In vitro differentiation of rat spermatogonia into round spermatids in tissue culture.

STUDY QUESTION: Do the organ culture conditions, previously defined for in vitro murine male germ cell differentiation, also result in differentiation of rat spermatogonia into post-meiotic germ cells exhibiting specific markers for haploid germ cells? SUMMARY ANSWER: We demonstrated the differentiation of rat spermatogonia into post-meiotic cells in vitro, with emphasis on exhibiting, protein markers described for round spermatids. WHAT IS KNOWN ALREADY: Full spermatogenesis in vitro from immature germ cells using an organ culture technique in mice was first reported 5 years ago. However, no studies reporting the differentiation of rat spermatogonia into post-meiotic germ cells exhibiting the characteristic protein expression profile or into functional sperm have been reported. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Organ culture of testicular fragments of 5 days postpartum (dpp) neonatal rats was performed for up to 52 days. Evaluation of microscopic morphology, testosterone levels, mRNA and protein expression as measured by RT-qPCR and immunostaining were conducted to monitor germ cell differentiation in vitro. Potential effects of melatonin, Glutamax® medium, retinoic acid and the presence of epidydimal fat tissue on the spermatogenic process were evaluated. A minimum of three biological replicates were performed for all experiments presented in this study. One-way ANOVA, ANOVA on ranks and student's t-test were applied to perform the statistical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Male germ cells, present in testicular tissue pieces grown from 5 dpp rats, exhibited positive protein expression for Acrosin and Crem (cAMP (cyclic adenosine mono phosphate) response element modulator) after 52 days of culture in vitro. Intra-testicular testosterone production could be observed after 3 days of culture, while when epididymal fat tissue was added, spontaneous contractility of cultured seminiferous tubules could be observed after 21 days. However, no supportive effect of the supplementation with any factor or the co-culturing with epididymal fat tissue on germ cell differentiation in vitro or testosterone production was observed. LIMITATIONS, REASONS FOR CAUTION: The human testis is very different in physiology from the rat testis, further investigations are still needed to optimize the organ culture system for future use in humans. WIDER IMPLICATIONS OF THE FINDINGS: The successful differentiation of undifferentiated spermatogonia using the testis explant culture system might be employed in future to produce sperm from human spermatogonia as a clinical tool for fertility preservation in boys and men suffering infertility. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: This work was supported financially by the Frimurare Barnhuset in Stockholm, the Paediatric Research Foundation, Jeanssons Foundation, Sällskåpet Barnåvard in Stockholm, Swedish Research Council/Academy of Finland, Emil and Wera Cornells Foundation, Samariten Foundation, the Swedish Childhood Cancer Foundation as well as through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. All authors declare no conflicts of interests.

Impact of hemoglobin levels on outcomes of adjuvant chemotherapy in resected non-small cell lung cancer: the JBR.10 trial experience.

BACKGROUND: Cisplatin-induced anemia may correlate with adverse events, poor quality of life (QoL), decreased adjuvant chemotherapy (ACT) dose intensity, shorter relapse-free survival (RFS) or overall survival (OS). METHODS: The JBR.10 trial demonstrated significantly longer survival with adjuvant cisplatin and vinorelbine (n=242) compared to observation (n=240) in patients with resected NSCLC [Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352(25):2640-2]. This exploratory analysis evaluates the predictive value of baseline (in all patients) and during-treatment (in ACT arm only) hemoglobin (Hb) levels on OS and RFS when adjusted for prognostic factors. Baseline (in all patients) and during treatment (in ACT arm only) Hb levels were also correlated with adverse events, QoL, morbidity and ACT dose intensity. RESULTS: Baseline Hb did not predict RFS or OS. However, there was a trend to shorter OS (p=0.1) when baseline Hb was <120g/L. Lower baseline Hb predicted increased hospitalization (p=0.04) and worse QoL (SOB item, p=0.03) but had no impact on adverse events or dose intensity. There was a trend to longer RFS (p=0.08) in patients with lower nadir during-treatment Hb and to longer OS (p=0.06) and RFS (p=0.08) in patients with maximum during-treatment Hb drop >30% that was not maintained when ACT dose intensity was included in the model. Maximum during-treatment Hb drop >30% correlated with increased lethargy (p=0.003) and worse QoL (fatigue item, p=0.07). CONCLUSIONS: Lower baseline and during-treatment Hb levels seem associated with poorer QoL, fatigue and increased hospitalization. There is a trend for shorter OS in patients with lower baseline Hb levels.

Lung transplantation in patients over the age of 50.

It is common to assign an upper age limit for potential lung transplant recipients. The influence of age on LTX outcome is, however not, documented. A review of our first 103 LTXs, 51 single LTXs and 52 double LTXs, includes 31 recipients aged 50-63 years (mean 55.3 +/- 3.9); 19 received single LTX, and 12 received double LTX. Indications for LTX in those aged greater than 50 included proportionately more patients with emphysema and interstitial lung disease. Actuarial survivals in those aged less than 50 at 12, 36, and 60 months were 68%, 60%, and 55%, and in those aged greater than 50 was 70%, 61%, and 61%, respectively. The causes of death reflect a tendency of younger patients to die from graft rejection and older patients to die from sepsis. Acute rejection more than 6 weeks posttransplant and chronic rejection were less frequent in older patients (P < 0.05). The 6-minute walk and modified Bruce protocol tests, the incidence of CMV pneumonitis, and the late post-LTX renal function were not related to age. In conclusion, in carefully selected candidates in their sixth and seventh decades, LTX is an acceptable operation for end-stage lung disease. The tendency of older patients to a lower incidence of late allograft rejection (acute or chronic) may reflect decreased immunological responsiveness with age.

Aspergillus infection in single and double lung transplant recipients.

To investigate the clinical manifestations of Aspergillus infections in lung transplant recipients, we reviewed the mycology and autopsy reports of all double (DLT=93) and single (SLT=48) lung transplant recipients from November 1983 to May 1993. Positive Aspergillus cultures were identified in 22% of the recipients (DLT=21, SLT=10). Colonization alone was present in 19 recipients (DLT=16, SLT=3). Complicated Aspergillus infection included Aspergillus bronchitis (DLT=1, SLT=1), aspergilloma (SLT=2), pulmonary invasive aspergillosis (DLT=1, SLT=2), disseminated aspergillosis (DLT=1, SLT=2), empyema (DLT=1), and a retroperitoneal abscess (DLT=1). Symptoms were seen only in patients with complicated lung infections and CXR abnormalities began in the native lung of four SLT recipients. Twenty patients survived (DLT=17, SLT=3) and 11 died (DLT=4, SLT=7) of disseminated aspergillosis (SLT=2), pulmonary invasive disease (DLT=1), bronchiolitis obliterans (DLT=2, SLT=2, CMV pneumonitis (SLT=1), diffuse alveolar damage (SLT=2), and hyperacute rejection (DLT=1). Complicated infection and mortality were more common in SLTs than DLTs (P<0.05). We conclude that infection with Aspergillus is not infrequent in the lung transplantation population. Single lung recipients develop more complicated infection than double lung recipients after Aspergillus infection with native lung being a potential source of infection.

Acute respiratory insufficiency from an aneurysm of the descending thoracic aorta.

A 70-year-old woman presented with life-threatening acute respiratory insufficiency resulting from tracheobronchial compression by a large calcified expanding aneurysm confined to the descending thoracic aorta. This combination has not previously been reported. Successful surgical correction was carried out. This report describes in detail the presentation, diagnosis, and steps involved in the management of this entity.

Cytomegalovirus viremia in lung transplant recipients receiving ganciclovir and immune globulin.

BACKGROUND: Cytomegalovirus (CMV) disease is an important cause of organ transplant-related morbidity and mortality. During the last 5 years at our institution, prophylactic ganciclovir and hyperimmune globulin have been routinely administered to lung transplant recipients whenever the donor or the recipient was CMV antibody-positive. We sought to assess the efficacy of prophylaxis on viremia, CMV disease, and bronchiolitis obliterans syndrome (BOS). METHODS: A retrospective chart review of 61 consecutive lung transplants performed between recipients between January 1993 and August 1995 was performed. Fifty-six patients who survived at least 1 month were analyzed. Patients were considered at risk for CMV disease whenever pretransplant donor or recipient serology was positive. RESULTS: Fourteen of the 39 patients at risk (36%) had viremia while on prophylaxis. The rate of CMV disease was 13% during the first 6 months following transplantation. A donor whose CMV serology was positive appeared to increase the risk of BOS in a Cox regression model (relative risk=2.4; 95% confidence interval=0.86-6.74; p=0.0957). Neither age, CMV infection (viremia or a positive specimen from BAL), recipient's serology at the time of transplantation, or CMV disease was associated with BOS. None of these variables was associated with mortality on Cox regression analysis or univariate analysis. CONCLUSIONS: Administration of combination ganciclovir and hyperimmune globulin prophylactic therapy to lung transplant recipients at risk for CMV infection and disease is associated with a relatively low incidence of disease, which appears only after prophylaxis treatment with ganciclovir is completed. Ganciclovir prophylaxis does not prevent CMV viremia; however, viremia while on prophylaxis is not predictive of disease.

Bronchiolitis obliterans organizing pneumonia (BOOP) in lung transplant recipients.

We reviewed all tissue specimens from 163 transplant patients (108 double lung transplant [DLT], 55 single lung transplant [SLT]) between November 1983 and January 1994 for abnormalities indicating bronchiolitis obliterans organizing pneumonia (BOOP) and found 17 cases (14 DLT and 3 SLT). Of the three SLTs, BOOP was diagnosed by open lung biopsy (OLB) in two and one was found at autopsy. Of the 14 DLTs, BOOP was diagnosed by transbronchial biopsy (TBB) specimens (9), OLB specimens (2), autopsy (1), TBB and OLB specimens (1), and OLB specimens and autopsy (1). BOOP was found between 1 and 43 months posttransplantation; time of survival from diagnosis was between 2 and 36 months with 9 patients presently alive. Concurrent pathologic diagnosis at the time of BOOP findings were as follows: acute rejection (7) (grade 1 [4] and grade 2 [3]), BO and grade 1 rejection (2), BO and grade 2 rejection (2), BO and Aspergillus infection (1), acute alveolar injury (1), acute alveolar injury and pulmonary embolus (1), acute rejection (grade 1) and Burkholderia cepacia pneumonia (1). No other pathologic diagnosis was found in 1 patient. In total, 11 of 17 patients (65%) had associated acute rejection. Of the 17 patients, 7 subsequently developed BO and 3 had BO before the finding of BOOP. Death occurred in 8 patients (5 DLT and the 3 SLT) between 2 and 6 months after the diagnosis. We conclude that BOOP is an important complication after lung transplantation; it was present in 13% of DLTs and 5% of SLTs. BOOP was most often associated with acute rejection.

Unilateral donor lung dysfunction does not preclude successful contralateral single lung transplantation.

Single lung transplantation remains limited by a severe shortage of suitable donor lungs. Potential lung donors are often deemed unsuitable because accepted criteria (both lungs clear on the chest roentgenogram, arterial oxygen tension greater than 300 mm Hg with an inspired oxygen fraction of 1.0, a positive end-expiratory pressure of 5 cm H2O, and no purulent secretions) do not distinguish between unilateral and bilateral pulmonary disease. Many adequate single lung grafts may be discarded as a result of contralateral aspiration or pulmonary trauma. We have recently used intraoperative unilateral ventilation and perfusion to assess single lung function in potential donors with contralateral lung disease. In the 11-month period ending October 1, 1990, we performed 18 single lung transplants. In four of these cases (22%), the donor chest roentgenogram or bronchoscopic examination demonstrated significant unilateral lung injury. Donor arterial oxygen tension, (inspired oxygen fraction 1.0; positive end-expiratory pressure 5 cm H2O) was below the accepted level in each case (246 +/- 47 mm Hg, mean +/- standard deviation). Through the sternotomy used for multiple organ harvest, the pulmonary artery to the injured lung was clamped. A double-lumen endotracheal tube or endobronchial balloon occlusion catheter was used to permit ventilation of the uninjured lung alone. A second measurement of arterial oxygen tension (inspired oxygen fraction 1.0; positive end-expiratory pressure 5 cm H2O) revealed excellent unilateral lung function in all four cases (499.5 +/- 43 mm Hg; p less than 0.0004). These single lung grafts (three right, one left) were transplanted uneventfully into four recipients (three with pulmonary fibrosis and one with primary pulmonary hypertension). Lung function early after transplantation was adequate in all patients. Two patients were extubated within 24 hours. There were two late deaths, one caused by rejection and Aspergillus infection and the other caused by cytomegalovirus 6 months after transplantation. Two patients are alive and doing well. We conclude that assessment of unilateral lung function in potential lung donors is indicated in selected cases, may be quickly and easily performed, and may significantly increase the availability of single lung grafts.

Prospective assessment of a standardized pathologic grading system for acute rejection in lung transplantation.

Using the recent standardization of the pathologic definitions for acute lung rejection, we prospectively evaluated 66 consecutive bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) specimens in 32 patients after lung transplantation. Clinical indications for bronchoscopies were surveillance (n = 44), rejection (n = 18), and infection (n = 4). Bronchoalveolar lavages were obtained from the right middle lobe or lingula in single lung transplant and from both sites in double lung transplant recipients. Cytosmears for differential cell counts were performed and 400 to 500 cells were counted. Five to eight TBB specimens were taken from two different lobes and stained with hematoxylin-eosin, elastic trichrome, and silver methenamine. Sixty-four of 66 sets of biopsy specimens were satisfactory, but 3 were eliminated because of presence of cytomegalovirus cytopathic changes. Of the remaining 61, rejection was presented in 45 (74 percent): grade 1 in 23 (38 percent), grade 2 in 19 (31 percent), and grade 3 in 3 (5 percent). In 30 of 42 (71 percent) surveillance biopsy specimens, rejection was present, grade 1 in 18 (43 percent) and grade 2 or 3 in 12 (28 percent). In TBBs performed for clinical suspicion of rejection, 15 of 18 TBB specimens (83 percent) showed rejection, grade 1 in 5 (28 percent) and grade 2 or 3 in 10 (55 percent). Of four biopsies performed for suspicion of infection, one was normal and three showed rejection in addition to infection. These three were eliminated from further analysis due to the limitation of the Lung Rejection Study Group criteria in distinguishing rejection from infection. Of the 45 episodes of rejection, 24 (53 percent) occurred during the first 3 months posttransplantation, 8 (18 percent) between 3 and 6 months and 13 (29 percent) after 6 months. Percentage of BAL lymphocytosis was significantly elevated in grade 2 or 3 rejection (28 +/- 4) when compared with grade 1 (15 +/- 3) or grade 0 (10 +/- 3) (p < 0.001). Bronchoalveolar lavage lymphocytosis also correlated with severity of rejection (r = 0.6). We conclude that according to the standardized criteria of the Lung Rejection Study Group, acute lung rejection occurs more frequently than clinically suspected early and late after transplantation and that BAL lymphocytosis correlates with the presence and severity of histologically proven rejection.

Pseudomonas cepacia in lung transplant recipients with cystic fibrosis.

Twenty-four isolated double lung transplants (LTXs) have been performed in 22 patients with cystic fibrosis, with a follow-up of 4 to 47 months. Prior to LTX, all patients were colonized with Pseudomonas aeruginosa, and ten patients were also colonized with Pseudomonas cepacia. Both organisms were specifically sought before LTX. All patients who grew P cepacia before LTX did so after LTX. Five additional patients only grew this bacterium after LTX. There was no difference between those who grew P cepacia and those who did not in terms of data before LTX for age, weight, pulmonary function, and 6-min walk. After LTX, 7 of the 15 patients who had ever grown P cepacia died. No patient who grew only P aeruginosa died. The median survival in the subgroup with P cepacia was 28 days. Five of the seven died as a direct result of P cepacia pneumonia and sepsis. One died of cyclosporin A (cyclosporine) neurotoxicity with concurrent P cepacia pneumonia, and one died at the time of a retransplant for graft failure (associated with three bouts of P cepacia pneumonia and cytomegalovirus). Four of seven had not grown this bacterium before LTX. There were no perioperative factors, including antibiotic choices, that distinguished survivors and nonsurvivors. Overall 1-year survival is about 70 percent (15/22). Fourteen bouts of P cepacia pneumonia occurred in 12 patients. Four empyemas, one lung abscess, one suppurative pericarditis, and five cases of sinusitis were also due to this bacterium. In conclusion, P cepacia is responsible for excess morbidity and mortality after LTX. This organism is particularly lethal if isolated for the first time after LTX. Factors predicting its acquisition in this setting are unknown. While it is possible that the facial sinuses may act as an unrecognized reservoir or that patients or equipment provide a source, further study into the epidemiology of this organism is necessary to improve the survival of colonized patients undergoing LTX.

Is there ever a role for salvage operations in limited small-cell lung cancer?

Combined modality treatment with chemotherapy and radiation produces tumor regression in most patients with small-cell lung cancer, but the impact on survival has been small, and less than 20% of patients with limited disease survive 2 years. Survival time is extremely short after failure to respond or relapse after treatment. Local control remains a problem, with one third of patients having recurrence only at the primary site. In an attempt to prolong survival and perhaps achieve cure, we undertook surgical resection in 28 patients with limited small-cell lung cancer who did not have complete remission with standard treatment or who had only local recurrence after treatment. There were 28 patients, 22 male and six female, median age 61 years (range 41 to 76). All patients had been treated with chemotherapy and 13 had received preoperative radiotherapy to the primary site and mediastinum. Eight patients underwent an operation for relapse after complete remission. Five patients had had no response to treatment, three had had a slight response followed by progression during chemotherapy, and 12 had achieved partial response but had greater than 3 cm residual masses. Twelve patients required pneumonectomy, 15 lobectomy, one patient had unresectable disease, and two had bulky residual masses after the operation. Three others had microscopic residual disease. Pathologic examination showed only small-cell lung cancer in 18 patients, mixed small-cell and non-small-cell in four, and only non-small-cell lung cancer in six. There were only four patients with stage I disease, 10 with stage II, and 14 with stage III. The median survival from the date of diagnosis for the entire group is 105 weeks and from the date of operation, 74 weeks. The projected 5-year survival rate is 23%. The two patients with residual masses died with local progression, and distant metastatic disease developed in 17 others. One patient died at 6 years without recurrent disease. Eight patients are alive 2 to 5 years after diagnosis. Seven of these patients required only a lobectomy, four had stage I disease, two had stage II, and two had stage III disease. Five had pure small-cell lung cancer and three had mixed small-cell and non-small-cell tumors. All of the patients with pathologic stage I disease remain alive compared with one of 10 with stage II disease and two of 14 with stage III. In summary, relapse or failure to respond to chemotherapy may be due to non-small-cell lung cancer or a mixed tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoid cystic carcinoma of the airway: thirty-two-year experience.

METHODS: We have reviewed our experience in 38 patients with adenoid cystic carcinoma of the upper airway seen between 1963 and 1995. The mean age was 44.8 years (15 to 80 years) with a male/female ratio of 1:1.1. Thirty-two of the 38 patients were treated by resection and reconstruction (primary anastomosis 28; Marlex mesh prosthesis 4). Twenty-six of the 32 patients undergoing resection received adjuvant radiotherapy. Six patients with unresectable tumors were treated primarily with radiotherapy only. RESULTS: Pathologic examination revealed local invasion beyond the wall of the trachea in all patients. In a majority, microscopic extension was found in submucosal and perineural lymphatics, well beyond the grossly visible or palpable limits of the tumor. Lymphatic metastases were relatively uncommon, occurring in only five of 32 (19%) patients undergoing resection. Metachronous hematogenous metastases occurred in 17 of 38 patients (44%). Thirteen of these 38 patients (33%) had pulmonary metastases. Sixteen of 32 resections were complete and potentially curative. There were two deaths within 30 days of operation. The mean survival in the 14 patients undergoing complete resection was 9.8 years (12 months to 29 years). Sixteen of 32 resections were incomplete (residual tumor at the airway margin on final pathologic examination), with one operative death occurring in this group. The mean survival in the 15 surviving patients was 7.5 years (4 months to 21 years). Six patients were treated with primary radiation only and had a mean survival of 6.2 years (2 months to 14.3 years). In the patients with pulmonary metastases, mean survival was 37 months (4 months to 7 years) from the time of diagnosis of the pulmonary metastasis until their death. CONCLUSION: Adenoid cystic carcinoma of the upper airway is a rare tumor, which is locally invasive and frequently amenable to resection. Although late local recurrence after resection is a feature of this tumor (up to 29 years), excellent long-term palliation is commonly achieved after both complete and incomplete resection. There was a small difference in survival between patients having complete and incomplete resection. Long periods of control can be obtained with radiotherapy alone. The best results, in this series of patients, were obtained by resection. Adjuvant radiotherapy is assumed to favorably influence survival.

Airway complications after double lung transplantation. Toronto Lung Transplant Group.

We have had success with en bloc double lung transplantation in the management of selected patients with end-stage parenchymal pulmonary disease. Airway complications have been more prevalent in our own experience with double lung transplantation than in reports of combined heart-lung transplantation from other centers. Between November 1986 and March 1989, 16 patients underwent double lung transplantation. Allografts were preserved by topical hypothermic immersion in 12 patients and by pulmonary artery flush with cold crystalloid solution in the most recent four patients. Thirteen patients underwent tracheal anastomosis and the most recent three patients underwent bilateral bronchial anastomoses. Fatal ischemic necrosis of the donor trachea and both main bronchi developed in three patients. Preterminal airway ischemia developed in a patient who had systemic sepsis. Partial anastomotic dehiscence, which went on to form fibrous strictures necessitating endoscopic placement of silicone rubber airway stents, developed in two additional patients. Two other patients had late strictures and required subsequent placement of bifurcation stents. There was no relationship between development of airway complications and gas exchange in the donor lungs, lung ischemic time, early postoperative gas exchange, early postoperative mean pulmonary artery pressure, or frequency of early postoperative rejection. Severe postoperative hypotension occurred in five of eight patients with airway complications and in three of eight patients without airway complications.

Infectious complications following isolated lung transplantation.

STUDY OBJECTIVE: To ascertain the incidence, types, morbidity, and mortality of infectious episodes in isolated lung transplant recipients. DESIGN: Retrospective chart review of patients who have undergone transplants over a six-year period in one institution. PATIENTS: Twenty-three single and 17 double lung transplants followed up between 2 and 68 months. RESULTS: Fifty-one episodes of infection occurred in the group with a slight predominance in the double lung transplants. The 32 episodes of bacterial infection constituted the largest group of infection and more than half of these were pneumonias. Organisms identified were predominantly Gram negative. While bacterial processes made up the bulk of infections, fatalities were rare. Viral and fungal infections were less common, but more often fatal. Of six cases of viral pneumonitis, two were fatal; two of five cases of invasive fungal infection were also fatal. Overall, six patients died of infection. CONCLUSION: Our findings support previous reports from heart-lung centers documenting a high rate of infectious complications, particularly pneumonia, in recipients of lung grafts. In our experience, bacterial infections are the most common (two of three infections), but have the lowest mortality. Efforts should be directed toward establishing effective prophylaxis programs and early detection of infection.

Pleural complications in lung transplant recipients.

Pleural complications occurred in 30 (22%) of 138 patients after 53 single and 91 double lung transplants between September 1986 and February 1993. These were defined for the purpose of this study as pneumothorax persisting beyond the first 14 postoperative days, recurrent pneumothorax, or any other pleural process that necessitated diagnostic or therapeutic intervention. Overall, a higher pleural complication rate was seen in double lung transplantation (25 of 30) than in single lung transplantation (5 of 30) with no differences noted in the frequency among preoperative diagnostic groups (p > 0.05). Pneumothorax was the most frequent complication, affecting 14 of 30 patients, with 6 of 14 cases occurring after transbronchial biopsy. All pneumothoraces in single (n = 4) and double lung transplantation (n = 10) resolved spontaneously or with chest tube thoracostomy. One patient required placement of a Clagett window after open lung biopsy and another required thoracotomy and pleural abrasion after transbronchial biopsy. Parapneumonic effusion was observed in 4 of 30 double lung transplantations with spontaneous resolution in all cases. Empyema affected 7 of 30 patients and occurred exclusively in the double lung transplant group. Sepsis developed in three of the patients with this complication and they subsequently died. The risk of empyema was independent of preoperative diagnosis (p > 0.05). Of interest, all patients with cystic fibrosis (n = 3) with complicating empyema had Pseudomonas cepacia in the pleural fluid. Other miscellaneous complications included subpleural hematoma, chylothorax, and hemothorax. The latter two necessitated thoracic duct and bronchial artery ligation, respectively. In summary, a significant proportion of lung transplant recipients will have pleural space complications. The vast majority of these will resolve spontaneously or with conservative procedures. These complications were not related to preoperative diagnosis nor associated with a significant prolongation of hospital stay (p > 0.05). Empyema is the only pleural space complication associated with increased patient mortality and, as such, is an important clinical marker for those at risk for sepsis and death.

Preoperative prediction for the use of cardiopulmonary bypass in lung transplantation.

Cardiopulmonary bypass has been widely used in the management of isolated single and double lung transplantations. Although there are certain clear-cut preoperative indications for cardiopulmonary bypass, in many patients the decision to use this modality is based on the hemodynamic consequences of intraoperative pulmonary artery clamping. We have performed 109 isolated lung transplantations. In 69 patients (38 single lung transplantations and 31 double lung transplantations) cardiopulmonary bypass was initiated only on the basis of intraoperative hemodynamics. We have analyzed preoperative data from these 69 patients to determine whether an intraoperative requirement for cardiopulmonary bypass can be predicted. Of 38 single lung transplantations, 12 necessitated cardiopulmonary bypass (all patients had restrictive lung disease). No patients with obstructive lung disease who underwent single lung transplantation required cardiopulmonary bypass (p < 0.001). For single lung transplantations, 6-minute walk, the arterial desaturation/oxygen requirements on exercise, and the right ventricular ejection fraction were all significantly different between the cardiopulmonary bypass and noncardiopulmonary bypass groups (p < 0.001). Of 31 double lung transplantations, 10 patients required cardiopulmonary bypass (seven had bronchiectasis, two had obstructive lung disease, and one had restrictive lung disease). For obstructive lung disease, no preoperative parameters predicted cardiopulmonary bypass. In conclusion, cardiopulmonary bypass is not necessary for most patients undergoing lung transplantation (in the absence of an absolute preoperative indication). Obstructive lung disease rarely necessitates cardiopulmonary bypass. In single lung transplantations, the subsequent requirement for cardiopulmonary bypass can be predicted from preoperative cardiopulmonary performance. For double lung transplantations, the requirement for cardiopulmonary bypass is usually dependent on unpredictable intraoperative factors.

Bilateral lung transplantation for cystic fibrosis. The Toronto Lung Transplant Group.

Between March 1988 and March 1991, 17 patients underwent bilateral lung transplantation for end-stage lung disease caused by cystic fibrosis. There were 11 male and six female patients. Ages ranged from 19 to 41 years (mean age 28 years). Preoperative mean arterial oxygen tension with the patient breathing room air was 54 +/- 6 mm Hg; forced vital capacity, 1.8 +/- 0.7 L; forced expiratory volume in 1 second, 0.9 +/- 0.3 L; and 6-minute walk test, 506 +/- 44 m. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone. Induction immunosuppression was obtained with Minnesota antilymphocyte globulin. All patients received perioperative antibiotics according to sputum cultures and sensitivities. There were six operative deaths, four of which resulted from bacterial infection. Two patients required a second transplantation, one receiving a single lung and one undergoing bilateral lung replacement. Significant functional improvement was observed in all survivors. At 3 months follow-up, mean arterial oxygen tension on room air was 95 +/- 6 mm Hg (p less than 0.01); forced vital capacity, 3 +/- 0.8 L (p less than 0.01); forced expiratory volume in 1 second, 2.6 +/- 0.9 L (p less than 0.01); and 6-minute walk test, 678 +/- 47 m (p less than 0.01). The actuarial survival rate was 66% at 3 months and 58% at 6, 12, and 24 months. The most frequent cause of morbidity and mortality was acute pneumonia resulting from Pseudomonas cepacia. For patients with respiratory failure caused by cystic fibrosis, bilateral lung transplantation is an effective treatment option associated with significant functional improvement.

Pulmonary transplantation. Early and late results. The Toronto Lung Transplant Group.

Between November 1983 and March 1991, we performed 50 single and 40 double lung transplants in 82 recipients. Early deaths occurred in six (13%) single and in eight (21%) double lung transplant recipients. Late deaths occurred in 11 (28%) single and in one (3%) double lung recipients. Twenty-three of 37 (62%) single and 17 of 24 (71%) double lung transplant recipients have survived at least 1 year after the operation. In patients surviving at least 3 months after the operation (36 of 47 single lung transplant [77%] and 28 of 37 double lung transplant recipients [76%]), significant improvement occurred in arterial blood gases, pulmonary function tests, and exercise capacity. During our initial experience, airway anastomotic complications were the main cause of early morbidity and mortality. With newer surgical techniques and improved perioperative care, airway complications are now uncommon. Infectious complications, either bacterial (Pseudomonas cepacia) or viral (cytomegalovirus), are now the main cause of early mortality. Chronic rejection in the form of obliterative bronchiolitis has become a frequent cause of late morbidity.

Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160).

OBJECTIVE: The rate of complete resection (50%) and the 5-year survival (30%) for non-small cell lung carcinomas of the superior sulcus have not changed for 40 years. Recently, combined modality therapy has improved outcome in other subsets of locally advanced non-small cell lung carcinoma. This trial tested the feasibility of induction chemoradiation and surgical resection in non-small cell lung carcinoma of the superior sulcus with the ultimate aim of improving resectability and survival. METHODS: Patients with mediastinoscopy-negative T3-4 N0-1 superior sulcus non-small cell lung carcinoma received 2 cycles of cisplatin and etoposide chemotherapy concurrent with 45 Gy of radiation. Patients with stable or responding disease underwent thoracotomy 3 to 5 weeks later. All patients received 2 more cycles of chemotherapy and were followed up by serial radiographs and scans. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed for significance by Cox regression analysis. RESULTS: From April 1995 to September 1999, 111 eligible patients (77 men, 34 women) were entered in the study, including 80 (72.1%) with T3 and 31 with T4 tumors. Induction therapy was completed as planned in 102 (92%) patients. There were 3 treatment-related deaths (2.7%). Cytopenia was the main grade 3 to 4 toxicity. Of 95 patients eligible for surgery, 83 underwent thoracotomy, 2 (2.4%) died postoperatively, and 76 (92%) had a complete resection. Fifty-four (65%) thoracotomy specimens showed either a pathologic complete response or minimal microscopic disease. The 2-year survival was 55% for all eligible patients and 70% for patients who had a complete resection. To date, survival is not significantly influenced by patient sex, T status, or pathologic response. CONCLUSIONS: (1) This combined modality treatment is feasible in a multi-institutional setting; (2) the pathologic complete response rates were high; and (3) resectability and overall survival were improved compared with historical experience, especially for T4 tumors, which usually have a grim prognosis.

Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients.

BACKGROUND: Methotrexate has been used successfully to treat refractory or recurrent rejection in heart transplant recipients. We therefore conducted an open pilot study to determine whether methotrexate is useful in the treatment of chronic rejection after lung transplantation. METHODS: Between December 1993 and January 1995 methotrexate was prescribed to 10 patients with persistent or progressive bronchiolitis obliterans despite multiple attempts to control the chronic rejection with conventional treatment (pulse steroids or antilymphocyte products, or both). Data from the nine patients with a minimum of 6 months of follow-up were collected. RESULTS: No patients have died. The spirometry data of the eight patients with declining values of forced expiratory volume in 1 second are presented. Before initiation of methotrexate therapy the median decline in forced expiratory volume in 1 second was 1.4 +/- 0.8 L, or 43% +/- 17%, from the highest preinterventional forced expiratory volume in 1 second value during the preceding 12 months. At 6 months the median decline in forced expiratory volume in 1 second from the time methotrexate therapy was started was 0.1 +/- 0.2 L, or 3% +/- 11%. At 9 months (n = 6) the value was 0.2 +/- 0.2 L, or 6% +/- 12%. At 12 months (n = 5) the median decline was 0.4 +/- 0.3 L, or 9% +/- 16%. In two patients there has been no further decline in forced expiratory volume in 1 second since methotrexate therapy was started (one patient has had a slight but sustained improvement). Five patients have had a reduction in forced expiratory volume in 1 second of 10% or less at most recent follow-up, and only one patient has derived no apparent benefit from methotrexate therapy. Toxicity has been minimal. CONCLUSIONS: Methotrexate is a potentially promising therapeutic alternative in the therapy of bronchiolitis obliterans syndrome in lung transplant recipients.