Douglas T. Cromack

Intraoperative Ultrasonographic Localization of Islet Cell Tumors: A Prospective Comparison to Palpation

The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

Localization and surgical treatment of occult insulinomas.

Management of patients with biochemical evidence of insulinoma and negative preoperative imaging studies (occult) tumors is controversial, varying from primarily medical management to aggressive, blind nearly total pancreatectomy to extirpate the tumor. Since 1982, 12 consecutive patients with occult insulinoma underwent preoperative portal venous sampling (PVS) for insulin followed by surgical exploration with intraoperative ultrasound (IOUS). Eleven of twelve patients (92%) had insulinoma removed and were cured. Portal venous sampling correctly predicted the location of the insulinoma in 9 patients (75%) and that no tumor would be found in another patient. A fourfold insulin gradient in the pancreatic tail of one patient correctly predicted that a distal pancreatectomy would remove the insulinoma despite the fact that neither palpation nor IOUS identified any tumor. Intraoperative ultrasound was the single best method to identify occult tumors because it correctly identified 10 of 11 insulinomas that were found, including five pancreatic head tumors that were not palpable. Palpation identified five insulinomas. Of the 10 tumors that were identified during operation by palpation or ultrasound, IOUS identified significantly more (100% versus 50%, p = 0.03) and guided the successful enucleation of each. The results support the strategy of preoperative PVS and operation with IOUS to localize and remove insulinoma in patients with occult tumors. Most tumors (75%) will be correctly localized to a specific pancreatic region by preoperative PVS and identified by IOUS (83%), allowing simple enucleation and biochemical correction of hypoglycemia. Morbid blind pancreatic resections are no longer indicated and long-term medical management of hypoglycemia should be reserved for the occasional patient (8%) who fails preoperative PVS and operation guided by IOUS.

Transforming growth factor β levels in rat wound chambers

Exogenous TGF-β accelerates healing in both normal and doxorubicin-treated rats, but whether it plays an intrinsic role in the natural healing process is unknown. Subcutaneous wound chambers in 16 F344 rats were aspirated from postwounding Day 3 through Day 16 for TGF-β levels and cytology. A soft agar assay and a competitive radioreceptor binding assay were used to determine TGF-β levels. Papanicolau staining and differential cell counts were used to determine cytology. Results were similar using either method for the determination of TGF-β levels. With the sensitive radioreceptor assay, low TGF-s levels on postwounding Day 4, mean 2.6 ng/ml, rose to a peak mean level of 20.4 ng/ml on Day 7 and fell significantly from peak level to a level of 5.4 ng/ml of Day 16. All TGF-β levels for postwounding Days 6 through 14 were significantly increased over the baseline TGF-β levels of Days 4 and 5 (P < 0.05). Day 16 TGF-β levels were not different from baseline. Cytologic changes were characterized by a linear decrease in total neutrophil count over the exam period and a concurrent linear increase in total lymphocyte and macrophage counts. TGF-β levels changed in a bell-shaped temporal sequence during healing, apparently unrelated to percentage lymphocyte, macrophage, or neutrophil count. Peak TGF-β levels occurred during the fibroblast proliferation and collagen synthesis phase of healing. This study presents the first evidence that TGF-β is present in a healing wound and suggests that it may be an intrinsic mediator of the healing process.

Current concepts in wound healing: growth factor and macrophage interaction.

Growth factors are potent wound healing promoters which accelerate incisional wound repair by distinct mechanisms. Transforming growth factor-beta (TGF-beta), a chemotactic factor, increases synthesis of extracellular matrix and stimulates granulation tissue. We demonstrated that a single topical dose of TGF-beta increased the wound breaking strength in normal models of tissue repair as well as in models of impaired wound repair, characterized by severe monocytopenia. PDGF, a chemotactic agent for inflammatory cells, with mitogenic activity, activates monocytes and stimulates collagen production, significantly increased the wound breaking strength with effects that lasted for up to 47 days. In contrast to TGF-beta, PDGF was only active in normal models of wound healing and its effects were dependent upon the presence of macrophages. PAF is a glycerophospholipid which chemotaxes and activates macrophages, but differs from growth factors in lacking mitogenic activity. A single topical dose of PAF significantly increased the wound breaking strength and promoted macrophage migration.

The local effects of cachectin/tumor necrosis factor on wound healing

Previous experimental studies have suggested that tumor necrosis factor (TNF) may have either a beneficial or a detrimental role in wound healing. Control and doxorubicin-treated (6 mg/kg, intravenously) rats underwent paired dorsal 5-cm linear wounds and had either vehicle or recombinant (r)TNF (0.5, 5, or 50 fig) applied locally to the wound. Paired wounds were harvested at 7 and 14 days after wounding and analyzed for wound-bursting strength (WBS) and activity of the gene for type 1 collagen and TNF. Doxorubicin treatment decreased WBS at 14 days but not at 7 days after wounding/Local application of 50 fig of rTNF decreased WBS in saline-treated rats and concentrations of 5 and 50 μg decreased WBS in doxorubicin-treated rats when measured 7 days after wounding. These effects dissipated when WBS was measured 14 days after wounding. Doxorubicin decreased wound collagen gene expression and local TNF treatment decreased wound collagen gene expression in saline-treated rats and further decreased it in doxorubicin-treated rats. The decrement in collagen gene expression induced by rTNF increased as the local dose of rTNF increased. The gene for TNF was not detectable in wounds from normal or doxorubin-treated rats at 3,7,10, or 14 days after wounding. These data suggest that the gene for TNF is not expressed in wounds and that the local application of TNF is detrimental to wound healing as it decreases WBS and activity of the gene for collagen.

Pulsatile activation of the hypothalamic-pituitary-adrenal axis during major surgery

To examine the response of the hypothalamic-pituitary-adrenal (HPA) axis to severe surgical stress, we measured the immunoreactive plasma levels of corticotropin-releasing hormone (CRH), corticotropin, cortisol, arginine-vasopressin (AVP), atrial natriuretic factor (ANF), neuropeptide Y (NPY), interleukin-1 (IL-1), IL-6, interferon gamma (INF), and tumor necrosis factor-alpha (TNF-alpha) in eight patients with Zollinger-Ellison syndrome (ZES) or mediastinal parathyroid carcinoma, all undergoing major surgery with a standardized anesthetic technique. Blood samples were drawn the morning before surgery, every 10 to 30 minutes throughout surgery (average, 308.7 +/- 15 minutes), and every morning for the next 4 postoperative days (POD). During surgery, plasma CRH concentrations were slightly but not significantly elevated compared with those before surgery and with those of the next 4 POD. However, the values were within the normal range (less than 2.2 pmol/L) and showed 8.9 +/- 0.6 pulses (one pulse every 34.7 +/- 1.6 minutes). Plasma corticotropin, on the other hand, was quite elevated, but was also released in a pulsatile fashion during the surgical procedure (one pulse every 36.7 +/- 1.6 minutes). Most of these secretory episodes of corticotropin were temporally related to those of CRH. Corticotropin returned to basal levels on the first POD and remained so for all 4 POD. Plasma cortisol concentrations increased steadily during surgery and remained elevated the first POD. Cortisol showed 6.2 +/- 1.1 pulses during the operative sampling period (one pulse every 71.8 +/- 13 minutes). Plasma AVP concentrations were also markedly elevated during surgery, but individual secretory pulses were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.

Acceleration of soft tissue repair by a thrombin-derived oligopeptide

Augmentation of thrombin-modulated chemotaxis and mitogenic activity within the early phase of soft tissue repair is now possible. Identification of high-affinity thrombin receptor binding domains within thrombin has enabled the synthesis of a family of peptides which interact with thrombin receptors and enhance in vitro mitogenesis. A single (5.0 micrograms/wound) application of the thrombin receptor-activating peptide (P517-30) significantly increased wound breaking strength from Day 5 (31% over controls) to Day 12. Two models of impaired healing created by radiotherapy (RT) were used to elucidate possible mechanisms of P517-30 action. Although P517-30 did not completely overcome the RT-induced healing impairments, it increased breaking strength under conditions of penetrating whole body RT-induced pancytopenia by 22% and of nonpenetrating surface RT-induced dermal cell damage by 42%. This suggests that P517-30 directly stimulates resident endothelial cells, fibroblasts, or other cells to overcome dermal and circulating monocytic deficits. These results suggest a method to accelerate wound healing with potential clinical applications and emphasize the activity of thrombin as a growth factor.

Pathology and treatment of impalpable breast lesions

With the increasing use of mammography, more needle-localized breast biopsies (NLBB) are being done. The purpose of this study was to analyze the pathology of impalpable breast lesions and the impact of NLBB on treatment strategies. From 1985 to 1990, 1,605 NLBB were performed, of which 321 (20%) were malignant. Twenty-five percent of malignant biopsies demonstrated in situ disease only. The average size of all lesions detected was 16 mm, and, for invasive cancer, 12 mm. Eighteen percent of invasive cancers had metastasized to the axillary lymph nodes. Surgical management consisted of mastectomy in 74% of patients and breast conservation treatment (BCT) in 26%. No significant difference in surgical management for women 50 years of age or younger compared with those older than 50 years of age was noted. Although the use of BCT for eligible women is recommended by the National Institutes of Health, it is not widely practiced, possibly reflecting less physician acceptance of BCT. These observations suggest that the detection of smaller, impalpable breast cancers has had no impact on treatment strategies.

Combined lateral column arthrodesis, medial plantar artery flap, and circular external fixation for Charcot midfoot collapse with chronic plantar ulceration.

INTRODUCTION Charcot neuroarthropathy is a progressing debilitating disease that is most commonly seen in patients with diabetes mellitus, especially those with dense peripheral neuropathy. In the disease’s early stages, increased blood flow to the lower extremity leads to generalized osteopenia. Combined with substantial increased weight-bearing activity, this results in a severe deformity with subsequent high plantar pressures, ulceration, and infection. The incidence of Charcot neuroarthropathy and its related complications are increasing in the United States. – 6 The Charcot foot is the greatest single relative risk factor in the development of a foot ulceration when compared with other known risk factors such as insensitivity to a 5.07-g monofilament, obesity, or history of a previous amputation or ulceration. The final common pathway leading to amputation in the diabetic patient typically involves ulceration and subsequent infection. Historically, the treatment for Charcot neuroarthropathy-induced deformity has consisted of bed rest, immobilization, total contact casting, and customized footwear and/or bracing. The goal of any treatment for the diabetic Charcot foot deformity is to create a plantigrade, stable, and braceable foot that will be free from significant risk for further breakdown, ulceration, and/or infection. The actual decision between conservative and surgical intervention depends on the degree of deformity, instability and subluxation, infection, osteomyelitis, patient compliance, medical comorbidities including end-stage renal disease, psychosocial issues, obesity, and life expectancy. Unfortunately, the evidence supporting the more conservative nonoperative treatment option for the Charcot foot is equivocal. The increased risk of amputation related to the nonoperative treatment of Charcot foot should alert wound care practitioners to use caution and close monitoring when conservatively treating Charcot patients with midfoot collapse combined with ulceration. It is estimated that up to 40% of Charcot patients with midfoot collapse will ultimately require surgery to achieve a functional end point that involves the use of commercially available shoe gear and custom in-shoe foot orthoses to decrease the potential for progressive deformity, reulceration, infection, and amputation. Worldwide, surgeons are attempting reconstruction of severe Charcot foot deformities with variable protocols and techniques. – 18 As a result, the literature mainly focuses on small case series or ‘‘how-to’’ manuscripts which, when critically reviewed, produce inconclusive outcomes. The authors believe that these deformities require management by a multidisciplinary diabetic foot team that collectively possesses a comprehensive understanding of the diabetic foot, the whole patient, and the functional deficits associated with the deformed foot. The surgeon, as part of the transdisciplinary team, needs to be well versed in plastic surgery techniques specific to the foot, ankle, and lower leg; various forms and techniques of external fixation; and the principles and application of both acute and chronic deformity correction. A successful outcome can be reached when surgery of the Charcot foot incorporates osseous stability, deformity correction, and concomitant soft tissue reconstruction. This article presents an overview of the surgical techniques used in a lateral column fusion, medial plantar artery flap, and the application of a tensioned ring external fixation device for perioperative and postoperative stability. The authors believe the article is beneficial to all medical and surgical specialties related to the treatment of diabetic limb salvage. It offers an alternative method of treatment to the diabetic Charcot foot ulcer that can be potentially