George A. Sarosi

Disconnect Between Incidence of Nonperforated and Perforated Appendicitis: Implications for Pathophysiology and Management

Objective:Appendicitis has been declining in frequency for several decades. During the past 10 years, its preoperative diagnosis has been made more reliable by improved computed tomography (CT) imaging. Thresholds for surgical exploration have been lowered by the increased availability of laparoscopic exploration. These innovations should influence the number of appendectomies performed in the United States. We analyzed nationwide hospital discharge data to study the secular trends in appendicitis and appendectomy rates. Methods:All appendicitis and appendiceal operations reported to the National Hospital Discharge Survey (NHDS) 1970–2004 were classified as perforated, nonperforated, negative, and incidental appendectomies and analyzed over time and by various demographic measures. Secular trends in the population-based incidence rates of nonperforated and perforated appendicitis and negative and incidental appendectomy were examined. Results:Nonperforated appendicitis rates decreased between 1970 and 1995 but increased thereafter. The 25-year decreasing trend was accounted for almost entirely by a decreasing incidence in the 10–19 year age group. The rise after 1995 occurred in all age groups above 5 years and paralleled increasing rates of CT imaging and laparoscopic surgery on the appendix. Since 1995 the negative appendectomy rate has been falling, especially in women, and incidental appendectomies, frequent in prior decades, have been rarely performed. Despite these large changes, the rate of perforated appendicitis has increased steadily over the same period. Although perforated and nonperforated appendicitis rates were correlated in men, they were not significantly correlated in women nor were there significant negative correlations between perforated and negative appendectomy rates. Conclusion:The 25-year decline in nonperforated appendicitis and the recent increase in appendectomies coincident with more frequent use of CT imaging and laparoscopic appendectomies did not result in expected decreases in perforation rates. Similarly, time series analysis did not find a significant negative relationship between negative appendectomy and perforation rates. This disconnection of trends suggests that perforated and nonperforated appendicitis may have different pathophysiologies and that nonoperative management with antibiotic therapy may be appropriate for some initially nonperforated cases. Further efforts should be directed at identifying preoperative characteristics associated with nonperforating appendicitis that may eventually allow surgeons to defer operation for those cases of nonperforating appendicitis that have a low perforation risk.

Subcellular targeting of oxidants during endothelial cell migration

Endogenous oxidants participate in endothelial cell migration, suggesting that the enzymatic source of oxidants, like other proteins controlling cell migration, requires precise subcellular localization for spatial confinement of signaling effects. We found that the nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase adaptor p47phox and its binding partner TRAF4 were sequestered within nascent, focal complexlike structures in the lamellae of motile endothelial cells. TRAF4 directly associated with the focal contact scaffold Hic-5, and the knockdown of either protein, disruption of the complex, or oxidant scavenging blocked cell migration. An active mutant of TRAF4 activated the NADPH oxidase downstream of the Rho GTPases and p21-activated kinase 1 (PAK1) and oxidatively modified the focal contact phosphatase PTP-PEST. The oxidase also functioned upstream of Rac1 activation, suggesting its participation in a positive feedback loop. Active TRAF4 initiated robust membrane ruffling through Rac1, PAK1, and the oxidase, whereas the knockdown of PTP-PEST increased ruffling independent of oxidase activation. Our data suggest that TRAF4 specifies a molecular address within focal complexes that is targeted for oxidative modification during cell migration.

The association of pretreatment health-related quality of life with surgical complications for patients undergoing open surgical resection for colorectal cancer.

Objective: The purpose of this study was to define the association between pretreatment health-related quality of life (HRQL) and surgical complications for patients with colorectal cancer. Summary Background Data: For patients with colorectal cancer, surgical complications arise from an interaction between underlying medical comorbidity, colorectal cancer severity, and quality and type of treatment provided. Measurement of HRQL provides a summarization of well-being in the context of medical comorbidity and colorectal cancer severity. The summarization of these factors may be useful in prospective risk assessment of patients about to undergo surgery for colorectal cancer. Methods: A single-institution, prospective, cohort study of patients with colorectal adenocarcinoma was performed from August 1, 1999, to March 31, 2002. Before treatment, all participants completed Medical Outcomes Survey SF-36 (SF-36); after the first year of the study, patients also completed the colorectal cancer module of the Functional Assessment of Cancer Therapy survey (FACT-C). Information was collected on demographics, treatment, tumor variables, and complications. Results: Ninety-seven patients have undergone open resection of their colorectal cancer. All patients completed SF-36; 65 completed FACT-C. Thirty patients (31%) experienced complications, including 4 (4%) deaths. Age, race, albumin level, American Society of Anesthesia class, specialty surgical training, tumor location, and stage were not associated with complications in univariate analysis. Patients experiencing surgical complications had significantly lower HRQL scores on SF-36 Social Functioning, General Health Perception, and Mental Health Index scales as well as the Mental Health Component summary score. FACT-C Social/Family, Emotional, Functional Well-Being scores, and the Colorectal Cancer Concerns score were also significantly lower for patients sustaining complications. When these HRQL scales were examined in a multivariate model including albumin level, tumor location, and ASA class, SF-36 Social Functioning (Odds Ratio [OR] = 0.98; 95% Confidence Interval [CI] = 0.97–0.99) and FACT-C Colorectal Cancer Concerns (OR = 0.89; 95% CI = 0.79–0.99) scales retained a significant association with complications. Conclusions: Pretreatment HRQL scores as measured by several scales of SF-36 and FACT-C were significantly associated with complications. Future studies should concentrate on defining the predictive role of HRQL in determining surgical outcome for patients with colorectal cancer.

Association of viral infection and appendicitis.

HYPOTHESIS What causes appendicitis is not known; however, studies have suggested a relationship between viral diseases and appendicitis. Building on evidence of cyclic patterns of appendicitis with apparent outbreaks consistent with an infectious etiology, we hypothesized that there is a relationship between population rates of appendicitis and several infectious diseases. DESIGN Epidemiologic study. SETTING The National Hospital Discharge Survey PATIENTS Estimated US hospitalized population. MAIN OUTCOME MEASURES International Classification of Diseases, Ninth Revision, Clinical Modification discharge diagnosis codes of the National Hospital Discharge Survey were queried from 1970 to 2006 to identify admissions for appendicitis, influenza, rotavirus, and enteric infections. Cointegration analysis of time series data was used to determine if the disease incidence trends for these various disease entities varied over time together. RESULTS Rates of influenza and nonperforating appendicitis declined progressively from the late 1970s to 1995 and rose thereafter, but influenza rates exhibited more distinct seasonal variation than appendicitis rates. Rotavirus infection showed no association with the incidence of nonperforating appendicitis. Perforating appendicitis showed a dissimilar trend to both nonperforating appendicitis and viral infection. Hospital admissions for enteric infections substantially increased over the years but were not related to appendicitis cases. CONCLUSIONS Neither influenza nor rotavirus are likely proximate causes of appendicitis given the lack of a seasonal relationship between these disease entities. However, because of significant cointegration between the annual incidence rates of influenza and nonperforated appendicitis, it is possible that these diseases share common etiologic determinates, pathogenetic mechanisms, or environmental factors that similarly affect their incidence.

Postoperative colorectal cancer surveillance.

The postoperative surveillance of patients who have undergone definitive initial therapy for colorectal cancer (CRC) is a topic of considerable controversy. The controversy exists largely because it has been difficult to prove a survival advantage for asymptomatic patients participating in posttreatment surveillance, compared with symptom-directed surveillance. For a benefit in survival to be realized for a surveillance program, it is essential not only that recurrent disease be identified, but also that potentially curative treatment options be available. Given this linkage, a surveillance program must be judged not only by its ability to identify disease recurrence, but also by the merits of available therapy for recurrent disease. The purpose of this article is to review the literature to familiarize the physician with the available data related to the possible benefits of surveillance both in terms of identification of disease and the curative treatment options for recurrent CRC.

The effect of tumor necrosis factor-α on microvascular permeability in an isolated, perfused lung

This study examines the hypotheses that TNF-&agr; causes a dose-dependent increase in the microvascular permeability of ex vivo buffer perfused lungs that is quantitatively similar to that caused by lipopolysaccharide (LPS) or thromboxane A2 (TxA2). We also postulated that TNF-&agr; potentiates the effect of interleukin-1&bgr; (IL-1&bgr;) or TxA2 receptor activation on pulmonary microvascular permeability. Lungs harvested from Wistar rats were perfused ex vivo with Krebs-Henseleit buffer containing 0, 10, 100, or 1000 ng/mL recombinant rat TNF-&agr;. Twenty minutes later pulmonary microvascular permeability was determined by measuring the capillary filtration coefficient (Kf) using a gravimetric technique. The effect of TNF-&agr; (100 ng/mL) on pulmonary Kf was compared with that of lungs exposed to LPS (400 &mgr;g/mL; E. coli 0111:B4) or a TxA2 receptor agonist (U-46619; 7 × 10−8). In other experiments, perfused lungs were exposed to TNF-&agr; plus IL-1&bgr; (1 ng/mL) or TNF-&agr; plus U-46619 after which Kf was measured. Exposure of ex vivo buffer perfused lungs to 10 − 1000 ng/mL TNF-&agr; had no effect on Kf whereas LPS and U-46619 was associated with a two- and six-fold increase in Kf, respectively (P < 0.05). The Kf of lungs exposed to TNF-&agr; plus IL-1 was similar to that of lungs exposed to TNF-&agr; alone. Lastly, the Kf of lungs exposed to TNF-&agr; plus U-46619 was not different than that of lungs exposed to U-46619 alone. In conclusion, TNF-&agr; at least when administered for a relatively brief period of time does not affect microvascular permeability in an isolated, buffer-perfused lung model.

Evaluation and management of patients with recurrent peptic ulcer disease after acid-reducing operations: A systematic review

This systematic review examines the evidence for commonly employed strategies of managing patients with recurrent ulcer disease after acid-reducing operations. Particular attention is given to recent evidence relating Helicobacterpylori (H. pylori) and nonsteroidal anti-inflammatory drugs (NSAIDs) to ulcer recurrence after operative therapy. MED LINE word searches of the literature from 1966 to 2001 identified 895 articles that cross-reference the terms “peptic ulcer disease (PUD),” “surgery,” and “recurrence.” Articles were selected for systematic review of evidence relating incomplete vagotomy, NSAIDs, and H. pylori to postoperative ulcer recurrence and evidence supporting common medical and surgical strategies. The relationship between incomplete vagotomy and recurrent ulcer disease is suggested by randomized controlled trials and well-designed prospective case series. The evidence that NSAID use is an important pathogenic factor in recurrent ulcer disease includes the relationship between NSAIDs and primary PUD, the occurrence of NSAID-induced ulcers in patients taking proton pump inhibitors, and case series demonstrating virulent ulcer disease in patients taking aspirin despite prior acid-reducing operations. The relationship between H. pylori infection and postoperative ulcer recurrence remains uncertain despite multiple controlled trials and well-designed case series that have documented high rates of H. pylori infection in postoperative patients. The initial management of patients with recurrent ulcer disease after acid-reducing operations consists of a protein pump inhibitor or a histamine-2 receptor antagonist and antibiotics directed at H. pylori, if present. Evidence for this regimen includes prospective randomized trials demonstrating the efficacy of cimetidine in healing ulcers after acid-reducing operations and prospective, randomized studies documenting the efficacy of histamine-2 receptor antagonists and protein pump inhibitors in the management of patients with primary PUD. The critical role that H. pylori infection plays in primary PUD and the minimal risks associated with H. pylori eradication strongly support the initiation of antibiotic therapy when H. pylori is present. The principal indication for operative management of recurrent PUD is the occurrence of ulcer complications that cannot be managed by medical or endoscopic means. The operative management of patients with failed acid-reducing operations is based on ulcer recurrence rates and morbidity and mortality rates in randomized and nonrandomized prospective trials of patients with primary PUD and retrospective case series of patients undergoing remedial operative procedures after various failed acid-reducing operations.