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Accurate and clinically practical methods for measuring the progress of acute wound healing is necessary before interventions designed to optimize and even accelerate acute wound healing can be applied. Complete wound closure rates and operative wound closure severity are irrelevant to most acute wounds since most are closed at the time of primary tissue repair and remain closed throughout healing. Analogous to chronic wound closure, the rate of increase of incision tensile strength progressively decreases as time passes and 100% unwounded tissue strength is never achieved making the endpoint definition of 'healed' vague. Conceptualizing acute wound healing in terms of its design elements with reintegration into a final outcome lends itself to the description of acute wound healing as a mathematical trajectory. Frequently such an equation is a rate expressing the change in an acute healing parameter, most often tensile strength, over time. Such an approach also normalizes misinterpretations in analysis or errors in theory developed by measuring healing parameters at fixed points in time. Distributions of fractional strength gain times (e.g., 85% normal strength) can be determined using statistical methodology similar that used for failure time of survival analysis. Preclinical studies show that acute wound healing trajectories can be shifted to the left from a 'normal' or 'impaired' curve to an accelerated or more 'ideal' curve. A useful method for measuring acute wound healing outcomes is therefore required before the basic science of acute wound healing is inevitably applied to the problem of acute surgical wounds. [ABSTRACT FROM AUTHOR]

Objective: This systematic review aims to assess what is known about convalescence following abdominal surgery. Through a review of the basic science and clinical literature, we explored the effect of physical activity on the healing fascia and the optimal timing for postoperative activity., Background: Abdominal surgery confers a 30% risk of incisional hernia development. To mitigate this, surgeons often impose postoperative activity restrictions. However, it is unclear whether this is effective or potentially harmful in preventing hernias., Methods: We conducted 2 separate systematic reviews using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The first assessed available basic science literature on fascial healing. The second assessed available clinical literature on activity after abdominal surgery., Results: Seven articles met inclusion criteria for the basic science review and 22 for the clinical studies review. The basic science data demonstrated variability in maximal tensile strength and time for fascial healing, in part due to differences in layer of abdominal wall measured. Some animal studies indicated a positive effect of physical activity on the healing wound. Most clinical studies were qualitative, with only 3 randomized controlled trials on this topic. Variability was reported on clinician recommendations, time to return to activity, and factors that influence return to activity. Interventions designed to shorten convalescence demonstrated improvements only in patient-reported symptoms. None reported an association between activity and complications, such as incisional hernia., Conclusions: This systematic review identified gaps in our understanding of what is best for patients recovering from abdominal surgery. Randomized controlled trials are crucial in safely optimizing the recovery period., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

This new paradigm revolves around meticulous wound bed preparation to allow the wound to proceed to endogenous healing or to set the stage for successful wound closure with autologous tissue.

Background: Current data addressing the role of robotic surgery for the management of colorectal disease are primarily from single-institution and case-matched comparative studies as well as administrative database analyses. The purpose of this study was to compare minimally invasive surgery outcomes using a large regional protocol-driven database devoted to surgical quality, improvement in patient outcomes, and cost-effectiveness., Methods: This is a retrospective cohort study from the prospectively collected Michigan Surgical Quality Collaborative registry designed to compare outcomes of patients who underwent elective laparoscopic, hand-assisted laparoscopic, and robotic colon and rectal operations between July 1, 2012 and October 7, 2014. We adjusted for differences in baseline covariates between cases with different surgical approaches using propensity score quintiles modeled on patient demographics, general health factors, diagnosis, and preoperative co-morbidities. The primary outcomes were conversion rates and hospital length of stay. Secondary outcomes included operative time, and postoperative morbidity and mortality., Results: A total of 2735 minimally invasive colorectal operations met inclusion criteria. Conversion rates were lower with robotic as compared to laparoscopic operations, and this was statistically significant for rectal resections (colon 9.0 vs. 16.9%, p < 0.06; rectum 7.8 vs. 21.2%, p < 0.001). The adjusted length of stay for robotic colon operations (4.00 days, 95% CI 3.63-4.40) was significantly shorter compared to laparoscopic (4.41 days, 95% CI 4.17-4.66; p = 0.04) and hand-assisted laparoscopic cases (4.44 days, 95% CI 4.13-4.78; p = 0.008). There were no significant differences in overall postoperative complications among groups., Conclusions: When compared to conventional laparoscopy, the robotic platform is associated with significantly fewer conversions to open for rectal operations, and significantly shorter length of hospital stay for colon operations, without increasing overall postoperative morbidity. These findings and the recent upgrades in minimally invasive technology warrant continued evaluation of the role of the robotic platform in colorectal surgery.

Primary ventral hernias and ventral incisional hernias have been a challenge for surgeons throughout the ages. In the current era, incisional hernias have increased in prevalence due to the very high number of laparotomies performed in the 20(th) century. Even though minimally invasive surgery and hernia repair have evolved rapidly, general surgeons have yet to develop the ideal, standardized method that adequately decreases common postoperative complications, such as wound failure, hernia recurrence and pain. The evolution of laparoscopy and ventral hernia repair will be reviewed, from the rectoscopy of the 4(th) century to the advent of laparoscopy, from suture repair to the evolution of mesh reinforcement. The nuances of minimally invasive ventral and incisional hernia repair will be summarized, from preoperative considerations to variations in intraoperative practice. New techniques have become increasingly popular, such as primary defect closure, retrorectus mesh placement, and concomitant component separation. The advent of robotics has made some of these repairs more feasible, but only time and well-designed clinical studies will tell if this will be a durable modality for ventral and incisional hernia repair.

Purpose: Our objective was to assess the relationship between high blood glucose levels (BG) in the early postoperative period and the incidence of surgical site infections (SSIs), sepsis, and death following colorectal operations., Methods: The Michigan Surgical Quality Collaborative database was queried for colorectal operations from July 2012 to December 2013. Normoglycemic (BG < 180 mg/dL) and hyperglycemic (BG ≥ 180 mg/dL) groups were defined by using the highest BG within the first 72 h postoperatively. Outcomes of interest included the incidence of superficial, deep, and organ/space SSIs, sepsis, and death within 30 days. Initial unadjusted analysis was followed by propensity score matching and multiple logistic regression modeling after adjusting for significant predictors. Separate analyses were performed for previously diagnosed diabetic and non-diabetic patients., Results: A total of 5145 cases met inclusion criteria, of which 1072 were diabetic. For diabetic patients, there was a marginally significant association between high BG and superficial SSI in the unadjusted analysis (OR = 1.75, p = 0.056), but not in the adjusted analysis (OR = 1.35, p = 0.39). There was no significant relationship between elevated BG and deep SSI, organ/space SSI, sepsis, or death among diabetic patients. For non-diabetic patients, there was a significant association between high BG and superficial SSI (OR = 1.53, p = 0.03), sepsis (OR = 1.61, p < 0.01), and death (OR = 2.26, p < 0.01), but not deep or organ/space SSI., Conclusions: Following colorectal operations, superficial SSI, sepsis, and death are associated with postoperative serum hyperglycemia in patients without diabetes, but not those with diabetes. Vigilant postoperative BG monitoring is critical for all patients undergoing colorectal surgery.

Background: The role of hepato-imino diacetic acid scan (HIDA) in the diagnosis of acute cholecystitis remains controversial when compared with the more commonly used abdominal ultrasound (AUS)., Methods: The diagnostic imaging workup of 1,217 patients who presented to the emergency department at a single hospital with acute abdominal pain and suspicion of acute cholecystitis was reviewed to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AUS and HIDA., Results: In patients undergoing both imaging modalities, HIDA had significantly higher sensitivity (90.7% vs 64.0%, P < .001) and specificity (71.4% vs 58.4%, P = .005) than AUS for the diagnosis of acute cholecystitis. Additionally, PPV and NPV of HIDA (56.2% and 95.0%, respectively) were higher than PPV and NPV of AUS (38.4% and 80.0%, respectively) when both imaging modalities were used for the same patient., Conclusion: In adults with acute abdominal pain, HIDA significantly increases the accuracy of the correct diagnosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs have become an important component of narcotic-sparing postoperative pain management protocols. However, conflicting evidence exists regarding the adverse association of nonsteroidal anti-inflammatory drug use with intestinal anastomotic healing in colorectal surgery., Objective: This study compares patients receiving nonsteroidal anti-inflammatory drugs on postoperative day 1 with patients who did not receive nonsteroidal anti-inflammatory drugs with regard to the occurrence of anastomotic leaks., Design: This is a retrospective study from a protocol-driven prospectively collected statewide database. A propensity score model was used to adjust for differences between the groups in patient demographics, characteristics, comorbidities, and laboratory values., Settings: The multicenter data set used in this analysis represents a variety of academic and community hospitals within the state of Michigan from July 2012 through February 2014., Patients: Nonpregnant patients over the age of 18 who underwent colon and rectal surgery with bowel anastomosis were selected., Main Outcome Measures: Occurrence of anastomotic leak, composite surgical site infection, sepsis, and death within 30 days of surgery were the primary outcomes measured., Results: A total of 4360 patients met inclusion criteria, of which 1297 (29.7%) received nonsteroidal anti-inflammatory drugs and 3063 (70.3%) did not receive nonsteroidal anti-inflammatory drugs. There was no statistically significant difference between the 2 groups in the proportion of cases with anastomotic leak (OR, 1.33; CI, 0.86-2.05; p = 0.20), composite surgical site infection (OR, 1.26; CI, 0.96-1.66; p = 0.09), or death within 30 days (OR, 0.58; CI, 0.28-1.19; p = 0.14). There was a significantly greater risk of sepsis for patients given nonsteroidal anti-inflammatory drugs than for those patients not given nonsteroidal anti-inflammatory drugs (OR, 1.47; CI, 1.05-2.06; p = 0.03)., Limitations: This is a nonrandomized study performed retrospectively, and it is based on data collected only within a subset of hospitals in the state of Michigan., Conclusions: No statistically significant increase in the proportion of patients with anastomotic leak was observed when prescribing nonsteroidal anti-inflammatory drugs for analgesia in the early postoperative period for patients undergoing elective colorectal surgery. Unexpectedly, there was an increased risk of sepsis that warrants further investigation (see video, Supplemental Digital Content 1, http://links.lww.com/DCR/A192, for a synopsis of this study).

Background: Incisional hernias are a complication in 10% of all open abdominal operations and can result in substantial morbidity. The purpose of this study was to determine whether inhibiting abdominal muscle contraction influences incisional hernia formation during the fascial healing after laparotomy. We hypothesized that decreasing the deformation of the abdominal musculature would decrease the size or occurrence of an incisional hernia., Methods: Using an established rat model for incisional hernia, a laparotomy through the linea alba was closed with 1 mid-incision, fast-absorbing suture. Three groups were compared: a sham group (sham; n = 6) received no laparotomy, and the saline hernia (SH; n = 6) and Botox hernia (BH; n = 6) groups were treated once with equal volumes of saline or botulinum toxin (Botox, Allergan) before the incomplete laparotomy closure. On postoperative day 14, the abdominal wall was examined for herniation and adhesions, and contractile forces were measured for abdominal wall muscles., Results: No hernias developed in the sham rats. Rostral hernias developed in all SH and BH rats. Caudal hernias developed in all SH rats, but in only 50% of the BH rats. Rostral hernias in the BH group were 35% shorter and 43% narrower compared with those in the SH group (P < .05). The BH group had weaker abdominal muscles compared with the sham and SH groups (P < .05)., Conclusion: In our rat model, partial paralysis of abdominal muscles decreases the number and size of incisional hernias. These results suggest that contractions of the abdominal wall muscle play a role in the pathophysiology of the formation of incisional hernias., (Published by Elsevier Inc.)

We compared fascial wounds repaired with non-cross-linked intact porcine-derived acellular dermal matrix versus primary closure in a large-animal hernia model. Incisional hernias were created in Yucatan pigs and repaired after 3 weeks via open technique with suture-only primary closure or intraperitoneally placed porcine-derived acellular dermal matrix. Progressive changes in mechanical and biological properties of porcine-derived acellular dermal matrix and repair sites were assessed. Porcine-derived acellular dermal matrix-repaired hernias of additional animals were evaluated 2 and 4 weeks post incision to assess porcine-derived acellular dermal matrix regenerative potential and biomechanical changes. Hernias repaired with primary closure showed substantially more scarring and bone hyperplasia along the incision line. Mechanical remodeling of porcine-derived acellular dermal matrix was noted over time. Porcine-derived acellular dermal matrix elastic modulus and ultimate tensile stress were similar to fascia at 6 weeks. The biology of porcine-derived acellular dermal matrix-reinforced animals was more similar to native abdominal wall versus that with primary closure. In this study, porcine-derived acellular dermal matrix-reinforced repairs provided more complete wound healing response compared with primary closure.

Background: Incisional hernia is the most common complication of abdominal surgery leading to reoperation. In the United States, 200,000 incisional hernia repairs are performed annually, often with significant morbidity. Obesity is increasing the risk of laparotomy wound failure., Methods: We used a validated animal model of incisional hernia formation. We intentionally induced laparotomy wound failure in otherwise normal adult, male Sprague-Dawley rats. Radio-opaque, metal surgical clips served as markers for the use of x-ray images to follow the progress of laparotomy wound failure. We confirmed radiographic findings of the time course for mechanical laparotomy wound failure by necropsy., Results: Noninvasive radiographic imaging predicts early laparotomy wound failure and incisional hernia formation. We confirmed both transverse and craniocaudad migration of radio-opaque markers at necropsy after 28 d that was uniformly associated with the clinical development of incisional hernias., Conclusions: Early laparotomy wound failure is a primary mechanism for incisional hernia formation. A noninvasive radiographic method for studying laparotomy wound healing may help design clinical trials to prevent and treat this common general surgical complication., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To determine whether primary or mesh herniorrhaphy reverses abdominal wall atrophy and fibrosis associated with hernia formation., Background: We previously demonstrated that hernia formation is associated with abdominal wall atrophy and fibrosis after 5 weeks in an animal model., Methods: A rat model of chronic incisional hernia was used. Groups consisted of uninjured control (UC, n = 8), sham repair (SR, n = 8), unrepaired hernia (UR, n = 8), and 2 repair groups: primary repair (PR, n = 8) or tension-free polypropylene mesh repair (MR, n = 8) hernia repair on postoperative day (POD) 35. All rats were killed on POD 70. Intact abdominal wall strips were cut perpendicular to the wound for tensiometric analysis. Internal oblique muscles were harvested for fiber type and size determination., Results: No hernia recurrences occurred after PR or MR. Unrepaired abdominal walls significantly demonstrated greater stiffness, increased breaking and tensile strengths, yield load and yield energy, a shift to increased type IIa muscle fibers than SR (15.9% vs 9.13%; P < 0.001), and smaller fiber cross-sectional area (CSA, 1792 vs 2669 μm(2); P < 0.001). PR failed to reverse any mechanical changes but partially restored type IIa fiber (12.9% vs 9.13% SR; P < 0.001 vs 15.9% UR; P < 0.01) and CSA (2354 vs 2669 μm(2) SR; P < 0.001 vs 1792 μm(2) UR; P < 0.001). Mesh-repaired abdominal walls demonstrated a trend toward an intermediate mechanical phenotype but fully restored type IIa muscle fiber (9.19% vs 9.13% SR; P > 0.05 vs 15.9% UR; P < 0.001) and nearly restored CSA (2530 vs 2669 μm(2) SR; P < 0.05 vs 1792 μm(2) UR; P < 0.001)., Conclusions: Mesh herniorrhaphy more completely reverses atrophic abdominal wall changes than primary herniorrhaphy, despite failing to restore normal anatomic muscle position. Techniques for hernia repair and mesh design should take into account abdominal wall muscle length and tension relationships and total abdominal wall compliance.

Background: Obesity increases the risk of laparotomy dehiscence and incisional hernia. The aim of this study was to measure the biological effect of obesity on laparotomy wound healing and the formation of incisional hernias., Methods: Normal-weight Sprague-Dawley (SD) and obese Zucker rats were used in an established laparotomy wound healing and incisional ventral hernia model. Mechanical testing was performed on abdominal wall strips collected from laparotomy wounds. Hernia size was measured by digital imaging. Picrosirius staining for collagen isoforms was observed with polarized microscopy. Abdominal wall fibroblasts were cultured to measure collagen matrix remodeling and proliferation., Results: Laparotomy wound healing was significantly impaired in obese rats. Mechanical strength was lower than in normal-weight rats. Yield load was reduced in the obese group at all time points. Picrosirius red staining showed increased immature type III collagen content and disorganized type I collagen fibers within laparotomy wounds of obese rats. Wound size was significantly larger in the obese group. Collagen matrix remodeling was impaired with fibroblasts from obese rats, but there was no difference in fibroblast proliferation between the obese and normal-weight groups., Conclusions: We observed for the first time that laparotomy wound healing is impaired in obese rats. The recovery of laparotomy wound strength is delayed due to abnormal collagen maturation and remodeling, possibly due to a defect in fibroblast function. Strategies to improve outcomes for laparotomy wound healing in obese patients should include correcting the wound healing defect, possibly with growth factor or cell therapy.

Background: Laparotomy wound load forces are reduced when dehiscence and incisional hernia formation occur. The purpose of this study was to determine the effects of strain loss on abdominal fascial fibroblast proliferation, orientation, and collagen compaction function., Methods: Cultured rat linea alba fibroblasts were subjected to continuous cyclic strain (CS), CS interrupted at 24 or 48 hours followed by culture at rest (IS-24 and IS-48) or were cultured without mechanical strain (NS). Cell number was measured and images analyzed for cell orientation. Fibroblasts from these groups were seeded onto the surface of (FPCL-S) or mixed into (FPCL-M) a collagen gel matrix and gel area was measured over time., Results: Continuous strain stimulated proliferation when compared with the nonstrained cells. The loss of strain (IS) delayed proliferation compared with CS throughout (P < .05). CS fibroblasts aligned perpendicular to the direction of strain within 12 hours. Within 12 hours of strain loss, IS-48 fibroblasts became significantly less aligned (P < .0001), and seemed similar to the randomly organized NS fibroblasts 48 hours after strain removal. The CS and IS-24 groups demonstrated faster and greater overall FPCL-M compaction than both the IS-48 and NS groups (P < .0002). The CS group contracted the gel faster than the NS group in FPCL-S (P = .029)., Conclusion: Mechanical strain rapidly induces a proliferative, morphologic, and functional response in abdominal wall fibroblasts that is dependent on the continued presence of the strain signal and quickly lost when the load force is removed. The loss of wound edge tension that occurs during laparotomy wound separation and hernia formation may contribute to impaired wound healing through loss of a key stimulatory mechanical signal with important implications for abdominal wall reconstruction., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objectives: Implanted mesh for inguinal hernia repair is often difficult to visualize with gray scale sonography and may present without the knowledge of the sonographer. We sought to evaluate the utility of the twinkling artifact produced by inguinal mesh to assist in mesh identification., Methods: Two reviewers evaluated focused sonographic examinations of 44 inguinal regions, 24 of which had implanted inguinal mesh. The sonographic examinations consisted of static gray scale and color Doppler images with both linear and curvilinear array transducers. The presence of the twinkling artifact and visibility of the mesh were graded on a 4-point visibility scale., Results: Inguinal mesh was not easily identified on gray scale imaging using either the curvilinear array (P = .5) or linear array (P = .5) transducer. The mesh was definitely seen in 3 of 24 inguinal regions using the linear array transducer and 2 of 24 inguinal regions using the curvilinear array transducer. In 79% of inguinal regions with mesh, the twinkling artifact was produced with the curvilinear array transducer only. The artifact was not elicited when using the linear array transducer. With the use of the curvilinear array transducer and the presence of the twinkling artifact, there was a significant chance of correctly identifying the presence of mesh (P < .005) in the entire study group., Conclusions: Standard gray scale imaging alone is not reliable when identifying inguinal mesh. The twinkling artifact was present in 79% of inguinal regions with mesh when evaluated with a low-frequency curvilinear array transducer.

Objective: The purposes of this study were (1) to review the sonographic in vitro and in vivo appearances of mesh for surgical repair of abdominal wall hernias, (2) to describe sonographic techniques and discuss the limitations of sonography in evaluation of mesh hernia repair, and (3) to illustrate common complications after mesh repair shown with sonography., Methods: We identified interesting cases from the musculoskeletal sonographic database as well as from the teaching files of the authors, with surgical or other cross-sectional imaging corroboration., Results: A compilation of the sonographic appearances of mesh used for anterior abdominal wall and inguinal hernia repair and complications diagnosable by sonography is presented., Conclusions: Sonography can be effective for evaluation of mesh and complications after mesh repair of anterior abdominal wall and inguinal hernias.

Objective: Growth factors demonstrate mixed results improving wound healing. Amnion-derived multipotent cells release physiologic levels of growth factors and tissue inhibitors of metalloproteinases. This solution was tested in models of acute and chronic wound healing., Methods: Acute model: Sprague-Dawley rats underwent laparotomy incisions. The midline fascia was primed with phosphate-buffered saline, unconditioned media, or amnion-derived cellular cytokine suspension prior to incision. Breaking strength of laparotomy wounds was tested with an Instron tensiometer. Incisional hernia formation was measured after 28 days. Chronic model: Chronic, infected granulating wounds were produced in rats by excising full thickness burn eschars inoculated with Escherica coli. Granulating wounds were treated with unconditioned media or amnion-derived cellular cytokine suspension. Treatments were applied either on day 0 and day 7 or day 0 and then every other day. Wounds were traced every 72 hours and biopsied for quantitative bacteriology., Results: Acute model: Priming with amnion-derived cellular cytokine suspension increased the breaking strength of laparotomy incisions in comparison with phosphate-buffered saline or unconditioned media (P < .05). Acute wound failure and incisional hernia formation was 100% in the phosphate-buffered saline and unconditioned media groups and 18% in the amnion-derived cellular cytokine suspension-treated group (P <.05). Chronic model: The rate of wound closure was accelerated in amnion-derived cellular cytokine suspension-treated chronic wounds (P < .05). Multidosing improved the effect., Conclusions: A physiologic solution of cytokines and tissue inhibitors of metalloproteinases improves healing in models of acute and chronic wounds. Such a cocktail can be produced from amnion-derived multipotent progenitor cells.

Abdominal wall hernias occur when tissue structure and function are lost at the load-bearing muscle, tendon, and fascial layer. The fundamental biologic mechanisms are primary fascial pathology or surgical wound failure. In both cases, cellular and extracellular molecular matrix defects occur. Primary abdominal wall hernias have been associated with extracellular matrix diseases. Incisional hernias and recurrent inguinal hernias more often involve a combination of technical and biologic limitations. Defects in wound healing and extracellular matrix synthesis contribute to the high incidence of incisional hernia formation following laparotomy.

Objective: Acute wound failure is a common complication following surgical procedures and trauma. Laparotomy wound failure leads to abdominal dehiscence and incisional hernia formation. Delayed recovery of wound-breaking strength is one mechanism for laparotomy wound failure. Early fascial wounds are relatively acellular, and there is a delay in the appearance of acute wound growth factors and cytokines. The objective of this study was to accelerate and improve laparotomy wound healing using amnion-derived multipotent cells (AMPs). AMPs' nonimmunogenic phenotype and relative abundance support its role as a cell therapy., Methods: AMPs were injected into the load-bearing layer of rat abdominal walls prior to laparotomy, and cell viability was confirmed. Wound mechanical properties were measured over 28 days. The incidence and severity of laparotomy wound failure was measured in an incisional hernia model., Results: AMP cells were viable in laparotomy wounds for at least 28 days and did not migrate to other tissues. Laparotomy wound-breaking strength was increased by postoperative day 7 following AMP therapy. AMP therapy reduced the incidence of hernia formation and the size of hernia defects. Histology suggested stimulated wound fibroplasia and angiogenesis., Conclusions: AMP cell therapy reduces the incidence of laparotomy wound failure by accelerating the recovery of wound-breaking strength. This results in fewer incisional hernias and smaller hernia defects.

Objective: The purpose of this article is to show the typical locations of anterior abdominal wall and inguinal region hernias and to illustrate their sonographic appearances and describe pitfalls in clinical diagnosis of hernias that may be resolved with sonography., Conclusion: Awareness of the expected locations of anterior abdominal wall hernias and potential clinical pitfalls allows an accurate diagnosis of a hernia and helps in differentiating a hernia from other abnormalities.

Objective: The purpose of this study is to measure abdominal wall myopathic histologic and mechanical changes during incisional herniation and its effect on incisional hernia repairs., Summary Background Data: Unloaded skeletal muscles undergo characteristic atrophic changes, including change in fiber type composition, decreased cross-sectional area, and pathologic fibrosis. We hypothesize that these atrophic changes decrease muscle elastic properties and may contribute to the high laparotomy wound failure rate observed following incisional hernia repair., Methods: A rat model of chronic incisional hernia formation was used. Failing midline laparotomy incisions developed into incisional hernias. Controls were uninjured and sham laparotomy (healed) groups. Internal oblique muscles were harvested for fiber typing, measurement of cross-sectional area, collagen deposition, and mechanical analysis. Mesh hernia repairs were performed on a second group of rats with chronic incisional hernias or acute anterior abdominal wall myofascial defects., Results: The hernia group developed lateral abdominal wall shortening and oblique muscle atrophy. This was associated with a change in the distribution of oblique muscle fiber types, decreased cross-sectional area, and pathologic fibrosis consistent with myopathic disuse atrophy. These muscles exhibited significant decreased extensibility and increased stiffness. The healed (sham) laparotomy group expressed an intermediate phenotype between the uninjured and hernia groups. Recurrent hernia formation was most frequent in the chronic hernia model, and hernia repairs mechanically disrupted at a lower force compared with nonherniated abdominal walls., Conclusions: The internal oblique muscles of the abdominal wall express a pattern of changes consistent with those seen in chronically unloaded skeletal muscles. The internal oblique muscles become fibrotic during herniation, reducing abdominal wall compliance and increasing the transfer of load forces to the midline wound at the time of hernia repair.

The fundamental mechanism for hernia formation is loss of the mechanical integrity of abdominal wall structural tissue that results in the inability to offset and contain intra-abdominal forces during valsalva and loading of the torso. There is evidence that genetic or systemic extracellular matrix disorders may predispose patients to hernia formation. There is also evidence that acute laparotomy wound failure leads to hernia formation and increases the risk of recurrent hernia disease. It may be that hernia formation is a heterogeneous disease, not unlike cancer, where one population of patients express an extracellular matrix defect leading to primary hernia disease, while other subsets of patients acquire a defective, chronic wound phenotype following failed laparotomy and hernia repairs. It is evident that an improved understanding of structural tissue matrix biology will lead to improved results following abdominal wall reconstructions.

Background: An improved understanding of load-bearing soft tissue repair suggests that the mechanism for the improved outcomes after alloplastic incisional herniorrhaphy involves more than simple tissue replacement or material strength. We test the hypothesis that postrepair abdominal wall elastic properties are most predictive of successful abdominal wall reconstruction., Methods: A rodent model of chronic incisional hernia formation was used. Midline incisional hernias were repaired primarily with suture (n = 24) or polypropylene mesh (n = 24). Rodents were sacrificed at serial postoperative time points over 60 days. Intact abdominal wall strips were cut perpendicular to the wound for tensiometric analysis. Biopsies of wound provisional matrix were obtained for biochemical analysis., Results: Recurrent incisional hernia formation was significantly decreased in the mesh-repair group, compared with the suture-repair group (5/24 vs 14/24, P = .02). Mesh-repaired abdominal walls demonstrated significantly more elongation (P < .01) and less stiffness (P < .01). Toughness was equal between wounds, although the suture-repaired wounds had increased recovery of tensile strength (P < .01). There were no significant differences in collagen deposition after postoperative day 7., Conclusions: Mesh incisional herniorrhaphy increases abdominal wall elastic properties as measured by increased elongation and reduced stiffness. Increased abdominal wall elasticity after incisional hernia repair in turn results in lower recurrence rates.

Early deep venous thrombosis (DVT) resolution is associated with neutrophil (PMN) influx. This study examined the role of PMNs in thrombus neovascularization and vein wall injury after DVT. A rat model of DVT by inferior vena cava (IVC) ligation was performed with control serum or rabbit anti-rat PMN serum administered perioperatively with sacrifice at 2 and 7 days. At 2 days, neutropenic rats had 1.6-fold larger thrombi (P = .04) and 1.4-fold higher femoral venous pressures by water manometry (P = .008) but no difference in thrombus neovascularization was observed. By 7 days, DVT sizes were similar, but vein wall injury persisted in the neutropenic rats with a 2.0-fold increase in vein wall stiffness by microtensiometry (P < .05), as well as a 1.2-fold increased thickness (P = .04). Collagen and profibrotic growth factors were significantly increased in neutropenic IVC at 7 days (all P < .05). Vein wall and intrathrombus uPA byWestern immunoblotting, and intrathrombus MMP-9 gelatinase activity were significantly less in neutropenic rats than controls (P < .001). Conversely, MMP-2 was significantly elevated in neutropenic IVC at 2 days after DVT. However, neutropenia induced 24 hours after DVT formation resulted in no significant increase in vein wall stiffness or collagen levels at 7 days, despite 1.4-fold larger thrombi (P < .05). These data suggest a critical early role for PMN in post DVT vein wall remodeling.

Background: Fascial wound failure alters the phenotype of the abdominal wall. This study introduces a novel animal model of progressive failure of the ventral abdominal wall fascia, which generates large incisional hernias., Material and Methods: A mechanistic model of incisional hernia was compared with a model of acute myofascial defect hernia repair. Using biological tissue repair markers, tensiometric measurements and recurrent hernia rate, we measured the mechanism by which incisional hernias regenerate abdominal wall structure and function after mesh and suture herniorrhaphy., Results: Recurrent incisional hernia formation was significantly increased after repairs of the hernia model, compared with the myofascial defect model (6/16 vs 0/16, P < .05). In the hernia model, there were significant decreases in the recovery of wound strength, energy, and extensibility before mechanical disruption, compared with the myofascial defect model. Unexpectedly, excision of fascial hernia wound edges did not significantly improve tissue repair outcomes in the hernia model group., Conclusions: Clinically accurate animal modeling can recreate the wound pathology expressed in mature incisional hernias. Progressive fascial wound failure decreases the fidelity of subsequent incisional hernia repair, compared with identically sized acute abdominal wall defect repairs. The mechanism appears to include decreased fascial wound strength and decreased tissue compliance after herniorrhaphy.

Hypothesis: Preemptive cholecystectomy in cardiac transplant patients with radiographic biliary pathology reduces the morbidity and mortality of biliary tract disease following heart transplantation compared with expectant management., Design and Setting: Institutional survey at the University of Washington, Seattle., Patients: Cardiac transplant recipients between January 1, 1992, and January 1, 2001. Main Outcome Measure Clinical course of patients who were diagnosed as having biliary tract disease following heart transplantation and were managed expectantly (observed) compared with the course of patients whose conditions were diagnosed and who underwent an operation., Results: Sixty (35.7%) of 168 cardiac transplant patients were evaluated for biliary tract pathologic condition. Of the 71.7% (43 of 60 patients) who had an abnormal radiographic evaluation, 46.5% (20 patients) had surgery on their biliary tract while the other patients were observed. Nine of the 23 patients who were followed up expectantly had cholelithiasis, 7 patients had gallbladder wall thickening, 5 patients had sludge in their gallbladder, and 2 had biliary dilatation. These patients were followed up for a mean +/- SD of 3.7 +/- 1.3 years; none developed biliary tract symptoms during this period. Cholecystectomies were completed for both emergent (7) and elective (14) indications. The mean +/- SD length of stay for patients who had emergent operations was 24.3 +/- 11.2 days, compared with 3.2 +/- 2.8 days for the patients who had elective operations. Seven (33%) of the 21 patients who had an operation had a significant complication and 1 patient died., Conclusions: These data suggest that the morbidity of an elective cholecystectomy in cardiac transplant patients is significant and equivalent to the morbidity associated with emergent procedures. Expectant management of patients with radiographic evidence of biliary tract pathology discovered after transplantation was safe in this series.

Abdominal wall fascial wound healing failure is a common clinical problem for general surgeons, manifesting in early postoperative fascial dehiscence as well as delayed development of incisional hernias. We previously reported that abdominal wall fascial incisions normally recover breaking strength faster than simultaneous dermal incisions in a rodent model. The accelerated fascial repair was associated with greater fibroblast cellularity within fascial wounds and increased wound collagen deposition. The current study was designed to determine whether accelerated fascial healing is the result of increased fascial fibroblast kinetic activity as measured by a more efficient fibroblast phenotype for binding to and remodeling a collagen matrix. Using a new model of abdominal wall repair, fibroblast cell cultures were developed from uninjured and wounded fascia and compared to dermal fibroblasts in order to define the fibroproliferative kinetic properties of abdominal wall fibroblasts. Fascial wound fibroblasts produced a more efficient and greater overall collagen lattice compaction compared to dermal fibroblasts. Acute fascial wound fibroblasts also showed enhanced cell proliferation compared to dermal fibroblasts but no significant differences in collagen production when normalized to cell number. These results suggest that fascial fibroblasts express distinct acute repair phenotypes and therefore a specific mechanism for fascial repair following injury.

Objective: We sought to reduce the high incidence of abdominal wall incisional hernias using sustained release growth factor therapy., Summary Background Data: Incisional hernias complicate 11% of abdominal wall closures, resulting in 200,000 incisional hernia repairs in the United States each year. Mechanical improvements alone in mesh, suture material, and surgical technique have failed to reduce the high rate of fascial wound failure., Methods: Sprague-Dawley rats underwent midline celiotomies that were closed with fast-absorbing suture to induce early biomechanical wound failure and incisional hernia formation. In primary wounds, fascial incisions were closed adjacent to a continuous release polygalactone polymer rod containing basic fibroblast growth factor (bFGF), no growth factor (control-rod), or without rods. In a second group, incisional hernias were repaired with either bFGF or control-rod therapy. Breaking strength was measured on postoperative day (POD) 7, and the incidence of incisional hernia formation was determined on POD 28., Results: Treatment with bFGF rods significantly increased fascial wound breaking strength. In the "hernia-prevention" experiments, incisional hernias developed in 90% of untreated incisions, 60% of control-rod incisions, and only 30% of bFGF-rod incisions (P < 0.05). In the "hernia-treatment" experiments, recurrent incisional hernias developed in 86% of control-rod incisions compared with only 23% of bFGF-rod treated incisions (P < 0.05). Immunohistochemistry demonstrated increased angiogenesis and collagen protein production in bFGF treated incisions., Conclusion: The treatment of abdominal fascial incisions with a sustained-release bFGF polymer significantly lowered the incidence of incisional hernias and the recurrence rate after repair.

Cytokine growth factor treatment of chronic wounds has met with mixed results. The chronic wound presents a hostile environment to peptides such as growth factors. Cytokine growth factors have not been studied extensively in acute wounds. However, incisional hernias are a major example of acute wound failure that has not been solved by various mechanical approaches. A biological approach to acute wound failure by use of cytokine growth factors may offer a new strategy. A rodent incisional hernia model was used. Seventy-six rats underwent 3-cm midline celiotomies and were closed with fine, fast-absorbing sutures to induce intentional acute wound failure. Group 1 received no other treatment. The midline fascia in Groups 2-10 was infiltrated with 100 microl of vehicle alone or vehicle containing various test cytokine growth factors. Necropsy was performed on postoperative day 28 and the wounds were examined for herniation. Incisional hernias developed in 83 percent (13/16) of untreated incisional and 88 percent (7/8) and 83 percent (5/6) of the two vehicle-treated incisions (PBS and carboxymethylcellulose). Hernia incidences were decreased by priming of the fascial incision with transforming growth factor-beta(2) (12%, 1/8), basic fibroblast growth factor (25%, 2/8) and interleukin-1 beta (50%, 3/6) (p < 0.05). Aqueous platelet-derived growth factor, becaplermin, insulin-like growth factor, and granulocyte macrophage-colony stimulating factor did not significantly decrease the incidence of acute wound failure (p > 0.05). A biological approach to acute wound failure as measured by incisional hernia formation can be useful in reducing the incidence of this complication. Transforming growth factor-beta(2), basic fibroblast growth factor, and interleukin 1 beta all eliminated or significantly reduced the development of incisional hernias in the rat model.

Acute wound healing failure is an important source of morbidity and mortality for surgical patients. Many incisional hernias, gastrointestinal anastomotic leaks, and vascular pseudoaneurysms occur despite patient optimization and standardized surgical technique. Modern surgical experience suggests that biologic and mechanical pathways overlap during "normal" acute wound healing. The cellular and molecular processes activated to repair tissue from the moment of injury are under the control of biologic and mechanical signals. Successful acute wound healing occurs when a dynamic balance is met between the loads placed across a provisional matrix and the feedback and feed-forward responses of repair cells.

Background: Approximately 200,000 incisional hernias are repaired annually in the United States. The high incidence (11-20%) and recurrence rate (24-54%) for incisional hernias have not changed appreciably in 75 years. Mechanical advances in suture material, incision orientation, and closure technique have failed to eliminate this common surgical complication. A biological approach to acute wound failure may offer a new strategy., Methods: A rodent incisional hernia model was used. Seventy rats underwent 5-cm midline celiotomies and were closed with fine, fast-absorbing sutures to induce intentional acute wound failure. Group 1 received no other treatment. The midline fascia in groups 2 and 3 was injected immediately prior to incision with 100 microl of vehicle alone or vehicle containing 1 microg of transforming growth factor beta(2) (TGF-beta(2)). Necropsy was performed on Postoperative Day 28 and the wounds were examined for herniation., Results: Incisional hernias developed in 88% (35/40) and 79% (11/14) of untreated incisions and those treated with vehicle alone. No hernias formed in the TGF-beta(2)-treated incisions (0/16, P < 0.05). Standard histology and immunohistochemistry demonstrated enhanced macrophage, lymphocyte, and fibroblast chemotaxis and increased collagen I and III production in TGF-beta(2) treated incisions., Conclusions: Treatment of abdominal wall fascial incisions with TGF-beta(2) prevented the development of incisional hernias in this rat model. TGF-beta(2) stimulated fascial macrophage and fibroblast chemotaxis as well as acute wound collagen production. A biological approach such as this may reduce the incidence of incisional hernia formation in humans., (Copyright 2001 Academic Press.)

Background: Optimal healing of the fascial layer is a necessary component of complete abdominal wall repair. The majority of acute wound healing studies have focused on the dermis. We designed a model of abdominal wall repair that, to our knowledge, for the first time simultaneously characterizes differences in the wound healing trajectories of the fascia and skin., Methods: Full-thickness dermal flaps were raised on the ventral abdominal walls of rats, and midline fascial celiotomies were completed. The dimensions of the flap were developed so as to have no detrimental effect on skin healing. The dermal flaps were replaced so that the fascial incisions would heal separately from the overlying skin incisions. Animals were killed 7, 14, and 21 days after operation and fascial and dermal wounds were harvested and tested for breaking strength. Fascial and dermal wounds were also compared histologically for inflammatory response, fibroplasia, and collagen staining., Results: Fascial wound breaking strength exceeded dermal wound breaking strength at all time points (9.16 +/- 2.17 vs 3.51 +/- 0.49 N at 7 days, P <.05). Fascial wounds also developed greater fibroblast cellularity and greater collagen staining 7 days after the incision. There was no difference in wound inflammatory response., Conclusions: Fascial incisions regain breaking strength faster than simultaneous dermal incisions. The mechanism for this appears to involve increased fascial fibroplasia and collagen production after acute injury.

Background: Abdominal wall wound failure remains a common surgical problem. The signals that activate normal fibroplastic repair versus regeneration pathways are unknown. Transforming growth factor beta levels rise during incisional healing but fall during hepatic regeneration. Changes in the injured host cytokine milieu may therefore differentially effect abdominal wall repair versus hepatic regeneration., Materials and Methods: Forty-eight rats were divided into four groups (n = 12). Groups 1-3 underwent sham celiotomy, 70% hepatectomy, or 80% enterectomy with anastamosis. Incisions from Group 4 were treated with either 1 microg of transforming growth factor beta(2) (TGF-beta(2)) or vehicle following hepatectomy. Isolated fascial and dermal incisions were harvested and tested for breaking strength on POD 7. Serum (TGF-beta(2)) and hepatocyte growth factor (HGF) levels were measured by ELISA., Results: Recovery of incisional wound breaking strength was delayed following hepatectomy but not enterectomy (P<0.002). The inhibitory effect was observed in both the fascia and the dermis of the abdominal wall. TGF-beta(2) levels were depressed in hepatectomy animals on POD 7, while at the same time HGF levels were elevated. Exogenous TGF-beta(2) shifted the healing trajectory of deficient wounds back toward a control pattern., Conclusion: Abdominal wall fascial and dermal healing is delayed during hepatic regeneration. Elevated HGF and depressed TGF-beta(2) suggest a host mechanism that prioritizes hepatic parenchymal regeneration over fibroplastic repair (scar). Observations such as these are needed as therapeutic wound healing enters the clinical realm., (Copyright 2001 Academic Press.)

Matrix metalloproteinases (MMPs) have been implicated in the growth and invasiveness of primary and metastatic tumors. Hypothesizing that MMP inhibition would slow cancer growth, the MMP inhibitor BB-94 (batimistat) was evaluated in an orthotopic animal model of human pancreatic carcinoma. Ten million human pancreatic cancer cells were surgically implanted into the pancreata of 30 athymic nu/nu mice. Intraperitoneal administration of 30 mg/kg BB-94 or vehicle control began 7 days after tumor implantation (13 mice with confirmed implantations in each group) and continued daily for 21 days, and then three times weekly until death or sacrifice at day 70. Representative tumors harvested from mice in each group were analyzed for presence and activity of MMP-2 and MMP-9. Animal weights were significantly higher in the BB-94-treated group at sacrifice (mean 58.4 +/- 7.9 g vs. 39.8 +/- 6.2 g; P < 0.05, Student's t test). The likelihood of survival to 70 days was significantly higher in the treated group (4 of 13 vs. 0 of 13, P < 0.05, Z-test for end points) than in the control group as was overall survival (P = 0.03, Wilcoxon test). Nine mice in the control group developed metastases to the liver, peritoneum, abdominal wall, or local lymph nodes, whereas only two mice in the BB-94 group had evidence of metastatic disease (P < 0.02, Fisher's exact test), in both instances confined to the abdominal wall. Tumors from treated mice manifested lower MMP activity than those from control animals. These reports support the use of MMP inhibitors alone or as an adjunct in the treatment of pancreatic cancer.

Background: The time required for incisional healing accounts for the majority of postoperative pain and convalescence. Impaired healing prolongs the process further. If a method for accelerating acute incisional wound healing could be developed, patients would benefit from decreased wound failure and an earlier return to their premorbid condition., Materials and Methods: In a rat dermal model, cytokine or vehicle infiltration prior to incision was performed using a single dose or four daily doses preincision. Planned incision sites were primed with the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) or platelet-derived growth factor BB (PDGF-BB) in an effort to activate the inflammatory phase of healing prior to wounding. At the time of incision closure, one half of the incisions were treated with transforming growth factor beta(2) (TGF-beta(2)). Incisional sites were biopsied and stained with hematoxylin and eosin and immunohistochemistry for inflammatory cells and fibroblast populations and breaking strength was measured., Results: Priming skin with GM-CSF or PDGF-BB mimicked the early inflammatory phase of wound healing. Macrophage staining (EB1) and fibroblast staining (vimentin) were significantly increased prior to incision. Inflammatory priming as well as priming coupled with TGF-beta(2) at the time of the incision closure synergistically improved breaking strength., Conclusion: This study demonstrates that sequential therapy consisting of priming of tissue with an inflammatory cytokine followed by application of a proliferative cytokine at the time of incision closure nearly doubles the breaking strength of an acute wound. By manipulating the inflammatory and early proliferative phases of wound healing with tissue growth factors, it may be possible to accelerate acute wound repair and shift the wound healing trajectory to the left., (Copyright 2000 Academic Press.)

Background: The level of expression of the alpha isoform of protein kinase C (PKC-alpha) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers., Methods: We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-alpha and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-alpha antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model., Results: Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P < .01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-alpha mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P < .01)., Conclusions: Tumorigenicity of pancreatic cancer is related directly to PKC-alpha expression in vivo as demonstrated by decreased survival when overexpressed. PKC-alpha expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo.

Our purpose was to determine if cytokines are produced systemically during acute pancreatitis. Proinflammatory cytokines are elevated during acute pancreatitis and have been implicated in the progression of pancreatitis-associated multiple organ dysfunction. Whether these mediators are produced within all tissues or very few specific organs is not known. Edematous pancreatitis was induced in adult male mice by IP injection of cerulein. Necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented diet. Animals were sacrificed as pancreatitis worsened, with multiple organs prepared for tissue mRNA and protein analysis by RT-PCR and immunoblotting. Pancreatitis severity was established by histologic grading and serum amylase and lipase. There was no cytokine mRNA or protein detectable prior to the induction of pancreatitis. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) mRNA and protein were detected within the pancreas early in the course of pancreatitis in both models, coinciding with the development of hyperamylasemia (both P < 0.001). Interleukin-6 was produced in the pancreas after pancreatitis was more fully developed (P < 0.001). IL-1 beta and TNF-alpha were subsequently produced in large amounts in lung, liver, and spleen but never within kidney, cardiac muscle, or skeletal muscle. A significant delay between pancreatic and distant organ cytokine production was always observed. It is concluded that proinflammatory cytokines are produced within the pancreas and within organs known to develop dysfunction during severe pancreatitis. Cytokine production is tissue specific, correlates with disease severity, and occurs within the pancreas first and subsequently within distant organs.

Matrix metalloproteinases (MMP) are enzymes responsible for extracellular matrix degradation, a critical component influencing the growth and metastatic potential of cancer. The purpose of this study was to determine the in vitro effects of MMP inhibition on human pancreatic cancer cells and to document its effect on cancer growth in vivo. The effect of MMP inhibition was determined using the MMP inhibitor BB-94 and a moderately differentiated pancreatic cancer cell line (HPAC). In vitro, a dose response curve was generated over 5 days utilizing the MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. In vivo, using an established orthotopic model for pancreatic cancer (LD100 = 80 days), 22 nude mice with orthotopic tumors (30 were implanted) received either BB-94 or vehicle beginning 4 days prior to implantation and continuing to death or sacrifice on Day 70. Mice were weighted weekly. At death/sacrifice, tumors were weighted, volume determined, and metastases/ distant spread documented. In vitro, BB-94 had little effect on HPAC proliferation at 40 ng/ml but achieved progressively greater to near complete inhibition at doses up to 4000 ng/ml while maintaining cell viability. In vivo, BB-94 significantly increased length of survival (69 +/- 0.1 days vs. 56 +/- 3.1 days) and necropsy weight (25.7 +/- 1.67 g vs. 19.8 +/- 1.14 g) while decreasing metastatic rate (1 vs. 20) and tumor size (0.14 +/- 0.02 g vs. 0.65 +/- 0.1 g). MMP inhibition limits HPAC proliferation in a dose-dependent fashion without direct cytotoxic effects in vitro. Mice harboring orthotopic tumors treated with BB-94 demonstrated significant reductions in tumor weight, volume, and metastases which corresponded to increased animal weight and prolonged survival.

BACKGROUND: Medullary thyroid cancer, a tumor of the parafollicular C cells, accounts for approximately 10% of all thyroid malignancies. An estimated 75% of cases are sporadic, and the remaining 25% are familial. METHODS: The author reviews the clinical features and diagnostic tests for this entity, as well as the surgical treatment of recurrent or persistent medullary carcinoma. RESULTS: Sporadic medullary thyroid cancer typically presents as an isolated unilateral mass. Familial tumors tend to be multifocal and bilateral. In patients with multiple endocrine neoplasia type 2A, pheochromocytomas and parathyroid hyperplasia also may develop. Care is taken to avoid operating on a patient with occult pheochromocytoma. Total thyroidectomy and central lymph node dissection are the keys for successful surgical treatment. CONCLUSIONS: Surgery is the cornerstone of treatment for medullary carcinoma of the thyroid. Genetic testing using the ret oncogene allows identification of individuals who are at risk for the disease or those with early-stage disease.

Background: The signal transduction pathways important in regulating the growth and differentiation of malignant cells are poorly understood. Recent evidence has implicated activation of the protein kinase C (PKC) family of signaling proteins in pancreatic carcinoma during cytokine-induced cytostasis and differentiation., Methods: A human pancreatic adenocarcinoma (HPAC) cell line was exposed to tumor necrosis factor-alpha (TNF-alpha; 40 ng/ml) for 6 days. Cytostasis and viability were confirmed by daily MTT [(3(4,5)-dimethyl-thiazol-2-yl) 2,5-diphenyl-tetrazolium bromide] and trypan exclusion assay. Protein fractions were isolated daily and subjected to immunoblot analysis for the normal (terminally differentiated) pancreatic ductal cell marker carbonic anhydrase II (CA II) as well as specific PKC isoforms (alpha, beta, gamma, eta, and zeta)., Results: Growth arrest occurred in HPAC cells after exposure to TNF-alpha for 48 h, with viability maintained above 90% throughout the 6-day time course. CA II immunoreactivity was not detected in untreated controls but appeared after 2 days of TNF-alpha exposure, peaking on day 6. Concurrently, TNF-alpha induced the selective downregulation of PKC-alpha, whereas PKC-gamma levels increased. PKC-beta and PKC-eta immunoreactivity did not change. The atypical PKC-zeta isoform developed a doublet banding pattern in response to TNF-alpha, although overall PKC-zeta levels did not change., Conclusions: TNF-alpha-induced growth arrest and differentiation in HPAC cells is associated with the selective downregulation of PKC-alpha and upregulation of PKC-gamma.

Background: Tumor necrosis factor (TNF) is produced in large amounts within the pancreas, lungs, and liver during severe acute pancreatitis and is believed to mediate many of the detrimental consequences typical of this disease. Investigations into the benefit of TNF antagonism have suggested that TNF may also mediate processes that are protective to the host., Methods: With the hypothesis that timing plays a role in these dissenting views, TNF was antagonized either prophylactically or therapeutically with a recombinant form of the soluble type I TNF receptor (TNFbp) during a lethal model of necrotizing pancreatitis induced by feeding a choline-deficient diet. Mortality was determined for 10 days in 390 female mice divided into three groups: control, TNFbp early (time, 0 to 5 days), and TNFbp late (time, 1.5 to 5 days). Pancreatitis severity and cytokine production were assessed daily., Results: Animals in the control group had a 75% mortality rate that was significantly decreased by prophylactic TNF blockade (64%, p < 0.05). Delaying TNF antagonism until serum cytokines were elevated and pancreatitis was manifest decreased mortality to 42% (p < 0.001 versus control, p < 0.01 versus early). Early and late TNF blockade decreased pancreatic edema and serum amylase, lipase, interleukin-1, and interleukin-6 (all p < 0.05) but not TNF. Late antagonism typically resulted in the greatest attenuation of all these parameters., Conclusions: Blockade of TNF by the administration of a soluble TNF receptor attenuates the severity of pancreatitis, decreases the production of associated inflammatory cytokines, and significantly improves survival. Delaying antagonism until pancreatitis is manifest and circulating cytokines are elevated but not yet maximal appears to be more protective than simple prophylactic TNF antagonism.

Objective: To examine the intrapancreatic production of tumor necrosis factor (TNF) alpha and define its cell of origin during acute pancreatitis., Design: Acute necrotizing pancreatitis was induced in adult male mice by administering cerulein (50 micrograms/kg intraperitoneally four times over 3 hours). Animals were killed at 0, 0.5, 1, 2, 4, 6, and 8 hours, with the severity of pancreatitis established by blind histologic grading and serum amylase, lipase, and TNF levels. The expression of TNF messenger RNA within the pancreas was established by the reverse transcription polymerase chain reaction. Intrapancreatic TNF protein was analyzed by enzyme-linked immunosorbent assay, Western blot, and immunohistochemical methods., Results: Acute pancreatitis was manifest within 1 hour of the first cerulein injection and increased in severity through 8 hours. There was no constitutive expression of TNF messenger RNA within the pancreas, but transcripts were induced within 30 minutes following the onset of pancreatitis, increasing through 4 hours. Intrapancreatic and serum TNF peptide levels became detectable at 1 hour and increased over 6 hours (both P < .001 vs control), with intrapancreatic levels rising faster and attaining concentrations three times higher than time-matched serum levels (P < .01). Immunohistochemical staining demonstrated the progressive infiltration of macrophages into the pancreas that stained heavily for TNF (P < .01 vs control)., Conclusions: Tumor necrosis factor gene expression is induced locally during acute pancreatitis, resulting in large amounts of intrapancreatic TNF with levels consistently higher than those found in the serum. The overall rise in both tissue and serum TNF concentrations correlates directly with the severity of pancreatic damage and inflammation. The infiltrating macrophage appears to contribute most to this process.