M. Wayne Flye

Evaluation of computed tomography in the detection of pulmonary metastases. A prospective study

Conventional linear x‐ray tomography is often used to search for pulmonary metastases but tends to underestimate extent of disease when compared with operative findings. In a prospective study, operative findings were correlated with computed axial tomography and conventional linear tomography performed on 25 patients with a history of extrathoracic malignancy and pulmonary nodules. Computed tomography detected 69 nodules of which 31 proved to be metastases. Conventional linear tomography detected 38 nodules of which 25 were metastases. Of the 54 resected nodules measuring >3 mm, computed tomography detected 42; whereas conventional tomography detected 32. Only six of the 31 additional nodules (20%) detected by computed tomography and not by conventional tomography proved to be metastases. These results suggest that computed tomography is more sensitive than conventional tomography in detecting small pulmonary nodules; however, there is diminished specificity in identifying metastatic nodules. Cancer 43:913–916, 1979.

Prospective evaluation of aspiration needle, cutting needle, transbronchial, and open lung biopsy in patients with pulmonary infiltrates.

Twenty consecutive patients with pulmonary infiltrates undiagnosed by routine, noninvasive methods were entered into a prospective study designed to evaluate the diagnostic yield of four methods of lung biopsy. Percutaneous aspiration needle, cutting needle, transbronchial, and open (anterior thoracotomy) biopsy were performed synchronously on all patients. Specimens were evaluated by microbiological, virological, and pathological methods. The diagnostic yields of the four methods were as follows: aspiration needle, 29%; cutting needle, 53%; transbronchial, 59%; and open lung biopsy, 94%. Open lung biopsy was significantly better in yielding a diagnosis than aspiration needle (p less than 0.001), cutting needle (p less than 0.001), and transbronchial biopsy (p less than 0.04).

The Treatment of Recurrent Malignant Pleural Effusion

Effective control of a recurrent malignant pleural effusion can greatly improve the quality of life of the cancer patient. At least a dozen different techniques have been advocated for controlling this common complication of malignant disease. The present review collects and examines the clinical results of all techniques designed to treat this problem. The pathophysiology and diagnostic evaluation of the effusion are also discussed. On the basis of comparisons involving effectiveness, morbidity, and convenience, we recommend intrapleurally administered tetracycline with thoracostomy drainage as the technique of choice. Instillation of a talc suspension with thoracostomy drainage is also a safe and effective technique and should be employed when tetracycline fails or is contraindicated.

Management of Nontraumatic Chylothorax

Twenty-two patients with chylothorax have been treated at the National Institutes of Health since 1955. In 9 of these patients, the condition resulted from an antecedent operation and in 13, it occurred without a history of prior operation (nontraumatic). All 6 of the patients with tumors in whom nontraumatic chylothorax developed had a lymphoma. Four of these 6 also had a chylous ascites, while 6 of the 7 patients without tumors had an associated chylous ascites. Only 3 of the 13 patients with nontraumatic chylothorax responded to nonoperative therapy alone with stabilization of the pleural effusions. A single patient with systemic lupus erythematosus responded to steroid therapy. In contrast, 3 of 4 patients who underwent thoracotomy for nontraumatic chylothorax had permanent relief of their chylous pleural effusions. In the absence of medically treatable disease, thoracotomy with ligation of the thoracic duct and/or pleurectomy or pleurodesis can provide substantial palliation for patients with nontraumatic chylothorax, even when a discrete source of lymph leakage cannot be localized or ascites is present. Early surgical therapy of nontraumatic chylothorax is advocated in such circumstances.

Aggressive pulmonary resection for metastatic osteogenic and soft tissue sarcomas

From July, 1974, to July, 1979, 36 patients with osteogenic sarcoma and 25 patients with soft tissue sarcoma underwent a total of 95 thoracotomies for resection of isolated pulmonary metastases. In only 6 patients could all palpable disease not be resected, although it was certain that microscopic disease remained in some patients. Twenty-six patients underwent more than 1 thoracotomy. The pulmonary lesions were found not to be metastases in 4 patients with osteogenic sarcoma and 4 with soft tissue sarcoma. The four-year survival for patients with nonsynchronous metastases from osteogenic sarcoma was 44%, not significantly different from a survival of 35% for patients with soft tissue sarcoma. The 6 patients with synchronous osteogenic sarcoma metastases all died within 16 months. Survival following thoracotomy did not correlate statistically with time from primary tumor resection to lung recurrence, unilateral versus bilateral disease, or number of nodules. For the 33 patients in whom tumor doubling time could be calculated, survival with either type of sarcoma was significantly better in patients with a tumor doubling time greater than 40 days versus a tumor doubling time less than or equal to 40 days. Any patient with metastatic osteogenic sarcoma or soft tissue sarcoma confined to the lungs should be considered for resection in conjunction with chemotherapy.

Autoregulation by Eicosanoids of Human Kupffer Cell Secretory Products A Study of Interleukin-1, Interleukin-6, Tumor Necrosis Factor-α, Transforming Growth Factor-β, and Nitric Oxide

ObjectiveMethods employed previously to analyze the secretory behavior of rodent Kupffer cells (KC) were used to examine the human KCs secretory response to lipopolysaccharide (LPS). Summary Background DataAs the resident hepatic macrophage, the KC resides at the interface between the portal and systemic circulations. Consequently, this cell may play an integral role in the immune response to antigens and bacteria in the sinusoid. Study of cytokine production by the KC has relied predominantly on the rat as the source of these cells. Whether human KCs respond similarly to rat KCs after LPS stimulation has been a matter of speculation. MethodsKupffer cells obtained from seven human livers were tested under conditions identical to those used to study rat KCs. Kupffer cells rested for 12 hours after isolation were stimulated with LPS (2.5 μg/mL). Arginine concentration in the culture medium varied from 0.01 to 1.2 mM. To examine the role of eicosanoids, parallel culture wells received indomethacin (10 μM). Culture supematants were assayed for interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), prostaglandin E2 (PGE2), and nitric oxide. ResultsSimilar to the rat KC, LPS-stimulated human KCs released IL-1, IL-6, TNF-α, TGF-β, and PGE2. However, unlike rat KCs, nitric oxide could not be detected, regardless of whether the human KCs were exposed to LPS, interferon-γ (INF-γ), or LPS + IFN-γ. Similar to rat KCs, indomethacin prevented PGE2 release while significantly upregulating TNF-α, IL-1, and IL-6, but not TGF-β, consistent with an autoregulatory control of eicosanoids over proinflammatory cytokines. As has been shown in the rat, physiologic levels of L-arginine (0.01 mM) significantly enhanced LPS-induced PGE2 secretion relative to the response in medium containing standard L-arginine concentration (1.2 mM); however, unlike the rat KC, the humans cytokine response to LPS was not downregulated by this enhanced PGE2 release.

Effect of Ca2+ agonists in the perfused liver: determination via laser scanning confocal microscopy

Ca2+ is a critical intracellular second messenger, but few studies have examined Ca2+ signaling in whole organs. The amplitude and frequency of Ca2+ oscillations encode important cellular information. Using laser scanning confocal microscopy in the indo 1 acetoxymethyl ester dye-loaded rat liver, we investigated the effect of various Ca2+ agonists that act at distinct mechanistic sites on Ca2+ signaling. Perfusion with suprathreshold doses of arginine vasopressin (AVP) (2-20 nM) caused a single Ca2+ wave that originated in the pericentral vein region and spread centrifugally to the periportal area. Lower doses of AVP (0.2-2 nM) caused multiple Ca2+ waves and Ca2+ oscillations. Perfusion with ATP (1. 4-17.5 microM) caused rapid transient elevations in intracellular free Ca2+ concentration ([Ca2+]i) occurring in isolated hepatocytes or groups of hepatocytes throughout the lobule and were of shorter duration than those due to AVP. Also in contrast to AVP, there was no specific anatomic location within the hepatic lobule that was more susceptible to ATP. Thapsigargin and cyclopiazonic acid did not cause a Ca2+ wave but rather produced a uniform and fairly simultaneous increase in [Ca2+]i in all hepatocytes in the lobule. Perfusion with 14 microM ryanodine produced a single transient spike in [Ca2+]i in a small number (<2%) of hepatocytes. Dantrolene, an inhibitor of Ca2+ release, reduced the increased [Ca2+]i occurring after AVP. Insight into the mechanism of action of these Ca2+-active compounds on Ca2+ signaling in the intact liver is provided.Ca2+is a critical intracellular second messenger, but few studies have examined Ca2+ signaling in whole organs. The amplitude and frequency of Ca2+ oscillations encode important cellular information. Using laser scanning confocal microscopy in the indo 1 acetoxymethyl ester dye-loaded rat liver, we investigated the effect of various Ca2+ agonists that act at distinct mechanistic sites on Ca2+ signaling. Perfusion with suprathreshold doses of arginine vasopressin (AVP) (2-20 nM) caused a single Ca2+ wave that originated in the pericentral vein region and spread centrifugally to the periportal area. Lower doses of AVP (0.2-2 nM) caused multiple Ca2+ waves and Ca2+ oscillations. Perfusion with ATP (1.4-17.5 μM) caused rapid transient elevations in intracellular free Ca2+concentration ([Ca2+]i) occurring in isolated hepatocytes or groups of hepatocytes throughout the lobule and were of shorter duration than those due to AVP. Also in contrast to AVP, there was no specific anatomic location within the hepatic lobule that was more susceptible to ATP. Thapsigargin and cyclopiazonic acid did not cause a Ca2+ wave but rather produced a uniform and fairly simultaneous increase in [Ca2+]iin all hepatocytes in the lobule. Perfusion with 14 μM ryanodine produced a single transient spike in [Ca2+]iin a small number (<2%) of hepatocytes. Dantrolene, an inhibitor of Ca2+ release, reduced the increased [Ca2+]ioccurring after AVP. Insight into the mechanism of action of these Ca2+-active compounds on Ca2+ signaling in the intact liver is provided.

Aortic graft-enteric and paraprosthetic-enteric fistulas☆

Gastrointestinal hemorrhage is often a late manifestation of an aortoenteric fistula. Warning symptoms may include back or abdominal pain, fever, anemia, hematochezia, or melena. This entity results from erosion of the gastrointestinal tract by an adjacent vascular prosthesis. A paraprosthetic-enteric fistula represents a step in the formation of a true aortoenteric communication. Aggressive diagnostic studies, including endoscopy, aortography, barium contrast, computerized axial tomography, and radionuclide scanning, may allow earlier diagnosis and correction than have occurred in the past. Treatment should include graft excision, closure of the bowel defect, appropriate antibiotic therapy, and extraanatomic revascularization if collateral flow is not adequate. Our experience with 21 patients has illustrated the high mortality rate (74 percent) when operative treatment is delayed until massive hemorrhage occurs.

The Role of Thoracotomy in the Management of Pulmonary Metastases from Malignant Melanoma

Thirty-three patients over a 21-year period underwent thoracotomy for resection of suspected pulmonary metastases from malignant melanoma. Eleven patients were found to have nonmalignant disease (Group 1); 10 were found to have unresectable disease (Group 2); and 12 were rendered disease-free (Group 3). Of the patients found to have melanoma, 20 of 22 received post-operative chemotherapy. The median survival of the patients in Group 2 was 10.5 months (3 to 20 months); in Group 3 it was 12 months (3 to 35 months). There were no 5-year survivors. No factors distinguished the three groups preoperatively. Surgical resection still offers the greatest chance for long-term survival, based on reports of patients in the literature who have survived longer than 5 years following resection of pulmonary metastases from melanoma. Thoracotomy is especially useful for staging purposes in those patients found to have no metastatic disease.

Donor-specific antigen transfusion-mediated skin-graft tolerance results from the peripheral deletion of donor-reactive CD8+ T cells

Background. The mechanism of donor-specific transfusion (DST)-induced long-term skin-graft survival is examined in 2CF1 (2C×dm2) transgenic and B6F1 (C57BL/6×dm2) nontransgenic mice in which CB6F1 (Balb/c×B6) DST and donor skin grafts differ from 2CF1 or B6F1 recipients only at major histocompatibility complex class I Ld. Methods. Saline (control) or allogeneic CB6F1 spleen cells were injected intravenously into 2CF1 and B6F1 mice. One week later, CB6F1 tail skin was transplanted onto the dorsum of these mice. Fluorescence-activated cell sorter analysis (flow cytometric analysis) of peripheral blood was performed 2 days before DST, 5 days after DST, and 7, 14, 21, 28, and 75 days after skin grafting. Splenocyte responsiveness was measured by in vitro mixed lymphocyte culture and cytotoxic T lymphocyte. Cytokine protein production (interleukin [IL]-2 and interferon-&ggr;) was measured by enzyme-linked immunosorbent assay. Results. Whereas all CB6F1 skin grafts in control saline-treated 2CF1 and B6F1 mice were rejected, 100% of 2CF1 and B6F1 pretreated with CB6F1 DST accepted the class I Ld disparate donor skin indefinitely. DST followed by a CB6F1 skin graft led to a significant deletion of donor-reactive CD8+ T cells by fluorescence-activated cell sorter analysis and decreased production of the inflammatory cytokines IL-2 and interferon-&ggr;. The hyporesponsiveness of residual CD8+ T cells in mixed lymphocyte culture and cytotoxic T lymphocyte to Ld after DST was restored to normal by IL-2. Conclusion. These findings demonstrate that administration of DST uniformly results in long-term Ld+ skin-allograft acceptance. This tolerance induction is related to both a significant decrease in donor-reactive CD8+ transgenic T cells and anergy of the residual CD8+ T cells.