Retroviral delivery of RNA interference against Marek's disease virus in vivo.

The process of RNA interference (RNAi) has been exploited in cultured chicken cells and in chick embryos to assess the effect of specific gene inhibition on phenotypes related to development and disease. We previously demonstrated that avian leukosis virus-based retroviral vectors are capable of delivering effective RNAi against Marek's disease virus (MDV) in cell culture. In this study, similar RNAi vectors are shown to reduce the replication of MDV in live chickens. Retroviral vectors were introduced into d 0 chick embryos, followed by incubation until hatching. Chicks were challenged with 500 pfu of strain 648A MDV at day of hatch, followed by assays for viremia at 14 d postinfection. Birds were monitored for signs of Marek's disease for 8 wk. A stem-loop PCR assay was developed to measure siRNA expression levels in birds. Delivery of RNAi co-targeting the MDV gB glycoprotein gene and ICP4 transcriptional regulatory gene significantly reduced MDV viremia in vivo, although to lesser extents than were observed in cell culture. Concomitant reductions in disease incidence also were observed, and the extent of this effect depended on the potency of the MDV challenge virus inoculum. Successful modification of phenotypic traits in live birds with retroviral RNAi vectors opens up the possibility that such approaches could be used to alter the expression of candidate genes hypothesized to influence a variety of quantitative traits including disease susceptibility.

Congenital H-type tracheoesophageal fistula complicated by achalasia in an adult: report of a case.

A young adult with a congenital H-type tracheoesophageal fistula complicated by achalasia of the esophagus presented with complaints consistent with existing long-standing asthma. Only on direct questioning were esophageal aspects elicited. This combination of conditions proved difficult to diagnose even though suspected. Esophageal x-ray in the prone-oblique position proved valuable in the diagnosis and localization of the fistula. Correction of the obstruction of achalasia preceded fistula repair. Fistula repair involved sleeve resection of the trachea, with tracheal anastomosis after closure of the esophageal defect.

Salvage of a failed colon interposition in the esophagus with a free jejunal graft.

A patient who had sustained lye burns of the esophagus had undergone reconstruction with a colon interposition. Because of necrosis and stricture of the interposed colon, he was unable to manage salivary secretions and was maintained on gastrostomy feedings. The defect from the pharynx to the midmanubrial level was reconstructed with a free jejunal graft by using microvascular surgical techniques. At 18-month follow-up, barium swallow roentgenography showed flow through the jejunal and colonic segments and into the stomach. The patient gained 15.9 kg postoperatively and was able to consume a normal diet.

Observations on esophageal blood supply.

The recent surgical treatment of two patients with relatively complex esophageal problems is described. In one patient, a long segment of proximal intrathoracic esophagus was mobilized during the course of surgery, and it was noted that the esophagus was viable and had a good blood supply at the distal margin of resection. In the other, the entire cervical and intrathoracic esophagus remained viable after mobilization. The obvious viability of these long esophageal segments detached from the segmental blood supply prompted us to preserve and use them in reconstruction. These observations suggest that there is a rich intramural arterial and venous network complementing the segmental blood supply of the esophagus. Although previous studies have clearly demonstrated a rich intramural esophageal vasculature, to the best of our knowledge it had not been clearly demonstrated that such lengths of esophagus could be mobilized from their segmental blood supply and remain viable. The details of these two cases are presented and discussed to document this observation and the manner in which it was possible to modify the esophageal reconstruction favorably by the use of the mobilized segment of esophagus.

Barrett's esophagus occurring as a complication of scleroderma.

Two patients had both scleroderma and a columnar epithelium-lined lower esophagus (Barrett esophagus). Features of Barrett's esophagus included high esophageal strictures in both patients and ulcer craters in the columnar area of one. Biopsy confirmed columnar epithelium in the lower esophagus of each patient. In these patients, the Barrett esophagus probably was a complication of scleroderma and resulted from long-standing gastroesophageal reflux.

Pericardial reconstruction of the membranous trachea after resection of adenoid cystic carcinoma (cylindroma).

An intraluminal adenoid cystic carcinoma (cylindroma) in the patient reported herein involved just the membranous portion of the distal region of the trachea and extended caudally to include the carina and the membranous portions of both main-stem bronchi--a total linear involvement of 6 cm. The tumor occluded 90% of the airway in its greatest extension. Conservative resection of this extensive tumor was successfully performed by membranous tracheal reconstruction with a pedicled autogenous pericardial patch graft.

Mediastinal granuloma.

In a group of 47 patients with mediastinal granulomas, the most common clinical symptoms were cough, chest pain, dysphagia, hemoptysis, and dyspnea. The main laboratory findings were right paratracheal or hilar mass on chest roentgenogram, positive histoplasmin skin test, and caseating granuloma on histopathologic examination. Complications included fibrosing mediastinitis with superior vena cava obstruction, esophageal compression, and major upper airway compression. Treatment was usually surgical resection or evacuation of caseous contents. The prognosis in most patients with mediastinal granulomas appears to be good--long-term survival with minimal or no disability.

Horseshoe kidney associated with surgery of the abdominal aorta.

Of 53 patients with horseshoe kidney (9 in the present series), 45 underwent operation for an abdominal aortic aneurysm: 40 electively and 5 on an emergency basis. The remaining eight patients underwent revascularization for arteriosclerosis obliterans. Of the 53 patients, 35 (66%) had renal artery anomalies. The anomalous arteries prevented aortic repair in 6 patients (17%), were left undisturbed in 9 (26%), were revascularized in 7 (20%), and were ligated in 13 (37%). Partial nephrectomy was required in 2 of the 13 patients undergoing arterial ligation. Symphysiotomy was performed in 16 (30%) of the 53 patients. The following approach to management of horseshoe kidney associated with disease of the abdominal aorta is suggested. 1. Whenever a horshoe kidney is suspected, excretory urography, aortography, and, if necessary, selective renal arteriography should be obtained preoperatively. 2. Anomalous renal arteries arising from resected segments of the aorta should be revascularized whenever technically possible, usually by reimplantation of the renal artery into the aortic graft. 3. If an anomalous renal artery is ligated, the kidney should be inspected for signs of ischemia, and partial nephrectomy should be performed if ischemia occurs. 4. Symphysiotomy should be avoided. If division is necessary, symphysiectomy is preferable to symphysiotomy. In either circumstance, care need be taken lest there be fusion of the urinary collecting system and the renal parenchyma. In most patients with horseshoe kidney, aortic surgery has been accomplished without complication and with only minor alteration in surgical technique, even when the renal anomaly is first detected at surgical exploration.

Splenic arteriovenous fistula.

A patient with an uncalcified splenic artery aneurysm with an arteriovenous fistula and aneurysmal dilatation of the splenic vein who underwent splenectomy and resection of the fistula is described. Splenic arteriovenous fistulas are rare and are usually associated with aneurysms of the splenic artery. Patients with these fistulas frequently have signs and symptoms of portal hypertension and may often present with upper gastrointestinal hemorrhage. The patient described in this report was asymptomatic, and the only manifestation of the fistula was a loud, continuous bruit in the left flank noted on routine physical examination. Although an upper abdominal incision can be used to manage most splenic artery aneurysms, a left thoracoabdominal incision is advocated in the presence of an arteriovenous fistula, particularly in anticipation of portal hypertension or aneurysm of the splenic vein.

Current techniques for the surgical management of malignant lesions of the thoracic esophagus and cardia.

Cancers of the esophagus and cardia remain serious conditions that cause many thousands of deaths every year throughout the world. In North America, cancer of the esophagus and gastric cardia is an endemic disease of low order and stable incidence. Nevertheless, it is responsible for many deaths and considerable suffering. With current methods of treatment, substantial palliation and amelioration of patient disability are possible, and some patients gain long-term survival with comfort and even cure. A combination of surgical resection and reconstruction is the chief modern method of management of such cancers. Herein we discuss a variety of standard surgical procedures that are currently available and present detailed illustrations of these procedures. The selection of a specific operation depends largely on the site of the neoplasm. With all these procedures, function is restored and the local and regional neoplastic tissue is removed without compromising the potential for cure. Associated operative mortality is approximately 7%. The late results of the operations illustrated depend primarily on the cell type, grade, and stage of the neoplasm encountered at the time of surgical treatment. For patients who have undergone resection, 5-year survival rates have ranged from 15 to 54%, the results depending on the stage of the cancer. Of equal importance is the fact that oral diet can be maintained in 93% of patients despite recurrence of the neoplasm.

The primary surgical treatment of carcinoma of the breast: a changing trend toward modified radical mastectomy.

To study the effectiveness of a trend at the Mayo Clinic toward modifying the standard radical mastectomy, the 5-year survival of 873 women treated surgically for breast cancer from 1965 through 1968 was evaluated. The observed survival of 534 patients treated by the standard radical mastectomy was 85% when nodes were negative and 56% when nodes were positive. For 339 patients treated by the modified radical mastectomy, the observed survival was 80% and 48% when axillary nodes were negative and positive, respectively. In order to accomplish a more significant analysis of cancer risk and results of the two operative procedures, a relatively homogeneous group of 541 patients was established from the total group. In this homogeneous group, the observed survival of 336 patients treated by the standard radical mastectomy was 86% when nodes were negative and 66% when nodes were positive. For 205 patients treated by the modified radical mastectomy, the observed survival was 84% and 66% when axillary nodes were negative and positive, respectively. When patients were further analyzed and compared according to the extent of axillary-node involvement, age at the time of treatment, grade, size, location, and histopathologic type of tumor, and the use of postoperative irradiation, survival was essentially the same, irrespective of the type of mastectomy performed.

Dumbbell neurogenic tumors of the mediastinum. Diagnosis and management.

Among 706 collected cases of mediastinal neurogenic tumors were 69 patients (9.8%) with extension through an intervertebral foramen, so that the composite neoplastic mass was dumbbell-shaped. Although only 10% of these dumbbell tumors were malignant, the majority of the patients presented with neurologic symptoms of spinal cord compression. In about 40% of reported cases, the intraspinal component, although present, was not clinically apparent. Such cases of asymptomatic intraspinal extension should be suspected when special roentgenologic views of the spine demonstrate erosion of the vertebral pedicle or enlargement of the intervertebral foramen adjacent to the posterior mediastinal mass. Workup of these patients should include myelographic studies to determine whether a dumbbell tumor is indeed present; if it is, surgery should be carried out by a team of thoracic surgeons and neurosurgeons in a one-stage combined resection of both the intraspinal and the mediastinal component of the tumor. With early diagnosis and surgical intervention, long-term survival is the rule. When the patient is in the pediatric age bracket, an orthopedic surgeon should be included on the team to help minimize subsequent skeletal growth deformity.

Pulmonary alveolar microlithiasis. A review including ultrastructural and pulmonary function studies.

Pulmonary alveolar microlithiasis is a rare disease of unknown cause in which calcium phosphate microliths are deposited throughout the lungs. These deposits are of sufficient density to be almost diagnostic on chest roentgenograms. The Mayo Clinic experience with 8 patients is added to the approximately 120 cases reported in the world literature. The age range of all patients is from newborn to 80 years, with a mean age at diagnosis of about 35 years. No sexual predominance has been noted, but in about half of the reported cases a familial pattern has been found. The progression of the disease is generally very slow, some patients having been followed up for more than 30 years without evidence of change. No specific treatment is available. Pulmonary function studies demonstrate a tendency toward a restrictive pattern. Technetium-99m scanning and scanning and transmission electron microscopy are useful procedures for analysis of pulmonary alveolar microliths.

An integrated approach to evaluation of the solitary pulmonary nodule.

In this article, we describe an integrated approach for detection and evaluation of solitary pulmonary nodules. Initial evaluation of the solitary pulmonary nodule includes tomography, fluoroscopy, and comparison with previously obtained roentgenograms. Subsequently, thin-section computed tomography and phantom densitometry can be used for analysis, if indicated. The rationale for the use of computed tomography in the radiologic staging of bronchogenic carcinoma is to expedite and assist in the identification of the subset of patients with resectable tumors. For nonsurgical tissue diagnosis, fiberoptic bronchoscopy is generally the initial procedure for lesions 2.0 cm or larger in diameter, and transthoracic needle biopsy is used for those smaller than 2.0 cm.

Clinical application of a new endoscopic technique for detection of in situ bronchial carcinoma.

Hematoporphyrin is preferentially concentrated by cancer tissue and therefore is a potentially useful chemical marker. This report demonstrates the effectiveness of a photoelectric hematoporphyrin fluorescence detector used simultaneously with flexible fiberoptic bronchoscopy as a means of detecting and localizing bronchogenic carcinoma. The detector generates an audio signal when fluorescence is within the visual field of the bronchoscope. Of interest is that an audio signal was generated which indicated hematoporphyrin fluorescence in areas where no mucosal abnormality had been seen. These areas proved to be carcinoma in situ.

Pulmonary lymphangiomyomatosis: with particular reference to steroid-receptor assay studies and pathologic correlation.

The symptoms of progressive dyspnea, hemoptysis, spontaneous pneumothorax, chylous effusions, and cough in conjunction with ventilatory obstruction and abnormal gas exchange in a young woman should prompt the diagnosis of pulmonary lymphangiomyomatosis. Cytosol steroid-receptor assays and postmortem studies were conducted in an extensive investigation of a case of this disease. A biopsy specimen of the lung disclosed evidence of nuclear translocation of [3H]progesterone and the presence of a cytosolic receptor for progesterone, an indication that this disease could be treated effectively with progestin.

Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period.

During the first 10 years of the Mayo Lung Project, 68 roentgenographically inapparent ("occult") lung cancers were localized and apparently completely resected. A pathologic classification was developed based on depth of tumor infiltration. The five categories were (1) in situ carcinoma confined to surface epithelium or ducts of mucous glands or acini (23 cancers), (2) intramucosal invasion not greater than 0.1 cm from mucosal surface (12 cancers), (3) invasion to bronchial cartilages (11 cancers), (4) invasion to full thickness of bronchial wall (10 cancers), and (5) extrabronchial invasion (12 cancers). Multicentricity of lung cancer was studied in 54 patients, none of whom had a history of cancer of the respiratory tract, and all of whom had had "complete" surgical resection of the initial occult lung cancer (or cancers). Neoplasms that were initially multicentric occurred in 4 patients, and a subsequent primary lung cancer developed in 11. The rate of detection of second primary lesions was 42 per 1,000 person-years of observation. A high incidence of unresectable cancers and a low survival rate were noted among patients who had a subsequent primary tumor. These findings were primarily attributable to invasiveness of the subsequent primary cancer or to respiratory insufficiency that resulted from obstructive lung disease or previous pulmonary resection. Because of the high risk of development of a second primary cancer after initial surgical resection, it is important to treat the initial occult cancer as conservatively as possible consistent with "cure."

Multiple primary lung cancers. Results of surgical treatment.

During a 13-year period, multiple primary lung cancers were diagnosed in 80 consecutive patients. Forty-four patients had metachronous cancers. The initial pulmonary resection was lobectomy in 36 patients, bilobectomy in 3, pneumonectomy in 1, and wedge excision or segmentectomy in 4. The second pulmonary resection was lobectomy in 16 patients, bilobectomy in 2, completion pneumonectomy in 7, and wedge excision or segmentectomy in 19. There were two 30-day operative deaths (mortality rate, 4.5%). Actuarial 5- and 10-year survival rates after the first pulmonary resection for stage I disease were 55.2% and 27.0%, respectively. Five-year and 10-year survival rates for stage I disease after the second pulmonary resection were 41.0% and 31.5%, respectively. The remaining 36 patients had synchronous cancers. The pulmonary resection was lobectomy in 18 patients, bilobectomy in 3, pneumonectomy in 10, and wedge excision or segmentectomy in 8. There were two 30-day operative deaths (mortality rate, 5.6%). Actuarial overall 5- and 10-year survival rates after pulmonary resection were 15.7% and 13.8%, respectively. We conclude that an aggressive surgical approach is safe and warranted in most patients with multiple primary lung cancers and that the presence of synchronous primary cancers is ominous.

Management of instrumental perforations of the esophagus.

Experience with 47 consecutive instrumental perforations of the esophagus is described. Perforation occurred in the cervical esophagus in 18 patients, mid-thoracic esophagus in 12, and distal esophagus in 17. The majority of patients (87%) harbored a primary esophageal disorder necessitating esophageal instrumentation. Eight select patients were treated nonoperatively with one death; however, some form of morbidity with prolonged hospital stay occurred in half of these patients. In contrast, 39 patients underwent emergency surgical intervention. Only one death occurred in the 31 patients treated by local drainage and attempted closure of the perforation. However, three of six patients with distal perforations treated by esophageal resection with primary esophagogastrostomy died in the early postoperative period. Our results suggest that most instrumental perforations of the esophagus should be managed surgically. Drainage and closure of cervical perforations yields goods results. Esophageal resection with primary reconstitution of esophagogastric continuity should be reserved for select situations. Nonoperative management might be entertained in minimally symptomatic patients harboring a late, locally contained perforation without signs of ongoing sepsis.

A technique for continuous intercostal nerve block analgesia following thoracotomy.

Early after thoractomy, incisional chest pain may lead to a sequence of undersirable effects on respiratory function, in addition to causing patient discomfort. Pharmacologic blockade of the intercostal nerves innervating the incisional area can improve respiratory function as well as patient comfort. The postoperative production of continuous intercostal nerve blockade can be accomplished by the insertion of indwelling analgesic catheters at the time of thoracotomy closure.