Short-term and long-term outcomes after bilateral lung volume reduction surgery : prediction by quantitative CT.

OBJECTIVES: To evaluate selection criteria and duration of benefit for patients undergoing lung volume reduction surgery (LVRS). METHODS: Eighty-nine consecutive patients with severe emphysema who underwent bilateral LVRS were prospectively followed up for up to 3 years. Patients underwent preoperative pulmonary function testing, 6-min walk, chest CT, and answered a baseline dyspnea questionnaire. CT scans in 65 patients were analyzed for emphysema extent and distribution using the percentage of emphysema in the lung, percentage of normal lower lung, and the CT emphysema ratio (CTR, an index of the craniocaudal distribution of emphysema). All patients underwent at least 6 weeks of pulmonary rehabilitation prior to surgery. Outcome measures were FEV(1), 6-min walk distance, and transitional dyspnea index (TDI). RESULTS: Compared to baseline, FEV(1) was significantly increased at 3, 6, 12, 18, 24, and 36 months after surgery (p < or = 0.008). The 6-min walk distance increased from 871 feet (baseline) to 1,110 feet (3 months), 1,214 feet (6 months), 1,326 feet (12 months), 1,342 feet (18 months), 1,371 feet (24 months), and 1,390 feet (36 months) after surgery. Despite a decline in FEV(1) over time, 6-min walk distance was preserved. Dyspnea as measured by TDI improved at 3, 6, 12, 18, 24, and 36 months after surgery. A high CTR was the best predictor of a 12% increase over baseline and an absolute increase of 200 mL in FEV(1), although with a low area under the receiver operating characteristic curve. In addition, the sensitivity and negative predictive value of the CTR were limited. No radiographic or physiologic predictor was able to consistently predict a successful increase in walk distance or TDI. CONCLUSION: LVRS improves pulmonary function, decreases dyspnea, and enhances exercise capacity in many patients with severe emphysema, although improvement wanes 36 months after surgery.

Chemokine receptor 1 knockout abrogates natural killer cell recruitment and impairs type-1 cytokines in lymphoid tissue during pulmonary granuloma formation.

Mice with targeted mutation of chemokine receptor 1 (CCR1) were used to assess the contribution of CCR1 agonists to local, regional, and systemic inflammatory-related events during experimental pulmonary granuloma formation. Models of Th1 (type-1) and Th2 (type-2) cell-mediated lung granulomas were induced in wild-type (CCR+/+) and knockout (CCR1-/-) mice by embolizing Sepharose beads coupled to the purified protein derivative of Mycobacterium bovis or soluble antigens derived from Schistosoma mansoni eggs. Morphometric analysis indicated that granuloma sizes were unchanged in CCR1-/- mice, but flow cytometric analyses of dispersed granulomas revealed that natural killer cell recruitment to type-1 lesions was abrogated by 60%. Analysis of cytokine production by draining lymph node cultures showed altered expression in CCR1-/- mice characterized by reduced interleukin-2 and interferon-gamma in the type-1 response, and enhanced interleukin-5 and interleukin-13 in the type-2 response. Peripheral blood leukocytosis was also enhanced in the type-1 but not the type-2 response. These findings suggest that CCR1 agonists contribute to multiple immunoinflammatory events in the type-1 granulomatous response with natural killer cell accumulation being particularly sensitive to CCR1 disruption. Although functional efficacy of granulomas may be altered, chemokine redundancy and cytokine reserve seem to make the bulk of the exudative response resistant to CCR1 disruption.

Weight gain after lung volume reduction surgery is not correlated with improvement in pulmonary mechanics.

STUDY OBJECTIVES: Malnutrition and low body weight are common in patients with emphysema. Previous work has demonstrated correlation between severity of airflow obstruction and body weight. Lung volume reduction surgery (LVRS) is a recent advance in the treatment of patients with severe emphysema that results in improved pulmonary function. We formed the hypothesis that improved lung mechanics after LVRS would result in body weight gain. DESIGN: Retrospective chart review. PATIENTS: All patients who underwent bilateral LVRS for severe emphysema at the University of Michigan between January 1995 and April 1996 were eligible for the study. MEASUREMENTS AND RESULTS: Pulmonary function and body weight were measured preoperatively and at 3, 6, and 12 months postoperatively for patients who underwent bilateral LVRS between January 1995 and April 1996. The average weight gain in 38 patients returning for 12 months of follow-up was 3.8 +/- 0.9 kg, or 6.2% of the preoperative weight. Women gained significantly more weight than men (9.2 vs 2.2%, respectively) at 1 year. Interestingly, there was no correlation between change in weight and postoperative change in FEV(1), FVC, residual volume (RV), total lung capacity (TLC), or RV/TLC at 12 months. However, there was a statistically significant correlation between weight gained and improvement in diffusion of carbon monoxide measured 12 months postoperatively. CONCLUSIONS: This study shows that patients with severe emphysema gain weight after LVRS. These changes were independent of changes in pulmonary mechanics but may be a result of improved gas exchange. These findings provide further information about benefits of LVRS in patients with advance emphysema that are beyond simple changes in pulmonary function.

Effect of C-C chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses.

Monocyte chemotactic protein (MCP)-1 is postulated to play a role in cellular recruitment during inflammatory reactions. C-C chemokine receptor 2 (CCR2) is considered the major G-protein coupled receptor for MCP-1/JE. We reported that mice with knockout of the CCR2 gene display partially impaired type-1 granuloma formation. The present study similarly examined the effect of CCR2 deficiency on synchronously developing type-2 (Th2) cytokine-mediated lung granulomas elicited by embolization of beads coated with Ags of Schistosoma mansoni eggs. Systemically, blood monocytes were reduced by about half throughout the 8-day study period. At the local level, granuloma size and macrophage content were impaired during the early growth phase (days 1 to 2). By day 4, granuloma sizes were similar to controls. In granulomatous lungs, CCR2 knockout increased mRNA for CCR2 agonists, MCP-1, MCP-3, and MCP-5, but reduced IL-4 and IFNgamma mRNA. The latter was possibly related to decreased CD4+ T cell recruitment. Regionally, draining lymph nodes showed panlymphoid hyperplasia with impaired production of IFNgamma, IL-2, and IL-4, but not IL-5, IL-10, or IL-13. Analysis of procollagen gene expression indicated transient impairment of procollagen III transcripts on day 4 of granuloma formation. These findings indicate that agonists of CCR2 contribute to multiple facets of type-2 hypersensitivity granulomatous inflammation.

Preoperative echocardiographic evaluation of patients referred for lung volume reduction surgery.

BACKGROUND: The most efficient preoperative assessment for lung volume reduction surgery (LVRS) in patients with advanced emphysema is undefined. This study analyzed the preoperative assessment of patients by surface echocardiography (without and with dobutamine infusion), the results of which were used to exclude patients with significant pre-existing cardiac disease, a contraindication to LVRS, from the surgery. SETTING: A university-based, tertiary care referral center. METHODS: Patients with emphysema who met initial LVRS screening criteria underwent resting and stress surface echocardiography with Doppler imaging. Patients were evaluated prospectively for perioperative cardiac complications. RESULTS: Between July 1994 and December 1996, 503 candidates for LVRS were evaluated. Of these, 207 patients (81.8%) who had echocardiography performed at our institution formed the primary study group. Images were adequate for the analysis of chamber sizes and function in 206 patients (99.5%) undergoing resting echocardiography, and the images were adequate for wall motion analysis in 172 of 174 patients (98.9%) undergoing functional testing. Right heart abnormalities were common (40.1%). Significant pulmonary hypertension (> 35 mm Hg) was uncommon (5 patients, 5.4%) among the 92 patients who subsequently underwent right heart catheterization. Occult ischemia, left ventricular dysfunction, and valvular abnormalities also were uncommon. Thus, although Doppler imaging estimates of right ventricular systolic pressure were imperfect, echocardiographic findings of normal right heart anatomy and function excluded significant pulmonary hypertension. Ninety patients (43%) eventually underwent LVRS (70 bilateral and 20 unilateral). A total of 13 perioperative cardiac events occurred in 10 patients, 6 of whom had undergone preoperative echocardiography. No patient suffered acute myocardial infarction or cardiac death. CONCLUSIONS: Despite potential limitations due to severe obstructive lung disease, surface echocardiographic imaging is a feasible, noninvasive tool in this patient population to identify patients with evidence of cor pulmonale that suggests pulmonary hypertension. The routine use of surface resting and stress echocardiography for preoperative screening obviates the need for invasive right heart catheterization in many patients and results in a low incidence of significant perioperative cardiac complications.

Lung volume reduction surgery alters management of pulmonary nodules in patients with severe COPD.

OBJECTIVE: To examine the role of lung volume reduction surgery (LVRS) in expanding the treatment options for patients with single pulmonary nodules and emphysema. METHODS: Retrospective review of all patients undergoing LVRS at the University of Michigan between January 1995 and June 1996. Those undergoing simultaneous LVRS and resection of a suspected pulmonary malignancy formed the study group and underwent history and physical examination, pulmonary function tests, chest radiography, and high-resolution CT of the chest. If heterogeneous emphysema was found, cardiac imaging and single-photon emission CT perfusion lung scanning were performed. All study patients participated in pulmonary rehabilitation preoperatively. Age- and sex-matched patients who had undergone standard lobectomy for removal of pulmonary malignancy during the same period formed the control group. RESULTS: Of 75 patients who underwent LVRS, 11 had simultaneous resection of a pulmonary nodule. In 10 patients, the nodules were radiographically apparent with 1 demonstrating central calcification. Histologic evaluation revealed six granulomas, two hamartomas, and three neoplastic lesions (one adenocarcinoma, one squamous cell, and one large cell carcinoma). Preoperative FEV1 was 26.18+/-2.49% predicted in the LVRS group and 81.36+/-6.07% predicted (p=0.000001) in the control group, and the FVC was 65.27+/-5.17% predicted vs 92.18+/-5.53% predicted (p=0.002). Two LVRS patients had a PaCO2 >45 mm Hg while 11 exhibited oxygen desaturation during a 6-min walk test. Postoperative complications occurred in two LVRS patients and three control patients. The mean length of stay in the LVRS group (7.55+/-1.10 days) was not different than in the control group (8.81+/-1.56 days). Three months after LVRS and simultaneous nodule resection, FEV1 rose by 47%, FVC by 25%, and all study patients noted less dyspnea as measured by transitional dyspnea index. CONCLUSIONS: Simultaneous LVRS and resection of a suspected bronchogenic carcinoma is feasible and associated with minimal morbidity and significantly improved pulmonary function and dyspnea.

Lung lymphocyte elimination by apoptosis in the murine response to intratracheal particulate antigen.

Pulmonary immune responses are suited to determine mechanisms of lymphocyte elimination, as lung inflammation must be regulated tightly to preserve gas exchange. The self-terminating response of primed C57BL/6 mice to intratracheal challenge with the T cell-dependent Ag sheep erythrocytes (SRBC) was used to test the importance of lung lymphocyte apoptosis in pulmonary immunoregulation. Apoptosis of alveolar and interstitial lymphocytes was demonstrated morphologically, by three independent methods to detect DNA fragmentation, and by surface expression of phosphatidylserine. Apoptotic lymphocytes were exclusively CD4-, CD8-, B220-, but many were CD3+ and Thy 1+. Inhibiting apoptosis by in vivo cyclosporine treatment prolonged lung lymphocyte accumulation following SRBC challenge. Experiments using mice homozygous for the lpr or gld mutations showed that pulmonary lymphocyte apoptosis depended on expression of Fas (CD95) and its ligand (Fas-L). Pulmonary inflammation increased on repeated intratracheal SRBC challenge of lpr/lpr mice, in contrast to the waning response in normal mice. These results confirm that in situ lymphocyte apoptosis contributes to termination of immune responses in nonlymphoid organs, probably because of activation-induced cell death, and may be important in inducing tolerance to repeated antigen exposure.

Down-regulation of the afferent phase of T cell-mediated pulmonary inflammation and immunity by a high melanin-producing strain of Cryptococcus neoformans.

The interaction(s) between cryptococcal virulence factors and leukocytes involved in generating protective cell-mediated immunity is not well defined. Intratracheal inoculation of Cryptococcus neoformans strain 52 induced a vigorous T cell-mediated pulmonary inflammatory response that controlled the growth of the organism. In contrast, strain 145 induced a pulmonary inflammatory response that was delayed in onset, slower to develop, and ineffective in controlling the infection. In addition, the expansion of cryptococcus-specific lymphocytes in the pulmonary lymph nodes and titer of specific Abs in the serum of strain 145-infected mice were both diminished markedly. Of the known cryptococcal virulence factors, these two strains differed only in melanin production (52-low and 145-high). Heat-killed strain 145 cryptococci (HKC-145) that had been rendered melanin-negative induced TNF-alpha production by alveolar macrophages in vitro and stimulated vigorous cryptococcus-specific lymphoproliferation. In contrast, high melanin-containing HKC-145 inhibited TNF-alpha production and lymphoproliferation. In vivo, mice infected with melanin low strain 52, but not melanin high strain 145, had elevated levels of TNF-alpha in the bronchoalveolar lavage fluid. Mice co-infected with strains 145 and 52 generated a pulmonary inflammatory response resulting in increased long-term survival. Taken together, these studies demonstrate that melanin does not protect cryptococci from being eliminated in vivo by recruited, activated effector cells; but melanin can inhibit the recognition of the organism by host defenses, thereby down-regulating the afferent phase of T cell-mediated immunity, e.g., TNF-alpha production and lymphoproliferation.

The sensitivity of high-resolution CT in detecting idiopathic pulmonary fibrosis proved by open lung biopsy. A prospective study.

OBJECTIVES: To assess the sensitivity of high-resolution chest computed tomography (HRCT) in detecting idiopathic pulmonary fibrosis proved by biopsy specimen. To determine the degree of physiologic and pathologic abnormalities in patients with idiopathic pulmonary fibrosis who have a false-negative HRCT. DESIGN: Prospective 2-year study. SETTING: Tertiary care university hospital. PATIENTS: All patients with dyspnea and suspected interstitial lung disease referred to the University of Michigan for enrollment in the Idiopathic Pulmonary Fibrosis Specialized Center of Research (SCOR) protocol were included; 25 underwent open lung biopsy and formed the final study group. MEASUREMENTS: All patients underwent physiologic (pulmonary function, gas exchange, and exercise testing), radiologic (chest x-ray film and HRCT), and pathologic assessments (bronchoscopic and open lung biopsy). The results of HRCT were prospectively compared with results of standard pulmonary function tests, cardiopulmonary exercise testing, and open lung biopsy. RESULTS: Of 25 patients who had both HRCT and open lung biopsy, 3 patients (12%) had HRCTs that demonstrated no evidence of interstitial lung disease. These three patients had less severe disease based on clinical, radiographic, and physiologic (CRP) scores, gas exchange abnormalities, and pathologic scoring of open lung biopsy specimens, compared with those with an abnormal HRCT. CONCLUSION: We conclude that in the evaluation of patients with dyspnea and abnormal results of pulmonary function studies, a normal HRCT does not exclude early and clinically significant interstitial lung disease. In our patient population, physiologic testing was more sensitive than HRCT in detecting mild abnormalities in patients with idiopathic pulmonary fibrosis proved by biopsy specimen.

Glutamate regulates intracellular calcium and gene expression in oligodendrocyte progenitors through the activation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

Oligodendrocytes and their progenitors (O-2A) express functional kainate- and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors. The physiological consequences of activation of these receptors were studied in purified rat cortical O-2A progenitors and in the primary oligodendrocyte cell line CG-4. Changes in the mRNA levels of a set of immediate early genes were studied and were correlated to intracellular Ca2+ concentration, as measured by fura-2 Ca2+ imaging. Both in CG-4 and in cortical O-2A progenitors, basal mRNA levels of NGFI-A were much higher than c-fos, c-jun, or jun-b. Glutamate, kainate, and AMPA greatly increased NGFI-A mRNA and protein by activation of membrane receptors in a Ca(2+)-dependent fashion. Agonists at non-N-methyl-D-aspartate receptors promoted transmembrane Ca2+ influx through voltage-dependent channels as well as kainate and/or AMPA channels. The influx of Ca2+ ions occurring through glutamate-gated channels was sufficient by itself to increase the expression of NGFI-A mRNA. AMPA receptors were found to be directly involved in intracellular Ca2+ and NGFI-A mRNA regulation, because the effects of kainate were greatly enhanced by cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA but not kainate receptors. Our results indicate that glutamate acting at AMPA receptors regulates immediate early gene expression in cells of the oligodendrocyte lineage by increasing intracellular calcium. Consequently, modulation of these receptor channels may have immediate effects at the genomic level and regulate oligodendrocyte development at critical stages.

Effect of granulocyte-macrophage colony-stimulating factor on rat alveolar macrophage anticryptococcal activity in vitro.

Cryptococcus neoformans, a pathogenic fungus usually acquired by inhalation, causes the most common lethal mycosis in AIDS. The resident lung phagocytes, alveolar macrophages (AM phi), inhibit growth of C. neoformans poorly unless activated by cytokines such as IFN-gamma. In this study, we examined the effect of rat AM phi of the potent hematopoietic and M phi-activating cytokine, granulocyte-macrophage CSF (GM-CSF), alone and in combination with other cytokines. Rat AM phi monolayers were preincubated with 0.1 to 1000 U/ml GM-CSF without or with other recombinant cytokines, and then were incubated with viable C. neoformans (strain H99/C3D). Growth inhibition was assessed by counting cryptococcal CFU at 24 and 48 h of coculture; AM phi proliferation was assessed by measuring both uptake of [3H]TdR and AM phi numbers. AM phi preincubated with GM-CSF for 5 days (but not for shorter periods) inhibited growth of C. neoformans. Anticryptococcal activity required direct contact of AM phi with C. neoformans, but once induced by preincubation, did not require continued exposure to GM-CSF. Induction of anticryptococcal activity by GM-CSF was dose dependent (maximal induction at 250 U/ml), and was due to both increased ingestion and killing. GM-CSF induced AM phi proliferation, but anticryptococcal activity was not due totally to increases in AM phi numbers, indicating AM phi activation by GM-CSF. GM-CSF-induced AM phi proliferation was increased by IL-6, unchanged by IL-8, and abolished by LPS or IFN-gamma. However, IL-6 did not increase GM-CSF-induced anticryptococal activity. The combination of GM-CSF and IFN-gamma showed rapid and sustained anticryptococcal activity, unlike either cytokine alone. Our in vitro data suggest that the combination of GM-CSF and IFN-gamma may have beneficial effects on host defense against C. neoformans in vivo.

Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen.

To determine whether CD4+ T cells participate in the recruitment of other lymphocyte subsets to the lungs, we examined pulmonary immune responses in C57BL/6 mice treated in vivo with the MAb GK1.5, either intact (which depletes CD4+ cells) or as F(ab')2 fragments (which block CD4 molecules). After intratracheal challenge with sheep erythrocytes, antigen-primed mice treated with intact GK1.5 had marked decreases in lymphocytes and macrophages in bronchoalveolar lavage fluid and minimal parenchymal inflammation, compared to primed mice treated with an isotype-matched irrelevant antibody or with no antibody. At 7 d after challenge, flow cytometric analysis showed that numbers of Thy 1.2+ and B220+ cells, but not of CD8+ cells, were markedly decreased in lavage fluid of CD4-depleted mice. Similar suppression of the pulmonary immune response to intratracheal challenge was found in primed mice injected repeatedly with F(ab')2 fragments of GK1.5, which did not deplete CD4+ T cells, and in athymic mice. These findings indicate that, in response to a single intratracheal antigen challenge, recruitment to the lungs of leukocytes other than CD8+ T cells depends largely on CD4+ T cells, possibly because of signals requiring T cell activation via interactions with antigen-presenting cells.

Oral mucosa pigment changes in heavy drinkers and smokers.

The preliminary observation that heavy drinking and smoking produced oral mucosal changes consisting of splotchy areas of depigmentation surrounded by hyperpigmentation was tested. The study population was comprised of 52 patients from an alcohol detoxification ward, who were compared with 54 patients from psychiatric inpatient and day hospital services. Structured interviewing was developed for both samples of patients who met either diagnostic criteria for alcohol abuse or dependence, or criteria for alcoholism on the Short Form of the Michigan Alcohol Screening Test, and were identified as nonsmokers or as those who smoked one to three or more packs of cigarettes a day. Photographs of the inner surface of the lips, oral mucosa, and gingivae independently were rated for severity of oral pigment change by two raters blind to a patient's alcohol or smoking history. This study demonstrates that reported observable oral pigment changes identify patients who are heavy smokers and drinkers, and may be a useful diagnostic sign.

Central airway obstruction due to cytomegalovirus-induced necrotizing tracheitis in a patient with AIDS.

Cytomegalovirus (CMV) infection in patients with the acquired immunodeficiency syndrome (AIDS) can present as either disseminated disease, pneumonitis, retinitis, gastroenteritis, neuropathy, or a subclinical infection. We report a patient whose initial manifestation of CMV infection was severe central airways obstruction due to necrotizing tracheitis. At bronchoscopy, the lesion appeared deeply ulcerated, distinctly different from previously described airway lesions in patients with AIDS. Mucosal biopsies showed characteristic intranuclear and intracytoplasmic inclusions and cultures yielded only CMV. The patient responded partially to ganciclovir, steroids, and antibiotics against suspected anaerobic superinfection but died as a result of central nervous system disease believed due to toxoplasmosis or lymphoma. CMV infection of the upper airway should be considered in the patient with AIDS presenting with atypical cough or stridor and ulcerated endobronchial lesions.

Expression of Ia by murine alveolar macrophages is upregulated during the evolution of a specific immune response in pulmonary parenchyma.

These studies were performed to test the hypothesis that the evolution of a specific immune response in lung parenchyma upregulates the expression of Ia on surface membranes of murine alveolar macrophages. A secondary antibody-forming cell response to sheep erythrocytes was generated in lung parenchyma by intratracheal antigen challenge of systemically primed mice. During the immune response, alveolar macrophages were retrieved by bronchoalveolar lavage, and the percentages and total numbers of Ia-positive macrophages were measured by indirect immunofluorescence. The expression of Ia on surface membranes of lavaged alveolar macrophages increased in association with the generation of antibody-forming cell responses in lung tissue. This increase in Ia expression was antigen specific; intratracheal challenge with noncrossreacting antigen did not increase Ia expression. Nonspecific inflammation of the lung, induced by intratracheal hydrochloric acid, elicited increases in total numbers of macrophages that were similar in magnitude to those induced by specific immune responses, but increased Ia expression only modestly. In unprimed mice, intratracheal antigen challenge did not increase Ia expression by alveolar macrophages unless the mice had received immune splenocytes by adoptive transfer at the time of challenge. The results show that the generation of a specific immune response in pulmonary parenchyma upregulates the expression of Ia by murine alveolar macrophages in vivo and suggest that the accumulation of antigen-reactive lymphocytes in the lung plays an important role in this upregulation.

The mechanism of appearance of specific antibody-forming cells in lungs of inbred mice after immunization with sheep erythrocytes intratracheally. II. Dose-dependence and kinetics of appearance of antibody-forming cells in hilar lymph nodes and lungs of unprimed and primed mice.

We are conducting studies designed to define the cellular basis for the appearance and accumulation of specific antibody-forming cells (AFC) in lung parenchyma of mice after intrapulmonary deposition of sheep erythrocytes (SRBC). This study was performed: to compare qualitatively the AFC responses to intratracheally administered antigen among unprimed mice and among mice primed either by adoptive transfer of sensitized lymphocytes or by systemic immunization, and to define quantitatively the relationship between the appearance of AFC in hilar lymph nodes (HLN) and in lung parenchyma in these 3 groups of mice. Both antigen dose-response and kinetic analyses of the appearance of AFC in the HLN and lung parenchyma were performed. There was a direct relationship between the dose of SRBC administered intratracheally and the magnitude of the AFC-responses in HLN and lungs; AFC appeared in HLN at substantially lower intratracheally administered doses of SRBC than in lungs. The major effect of adoptive transfer or of systemic priming was to shift the dose-response curves significantly to the left, such that AFC appeared in HLN and lungs at lower antigen doses than in unprimed mice. Kinetic analyses showed that the initial appearance and the peak concentrations of AFC occurred earlier in HLN than they did in lung parenchyma. Priming shifted the kinetic curves to the left, accelerating the appearance of AFC; the sequential relationship between AFC appearance in HLN and in lungs was preserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Essential thrombocythemia and leukemic transformation.

Alkylating agents and 32P have been widely employed in the treatment of patients with essential thrombocythemia (ET). During a four-month period, we observed 3 cases of ET that had transformed into leukemia. Two patients had been treated with uracil mustard: One developed acute myelogenous leukemia 79 months after institution of therapy, and the other patient developed chronic myelomonocytic leukemia 24 months after the start of therapy. The third patient had been treated with busulfan, and ET evolved into myelofibrosis and eventually into acute undifferentiated leukemia with myelofibrosis. The patient who developed acute myelogenous leukemia was asymptomatic at the time of diagnosis of ET but was treated because his platelet count was greater than 1,000,000/mm3. He died 1 month after leukemic transformation, during induction chemotherapy. The other 2 patients presented with symptoms referable to their thrombocythemia. Review of the English literature revealed 12 other definite or probable cases of ET with leukemic transformation, all but 1 having been treated with alkylating agents and/or 32P. We propose that the natural history of ET may be similar to that of polycythemia vera, with evolution into leukemia being an unusual occurrence except in the setting of previous chemotherapy. Therefore, the current practice of treating asymptomatic patients with ET may not be justified, since administration of alkylating agents or 32P may increase the risk of subsequent development of leukemia.

Helium-oxygen gas therapy. Use and availability for the emergency treatment of inoperable airway obstruction.

Inoperable obstruction of the upper airway due to extrinsic malignancy may present as respiratory failure. We treated such a patient for 48 hours with 80 percent: 20 percent helium-oxygen delivered by a nonrebreathing mask while chemotherapy and radiation therapy reduced the tumor size. The need for intubation, mechanical ventilation, and high risk surgical intervention was avoided through the use of this gas therapy. We then surveyed San Francisco Bay area hospitals and found that fewer than one half could provide this potentially lifesaving gas therapy in an emergency situation. Physiologic basis of helium-oxygen gas therapy is reviewed and recommendations made for its use and availability.