS The mean pre-operative 25(OH)D for all subjects was 25 ng/mL, and the overall rate of post-operative hypocalcemia was 37.5%. Lower pre-operative 25(OH)D did not predict postoperative hypocalcemia (P = .96); however, it did predict the need for postoperative 1,25-dihydroxyvitamin D3 administration (P = .01). Lower postoperative PTH levels (P = .001) were associated with postoperative hypocalcemia. CONCLUSION Pre-operative 25(OH)D did not predict a postoperative decrease in serum calcium, although it did predict the need for 1,25-dihydroxyvitamin D3 therapy in hypocalcemic subjects. We recommend that 25(OH)D be assessed and, if indicated, repleted pre-operatively in patients undergoing total thyroidectomy.