Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett's Esophagus: A Phase 1 Pilot Study.

BACKGROUND: Chemopreventive effects of zinc for esophageal cancer have been well documented in animal models. This prospective study explores if a similar, potentially chemopreventive action can be seen in Barrett's esophagus (BE) in humans. AIMS: To determine if molecular evidence can be obtained potentially indicating zinc's chemopreventive action in Barrett's metaplasia. METHODS: Patients with a prior BE diagnosis were placed on oral zinc gluconate (14 days of 26.4 mg zinc BID) or a sodium gluconate placebo, prior to their surveillance endoscopy procedure. Biopsies of Barrett's mucosa were then obtained for miRNA and mRNA microarrays, or protein analyses. RESULTS: Zinc-induced mRNA changes were observed for a large number of transcripts. These included downregulation of transcripts encoding proinflammatory proteins (IL32, IL1ß, IL15, IL7R, IL2R, IL15R, IL3R), upregulation of anti-inflammatory mediators (IL1RA), downregulation of transcripts mediating epithelial-to-mesenchymal transition (EMT) (LIF, MYB, LYN, MTA1, SRC, SNAIL1, and TWIST1), and upregulation of transcripts that oppose EMT (BMP7, MTSS1, TRIB3, GRHL1). miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518, and -34a-5P). Of proteins analyzed by Western blot, increased expression of the pro-apoptotic protein, BAX, and the tight junctional protein, CLAUDIN-7, along with decreased expression of BCL-2 and VEGF-R2 were noteworthy. CONCLUSIONS: When these mRNA, miRNA, and protein molecular data are considered collectively, a cancer chemopreventive action by zinc in Barrett's metaplasia may be possible for this precancerous esophageal tissue. These results and the extensive prior animal model studies argue for a future prospective clinical trial for this safe, easily-administered, and inexpensive micronutrient, that could determine if a chemopreventive action truly exists.

New graft for low friction tunneling in vascular access surgery.

PURPOSE: Prosthetic accesses of the upper extremity have been in use for more than 25 years. Many different conduits have been employed; investigators have continually searched for a graft with superior properties. METHODS: We describe a prospective randomized study comparing the new Slider Graft (Atrium) with the Hybrid PTFE Graft (Atrium); the latter has been used for a number of years. The Slider Graft is also made of PTFE. For this study, both grafts were 6 mm in diameter and 40 cm in length. The Slider Graft has a low friction polyethylene sheath over its entire length. This sheath expedites the passage of the graft through the tunnel. At one end, the graft and the polyethylene sheath are attached to a metal tip. This tip has male threads, which may be inserted firmly into a Kelly Wyck, Atrium, or any standard non-sheath tunneling system. This alleviates graft separation, turning, and slipping during tunneling. The primary objective of this trial was to determine the safety and efficacy of the Slider Graft as compared to the Hybrid Graft in vascular access surgery. The secondary objective was to evaluate how tunneling effects graft performance. We randomized 60 subjects for this study with two equal arms. During surgery we measured various parameters including ease of tunneling, tunnel bleeding, anastomotic bleeding, graft sweating, and immediate patency. To assess arm edema we measured circumference 7.5 cm and 20 cm above the wrist, prior to surgery and in follow-up visits at 1 week, 1 month, and 3 months. Primary patency was also assessed at these visits and at 6, 9, and 12 months. RESULTS: Our results show tunneling with the Slider Graft is easier to accomplish (p = 0.0001) with reduced tunnel bleeding (p = 0.0047) and anastomotic bleeding (p = 0.042). Further, the Slider Graft virtually eliminated the complication of graft sweating and seroma development (p = 0.0005). This may be due to reduced stretching and graft wetting during insertion. At 180 days the Slider Graft demonstrated improved primary patency, which was statistically significant (p = 0.047). At 360 and 720 days the Slider Graft continued to demonstrate a trend toward improved primary patency (p = 0.160). CONCLUSIONS: This study suggests the Slider Graft has significant advantages when compared to the Hybrid Graft and highlights the importance of tunneling in creating prosthetic accesses.

LatisTM catheter: New technology for thrombectomy of vascular access grafts.

PURPOSE: The most common complication of vascular access surgery is thrombosis. This study compared the gold standard Fogarty Thrombectomy Catheter, to the new latis Catheter with an advanced monofilament matrix. METHODS: 30 patients with thrombosed access grafts were randomly assigned to undergo thrombectomy with the Fogarty or latis catheter. An angioscope measured remaining graft thrombi. RESULTS: Twenty-nine of 30 subjects were successfully thrombectomized. No statistical differences in age, gender, race, or extension graft requirements were found. Catheter use in the latis group was: 1 in 14 procedures, and 2 in 1 procedure; Fogarty group: 1 in 10 procedures, 2 in 3 procedures, and 3 in 2 procedures. The average number of catheter passes was: latis 3.06 (1-6 passes) and Fogarty 4.13 (1-9 passes). A trend in favor of the latis catheter was demonstrated; however, statistical significance was not reached (p = 0.067). The overall 6-month primary patency rates were latis (40%) and Fogarty (30%). The estimated patency at the 50th percentile for latis is 120 days and Fogarty 108 days. Statistical significance was not reached with a p-value of the Log-Rank statistic of 0.68 and a p-value of the Wilcoxon statistic of 0.78. CONCLUSIONS: The latis and Fogarty catheters are very similar. However, the latis balloon is more rugged with fewer catheters used and reduced number of passes. A difference in primary patency could not be demonstrated. The angioscope identified significant residual thrombus despite no returning thrombus from the catheter. Consequently, our protocol is modified to include the angioscope.

The utility of the VCS clip for creation of vascular access for hemodialysis: long-term results and intraoperative benefits.

UNLABELLED: The purpose of this study was to compare the effectiveness of the VCS vascular clip approximating system for the creation of hemodialysis access fistulas. 173 new vascular accesses were created, 92 prosthetic grafts and 81 autologous fistulas over a 40-month period. 50 sutured and 42 clipped fistulas comprised the prosthetic graft series, and 33 sutured and 48 clipped cases the autologous series. Risk factors associated with access patency were correlated and the primary patencies compared in the suture versus clipped group. A significant improvement in primary patency was noted for the clipped prosthetic group at all time points studied, with a positive trend also noted for clipped autologous fistulae. CONCLUSIONS: The vascular clipping system (the VCS system) provides both long-term and immediate advantages for vascular access construction. Clips have been used successfully to treat seven consecutive patients with upper extremity arterial steal syndrome without the technical difficulties associated with traditional methods of repair.

Preliminary prospective randomized experience with vascular clips in the creation of arteriovenous fistulae for hemodialysis.

BACKGROUND: A new vascular clipping system (VCS) has been introduced for clinical use. This study was developed to determine whether patency rates and treatment outcomes for anastomoses in hemodialysis access surgery can be improved by the application of this new technology. METHODS: During a 10-month period, 96 consecutive patients requiring autologous fistula, synthetic fistula, or graft revisions for hemodialysis were prospectively randomized into two treatment groups. Anastomoses were constructed with the VCS in 46 patients and with polytetrafluoroethylene (PTFE) suturing in 49 patients. The procedures were performed in an outpatient setting, at a large medical center, by one surgeon. Time to construct the anastomosis, amount of bleeding from the anastomotic site, and primary and secondary graft patencies were analyzed. RESULTS: The mean time to construct anastomoses in autologous and synthetic grafts using VCS clips was significantly shorter than with sutures (autologous 14 versus 22 minutes, P = 0.0001; and new grafts 26 versus 30 minutes, P = 0.04). Blood loss was less in anastomoses done with the VCS clip; however, statistical significance was reached only for autologous fistulas (P = 0.0001). At 2-year follow-up, primary and secondary patencies were similar for both the VCS and suture groups with the exception that a statistically significant improvement was found in secondary patency for autologous fistulas when performed with the VCS. CONCLUSIONS: The VCS clip is easy to use and produces a more rapid anastomosis with less bleeding. Primary and secondary patencies using the VCS clip were equivalent or improved when compared with standard suture. In our experience, no complications have been attributed to the use of the clip technique.

Potential pitfalls in the work-up and diagnosis of choanal atresia.

To increase an awareness of the developmental anatomy of the nasal cavity as it applies to the radiologic work-up of choanal atresia and frontoethmoidal cephaloceles, we report two cases that demonstrate potentially serious imaging pitfalls. Two neonates with nasopharyngeal obstruction were imaged with CT and MR. Both patients had surgically proved bilateral bony choanal atresia. In addition to choanal atresia, CT showed a radiolucent, or nonossified cribriform plate and mucoid secretions within the nasal fossa, adjacent to the cribriform plate, which approximated the attenuation of brain parenchyma. In one of the patients, a preoperative diagnosis of nasopharyngeal encephalocele resulted in surgical exploration. At surgery, however, the cartilaginous cribriform plate was found to be intact.

Lifestyle intervention: results of the Treatment of Mild Hypertension Study (TOMHS).

BACKGROUND: Questions regarding the efficacy of nonpharmacologic approaches for the treatment of stage 1 hypertension were addressed as part of the Treatment of Mild Hypertension Study (TOMHS), a 4-year, randomized clinical trial (N = 902). This report describes the lifestyle intervention program used in TOMHS, presents data on the lifestyle changes observed, and focuses on the effect of weight loss on blood pressure and blood lipid levels. METHODS: Participants were randomly assigned to receive either placebo or one of five different antihypertensive medications. All took part in a lifestyle intervention program to reduce weight and sodium and alcohol intake and to increase physical activity. RESULTS: Substantial changes from baseline levels were achieved for all lifestyle intervention variables. Mean weight change was -10.5 lb (-5.6%) at 1 year, -8.5 lb (-4.5%) at 2 years, -7.4 lb (-4.0%) at 3 years, and -5.7 lb (-3.0%) at 4 years. At 4 years, 70% of participants remained below baseline weight and 34% maintained a weight loss of 10 lb or greater. Mean change in urinary sodium excretion was -12.5 mmol/8 hr (-23%) at 1 year, -10.7 mmol/8 hr (-20%) at 2 years, -8.4 mmol/8 hr (-16%) at 3 years, and -4.6 mmol/8 hr (-9%) at 4 years. Alcohol intake declined by 1.6 drinks/week among drinkers at 4 years. Reported leisure physical activity increased by 86% at 1 year and remained 50% above baseline at 4 years. Beneficial changes in blood pressure and serum lipids were associated with these changes. CONCLUSIONS: These results support a role for lifestyle interventions as the initial treatment for stage 1 hypertension and demonstrate that such interventions can be successfully implemented in the clinical setting.

Multicenter validation study of real-time (B-mode) ultrasound, arteriography, and pathologic examination.

The ability of high-resolution ultrasound, angiography, and pathologic examination of endarterectomy specimens to identify and quantitate atherosclerosis was compared in a five-center study. The carotid bifurcation in 900 patients was evaluated by angiography and ultrasound. In 216 cases, high-quality endarterectomy specimens were available for comparison with the preoperative images. All comparisons were made in a blinded fashion. Results indicate that ultrasound is able to differentiate angiographically normal from abnormal arteries with a sensitivity of 88% (1077 of 1233 arteries) and accuracy of 79% (1251 of 1578 arteries). Angiographic stenoses equal to or greater than 50% diameter were accurately identified by ultrasound imaging in 72% (1133 of 1578 arteries) of cases, and this was improved by the addition of other functional data (i.e., Doppler spectral analysis and oculoplethysmography). There was only modest correlation of absolute measurements of lesion width, minimal lumen, and standard lumen by the two imaging techniques (r = 0.28 to 0.55). Ultrasound measurements of lesion width were on the average 2 mm greater than those of angiography. The lumen averaged 1.5 mm larger when measured by ultrasound techniques. In the subset in which data were available from endarterectomy specimens, ultrasound showed the best correlation with lesion width (mean difference -1.1 mm) and angiography correlated best with minimal lumen (mean difference -0.1 mm). Neither examination consistently identified ulcerated plaques. Although ultrasound imaging alone has limited usefulness in quantitating luminal stenosis, this can be improved by the use of Doppler spectral analysis and oculoplethysmography. Ultrasound is superior to angiography for quantifying atherosclerotic plaque (lesion width) and will be an important tool for further study of atherosclerotic lesions.

Clinical sequelae in patients with asymptomatic carotid bruits.

Noninvasive vascular laboratory evaluations were performed on 163 patients who presented with asymptomatic carotid bruits. Of these, 57 patients were identified as having a solely transmitted murmur. The remaining 106 patients had carotid disease. Based on hemodynamic criteria, 77 patients had compensated disease and 29 had uncompensated disease. These patients were followed for from 1 to 56 months (mean 31). Patients in the uncompensated group developed symptoms attributable to the extracranial territory at a higher rate than did patients in the compensated group, with differences continuing for 36 months. At 18 months the accumulated symptom rate for the uncompensated group (24.0%) was over twice that for the compensated group (11.4%). Patients in the uncompensated group also had a higher mortality rate. Differences occurred after 12 months and continued through 36 months. Of the 23 patients who died, 19 (82%) died due to cardiac disease, two due to cerebrovascular accidents, and two due to neoplastic disease. In view of the results of this study, a careful examination of patients with asymptomatic cervical bruits is warranted. This evaluation should take the form of a noninvasive vascular laboratory evaluation, which can help determine the proper course of patient management by measuring functional deficit and estimating anatomic severity.

Progressive neonatal airway obstruction secondary to cervical thymic cyst.

Cervical thymic cysts are extremely unusual neoplasms that only rarely produce signs and symptoms of upper airway tract compromise. Less than 7% of patients initially have dyspnea or hoarseness. We report the first known case of progressive neonatal airway obstruction secondary to a rapidly enlarging cervical thymic cyst. Because one half of these benign tumors may demonstrate mediastinal extension, computed axial tomography or B-mode ultrasonography or both is recommended prior to surgical excision. Review of the literature confirms that the majority are successfully removed via a transcervical approach without recurrence.

Malignant tumors of salivary glands. A university experience.

The management of salivary gland neoplasms continues to be a challenging clinical problem. Despite recent advances in histopathological classification, agreement among head and neck surgeons concerning optimum treatment is lacking. In attempts to eradicate the more malignant varieties of these tumors, surgeons have performed radical and multilating surgery. Radiation therapy has not been considered efficacious in many centers. A review of 93 maligant salivary gland tumors from 1955 to 1973 at the University of California, San Francisco, suggests that these tumors may be more radiosensitive than once thought. Radiation therapy combined with conservative surgical procedures may be as successful and perhaps more rational treatment than radical surgery alone.

The surgical management of recalcitrant malignant external otitis.

Aggressive medical management and surgical debridement is curative in most cases of malignant external otitis. Recently, four patients with this condition were treated at the University of California, San Francisco, who did not respond to conventional therapy. In each case, appropriate intravenous antibiotics, diabetic management, and extensive excision of involved tissue failed to eradicate the infection. Progression of the disease was evidenced by any one of the following: 1. Persistence of granulation tissue in the external auditory canal, 2. Development of cranial neuropathies during treatment, 3. Other signs or symptoms of active infection for more than two weeks after institution of therapy. Any one of these criteria was considered an indication for more radical surgical intervention. In three patients, the operative procedure consisted of a subtotal temporal bone resection to gain access to the primary focus of infection and provide adequate drainage. The common finding in each case was an abscess cavity in the soft tissues at the base of the skull. A description of the clinical course and surgical management of malignant external otitis forms the basis of this communication.

Relationship of muscle surface pH to noninvasive hemodynamic studies in arterial occlusive diseases.

To examine the possible relationship between Doppler pressures (DP) and pulse volume amplitude (PVR) with muscle surface pH (pHm), we studied 20 patients before, during, and after arterial reconstruction. The mean pHm for the claudication, rest pain, and ischemic gangrene groups differed from a control group and from each other. The pHm varied directly with DP and PVR for the 20 patients as a whole. After reconstructive surgery, improvement in pHm seemed to precede changes in DP and PVR in six patients with combined segment disease. Although pHm correlates generally with DP and PVR, it is invasive. Therefore, pHm should not be used as a routine screening test. Whereas DP and PVR may reflect the anaerobic activity of peripheral tissue, they may be less prompt than pHm in responding to acute changes in blood flow.

Noninvasive evaluation of asymptomatic carotid bruits.

Proper clinical management of a patient found to have an asymptomatic carotid bruit continues to be controversial, with wide differences of opinion concerning the advisability of angiography and surgery. A noninvasive cerebrovascular evaluation is described, which combines three separate but complimentary procedures: ocular pneumoplethysmography (OPPG), carotid audiofrequency analysis (CAA), and cerebral Doppler analysis. Such studies are particularly helpful in evaluating patients with an asymptomatic carotid bruit. The reliability and effectiveness of this approach was evaluated in a series of 165 consecutive patients with an asymptomatic bruit. Angiography was recommended in patients with positive results (42%) and safely withheld in those with negative findings (58%). There were two false-positive results and only one known false-negative interpretation.

Rational management of the asymptomatic carotid bruit.

A noninvasive cerebrovascular evaluation has been devised that combines three separate but complimentary procedures: ocular pneumoplethysmography (OPPG), carotid audiofrequency analysis (CAA), and cerebral Doppler analysis. This evaluation has proven particularly useful in examination of the asymptomatic carotid bruit, and the management of such patients is aided by noninvasive testing. Patients with a poorly compensated stenosis (reduced OPPG) are all considered candidates for angiography and surgery. For patients with a well-compensated (normal OPPG) but surgically important stenosis (abnormal CAA or Doppler), angiography and surgery are recommended in selected patients. Angiography and/or surgery are believed safely withheld in all remaining patients. The reliability and effectiveness of this approach is evaluated in a series of 100 consecutive patients with an asymptomatic carotid bruit. There were no false-positive results and only known false-negative interpretation.

Mammographic screening. Value in diagnosis of early breast cancer.

Analysis of the two-year results of a project screening asymptomatic women for breast cancer is presented. There were 10,008 women examined and 490 biopsies completed. There were 97 cancers found, of which 55 were nonpalpable; 36 of the 97 cancers were in women under 50 years of age. The incidence of axillary metastasis was 7% in the nonpalpable lesions. We suggest that mammography is useful in discovering curable breast cancer, even among younger women at least down to the age of 40. The potential benefit seems to greatly outweigh the theoretical carcinogenic hazard. Selection of candidates for mammography should be based on all risk factors, not just age. An attempt is made to correlate the results with the theoretical risks as proposed by others.

Selection of patients with lymphedema for compression therapy.

Seventeen patients with lymphedema were treated with intermittent external pneumatic compression. Two patients with hemodynamically significant venous obstruction showed no response to therapy. The response of the remaining fifteen patients varied with the degree of subcutaneous tissue fibrosis. Xeroradiographic estimates of tissue compressibility provided valuable prognostic information. Intermittent external pneumatic compression is an effective nonsurgical method of treatment in patients selected by xeroradiography.