Control of early Aspergillus mortality after lung transplantation: outcome and risk factors.

Historic treatment strategies in our institute had resulted in 10% Aspergillus mortality within the first posttransplant year. Despite nebulized amphotericin B (nAmB) prophylaxis, a significant incidence of Aspergillus infection, usually with poor outcome, is still reported. The aim of this single-center retrospective study was to evaluate the outcomes of patients receiving either standard nAmB or additional systemic caspofungin prophylaxis for selected high-risk patients. We also tried to define independent risk factors for either fungal infection or death. We followed 76 consecutive lung transplant patients performed at our center between 2002 and 2010 from the day of transplantation. The median follow-up duration was 953 days (2.6 years; range, 16-2,751 days). The endpoints were postoperative Aspergillus colonization or disease or death due to any cause. All patients received either nAmB deoxycholate (nAmBd, 15 patients) or nAmB lipid complex (nAmBLC, 61 patients). In addition, 33 patients also received short-term caspofungin prophylaxis. The overall cumulative mortality during the entire follow up was 14.5%. No clinically confirmed invasive Aspergillus infections (IPA) occurred during the first 2 postoperative years; however, there was 1 possible and 1 probable IPA. One patient died of bronchiolitis obliterans and IPA at 2 years 3 months. Twelve patients showed transient Aspergillus colonization. The antifungal prophylactic regimens were well tolerated. The risk factors for death were age >55 years and postoperative Aspergillus detection (P = .011 and P = .015, respectively). Preoperative Aspergillus colonization/disease was not a risk factor for death (P = 1.000). The strongest predictor of death was age >55 years, due to the elder probably being more susceptible to the adverse effects of immunosuppressants. Postoperative detection of Aspergillus still seems to be an indicator of a poorer outcome. Preoperative Aspergillus colonization is not necessarily a threat with prompt institution of antifungal prophylaxis.

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma.

Previous studies have shown both similar and distinct inflammatory changes in atopic and nonatopic asthma. This study was set to investigate the bronchial inflammatory cell infiltrate and subepithelial basement membrane (BM) tenascin deposition in subjects with newly diagnosed asthma and bronchial hyperresponsiveness (BHR). Seventy-nine asthmatic subjects (age 18-60 years) were recruited and 58 were atopic according to skin prick testing. The patients recorded asthma symptoms and peak flow measurements for 14 days. Lung function and BHR were measured by spirometry and histamine challenge. Serum eosinophil cationic protein (ECP) and blood eosinophils were assessed. Fiberoptic bronchoscopy was performed to obtain bronchial biopsies. Serum ECP was higher in the atopic group but eosinophil counts did not differ. There were no differences in inflammatory cells studied (activated eosinophils, T-lymphocytes, mast cells or macrophages) between nonatopic and atopic subjects. BM tenascin layer was significantly thicker in atopic compared with nonatopic subjects (7.6 vs 6.3 microm, P = 0.007). The thickness of tenascin correlated with eosinophil, T-lymphocyte, and macrophage counts, as well as with IL-4-positive cell counts and the correlation was seen only in atopic asthmatics. These findings suggest that inflammatory cells may have a regulatory role in tenascin expression in atopic asthma.

Investigative bronchoscopy and endobronchial biopsy is well tolerated in hyperreactive asthma patients.

The tolerability of 57 non-smoking asthma patients inhaling salbutamol as needed (ATS, 18--60 years, 60% < or = FEV1 < or =100%, PD15FEV1 <0.4 mg histamine) to fibreoptic bronchoscopy (FOB) and endobronchial biopsy was studied. The FOB was done in local Lignocaine anaesthesia, and from five to eight biopsy specimens were taken from the bronchial mucosa of the right lung. The tolerability was measured as cough/bronchospasm during the procedure (from 0 = normal to 3 = interrupted procedure), success of the procedure, and untoward occurrences. Twenty-seven of the 57 patients (48%) had no cough or bronchospasm during the FOB (score 0). Few coughs of no importance (score 1) were documented in 23 patients (40%). Seven patients (12%) had cough and/or bronchospasm interfering with the FOB procedure (score 2). The FOB procedure was not interrupted because of cough and/or bronchospasm (score 3) in any patient. Scores of cough and/or bronchospasm diminished progressively with the increase of PD15FEV1 histamine. The success of the procedure was 100%. Two patients had untoward medical occurrences requiring additional rescue medication (3.5%). In conclusion, we found that hyperreactivity predicts cough and/or bronchospasm during the FOB. Cough and/or bronchospasm are frequently observed during the bronchial procedure, but they are mild and of minor clinical importance. An investigational endobronchial procedure can be successfully performed in mildly or moderately obstructive asthmatic patients, even in cases with severe bronchial hyperreactivity.

Comparison of endobronchial and transbronchial biopsies with high-resolution CT (HRCIT) in the diagnosis of sarcoidosis.

High-resolution computed tomography (HRCT) has been shown to accurately visualise parenchymal infiltrates of sarcoidosis. The aim of this study was to compare the diagnostic yield (DY) of HRCT with that of endobronchial (EBB) and transbronchial (TBB) biopsies in establishing the diagnosis of sarcoidosis. Forty-five patients referred to Helsinki University Central Hospital with a presumptive diagnosis of sarcoidosis underwent fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL), EBB, TBB and HRCT. Thirty-seven of the patients were diagnosed as having sarcoidosis, 34 of whom showed a parenchymal infiltrate in HRCT. One of the three patients with no parenchymal findings, had positive findings in TBB, and all had lymphocytosis in BAL. The DY for sarcoidosis by EBB and TBB was 24.3% and 50.0%, respectively. The addition of EBB to TBB improved the DY by 8.3%, whereas adding TBB to EBB improved the DY by 30.6%. There were no major complications after the FOB, which was always performed under fluoroscopic control. In conclusion, HRCT is a valuable tool in diagnosing sarcoidosis. However, the HRCT findings cannot be seen in all patients with positive findings in lung biopsy, nor is the parenchymal infiltrate specific for sarcoidosis. Attempting biopsy-proven diagnosis of sarcoidosis is still recommended. Fiberoptic bronchoscopy with EBB and TBB under fluoroscopic control is a safe and well-tolerated procedure.

Cytological monitoring of peripheral blood, bronchoalveolar lavage fluid, and transbronchial biopsy specimens during acute rejection and cytomegalovirus infection in lung and heart--lung allograft recipients.

STUDY OBJECTIVES: Acute rejection and cytomegalovirus (CMV) infection are important complications after lung and heart--lung transplantation. We sought to investigate whether acute rejection and CMV infection demonstrated as CMV antigenemia had an effect on the cell profiles of peripheral blood (PB), bronchoalveolar lavage fluid (BAL-F), or TBB histology. PATIENTS AND DESIGN: In this prospective study, composition of cells in PB, BAL-F, and TBB samples from 20 lung or heart-lung transplantation patients were analyzed during episodes of acute rejection or CMV antigenemia. Rejection was graded according to the International Society for Heart and Lung Transplantation criteria. As controls, samples with no evidence of rejection or infection were used. To evaluate the effect of time on cellular findings, samples were divided into three groups according to time after transplantation: 1--30, 31--180, and more than 180 d after transplantation. RESULTS: Acute rejection was associated with mild blood basophilia (p<0.05; specificity 94%, sensitivity 42%). In BAL-F during rejection, the number of basophils (p<0.05), eosinophils (p<0.05), and lymphocytes (p<0.05; specificity 77%, sensitivity 64%) was increased compared to controls during the post-operative month 1. Later-occurring rejections were associated with increased amounts of neutrophils in BAL-F (p<0.05; specificity 82%, sensitivity 74%). In TBB histology, acute rejections were associated with perivascular and/or peribronchial infiltration of lymphocytes (p<0.001) and plasma cells (p<0.05) compared to controls. In our patients receiving gancyclovir prophylaxis, CMV antigenemia did not significantly alter the cell profiles in PB and BAL-F nor the inflammatory cell picture in TBB histology. CONCLUSION: TBB histology remains the 'gold standard' for diagnosing rejection in lung and heart-lung transplantation patients, as the inflammatory cell findings in TBB specimens are highly specific for rejection. The cellular changes associated with rejection, mild PB basophilia and increased proportions of lymphocytes in early- and neutrophils in later-occurring rejection, observed in BAL-F cannot be considered specific for rejection, but may warrant clinical suspicion of rejection.

Laser Doppler flowmetry detects early risk of tracheal anastomotic complications after lung transplantation.

Healing of tracheal anastomosis after en bloc double-lung or heart-lung transplantation was analysed with the aid of endoscopic laser Doppler flowmetry in 7 patients (group I) with successful bronchial artery revascularization (BAR) and in 5 patients (group II) without or with failed BAR. Fifteen patients undergoing coronary surgery served as a control group. Airway anastomotic index (AAI) was used to express the ratio of Doppler flowmetry values between donor and recipient airway. On postoperative day 1 the mean (range) AAI was 1.3 (1.1-1.6) in group I, 0.74 (0.25-1.0) in group II and 0.95 (0.7-1.4) in the controls.The difference was statistically significant between groups I and II (p = 0.01) and also between group I and the control group (p = 0.003). Two group II patients had low AAI (<0.5), and both developed airway anastomotic complications. We conclude that successful BAR increases blood flow in the airway anastomotic region, and that low AAI on the first postoperative day is a strong predictor of late airway anastomotic complications.

Docetaxel and irinotecan (CPT-11) in the treatment of malignant pleural mesothelioma--a feasibility study.

We chose to treat malignant pleural mesothelioma with a combination of docetaxel and irinotecan (CPT-11), because there have been preliminary reports that CPT-11 is active against mesothelioma, and docetaxel and CPT-11 were the most active agents in our in vitro experiments in human mesothelioma cell lines. Fifteen previously untreated patients with pleural mesothelioma (IMIG Stage III-IV) were given docetaxel 60 mg/m2 followed by CPT-11 190 mg/m2 on day 1, repeated every 3 weeks. All the patients were evaluable for toxicity and 13 patients were evaluated for response. No objective responses (complete or partial) were achieved, but there were two minor responses (overall response rate 15%) each of a duration of 4 months. Three patients had stable disease (23%); median time to progression was 7 months. Median survival in all the patients was 8.5 months from the first chemotherapy cycle and 11 months from diagnosis. Toxicity was severe with seven of 15 patients suffering neutropenic fever and six of 15 patients grade 3-4 diarrhea. The trial was discontinued because of toxicity and lack of activity. We do not recommend the combination of docetaxel and CPT-11 using the schedule presented here for further investigation in malignant mesothelioma. However, CPT-11 and docetaxel, individually, still warrant further study in this disease, especially in combination with cisplatin.

Bronchial artery revascularization improves tracheal anastomotic healing after lung transplantation.

The study aimed to clarify the role of direct bronchial artery revascularization (BAR) after en bloc double-lung (DLT) and heart-lung transplantation (HLT). Group I comprised eight patients with en bloc DLT or HLT and successful BAR, while group II included 14 DLT or HLT cases without BAR or with failed BAR. From these groups, 2 subgroups were extracted: group III, including 6 cases of en bloc DLT with successful BAR and group IV 10 HLT cases without or with failed BAR. Airway healing was evaluated at bronchoscopy and patency of BAR with angiography. Pulmonary viral, bacterial and fungal infections, rejections and bronchiolitis obliterans syndrome (BOS) were registered. Tracheal healing at 2 weeks and 3 months was better in group I than in group 1 (p = 0.003 and p = 0.05, respectively). Compared with group IV, tracheal anastomotic healing at 2 weeks was better in group III (p = 0.007) and tended to be better also after 3 months (p = 0.07). The incidence of infections, rejection or BOS did not differ between groups I and II. BAR thus improved healing of tracheal anastomosis.

Interferon-alpha and 13-cis-retinoic acid as maintenance therapy after high-dose combination chemotherapy with growth factor support for small cell lung cancer--a feasibility study.

This randomized phase II multi-center study was designed to determine the time to progression, duration of response and the feasibility of an intensified maintenance regime consisting of a combination of interferon (IFN)-alpha and retinoic acid after high-dose combination chemotherapy and radiotherapy in patients with small cell lung cancer. The patients received four courses of combination chemotherapy consisting of ifosfamide, carboplatin and etoposide, with higher doses of ifosfamide and carboplatin given in the first course, with routine growth factor support. Responding patients were then randomly assigned to one of three maintenance therapy arms. All patients with limited disease (LD) were given thoracic radiotherapy before maintenance therapy and those who had also achieved a complete response (CR) or minimal residual disease (MRD) received prophylactic cranial irradiation. In Arm 1 patients received IFN-alpha-2a, 6 MIU s.c. TIW for 4 weeks, followed by 3 MIU s.c. TIW, and 13-cis-retinoic acid 1 mg/kg/day p.o. BID daily. In Arm 2 patients received trophosphamide 100-150 mg/day p.o. BID. No maintenance treatment was given in Arm 3, the control group. Maintenance therapy was continued for 1 year. Eighty-five patients were treated according to the protocol. Twenty-one patients achieved CR, four achieved MRD and forty-two achieved partial responses to chemotherapy and radiotherapy. Sixty patients (71%) were randomly assigned for maintenance treatment. Median survival was 17.1 months in the IFN-alpha-retinoic acid arm, 12.4 months in the trophosphamide arm and 13.5 months in the control arm. One-year survival rates were 82, 56 and 55%, respectively. Duration of response was 6.5, 5.5 and 4.7 months, respectively. Time to progression was 8.6, 8.0 and 6.8 months, respectively The differences were not statistically significant. The IFN-alpha-retinoic acid maintenance treatment was well tolerated. Patients who received IFN-alpha-retinoid maintenance therapy lived longer after the onset of progressive disease. The treatment regime was effective, feasible and well tolerated.

Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy of the combination of vinorelbine and gemcitabine as a non-platinum chemotherapy regimen in patients with inoperable locally-advanced or metastatic non-small-cell lung cancer (NSCLC). Efficacy was assessed primarily in terms of response rate, and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Patients with cytologically- or histologically-proven stage IIIB-IV NSCLC, bi-dimensionally measurable lesions, adequate haematological, hepatic and renal function, WHO performance status < or = 2 and no previous chemotherapy or radiotherapy were eligible. The first 12 patients were entered in a pilot study and received vinorelbine (VNR) 30 mg/m2 on days 1, 8, 15 and 22, and gemcitabine (GEM) 1000 mg/m2 on days 1, 8 and 15, of a 28-day cycle. Subsequently, patients were entered in a phase II trial of VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle. Treatment consisted of three cycles of the chemotherapy, with a further three cycles for those patients who achieved stable disease or a complete or partial response (CR/PR) to the first three cycles. Patients who had achieved CR or PR after six cycles continued with the treatment until relapse. RESULTS: The dosage and scheduling of VNR and GEM in the pilot study resulted in neutropenia necessitating reductions or delays in treatment, and consequently low dose intensity. The schedule was thus modified to VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle for the phase II trial. Thirty-three patients were enrolled in the phase II trial, and 28 were evaluable for response. The overall intent-to-treat response rate of all 45 patients was 40% (18 of 45), comprising 4 CR (9%) and 14 PR (31%). For the 28 evaluable patients who received the fortnightly chemotherapy the response rate was 46% (13 of 28), CR 11% (3 of 28) and PR 36% (10 of 28). Seven patients (25%) had stable disease. The one-year cumulative survival rate for the 33 patients receiving the fortnightly chemotherapy was 24% and median time-to-progression 4 months (range 1-16 months). Median survival for these patients was eight months. Nine out of twelve patients in the pilot study (75%) suffered grade 3-4 neutropenia. There was one toxic death, attributed to neutropenic fever and sepsis, and two cases of pulmonary embolism. One patient suffered Grade 4 thrombocytopenia. Only eight patients (24%) on the fortnightly schedule suffered grade 3-4 neutropenia, resulting in dose reductions or delays for three of them (9%). None of the patients on the fortnightly schedule suffered thrombocytopenia or anaemia. CONCLUSIONS: The fortnightly schedule of gemcitabine and vinorelbine was a well-tolerated out-patient regimen, producing response and survival rates comparable to those of cisplatin combination regimens, but with a more favourable toxicity profile. Gemcitabine and vinorelbine should now be tested in a triplet combination with a taxane as the third drug, or against a platinum-containing regimen in a phase III study.

High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma.

Twenty six patients with pleural mesothelioma of UICC stage I-IV excluding M1 disease (46% of whom had stage I disease and 38% stage III disease) were treated intravenously with high dose MTX (3 g) and calcium folinate rescue three times at intervals of 2 weeks and three times at intervals of 3 weeks. Natural interferon (IFN)-alpha (3 MIU days 2-10) and recombinant IFN-gamma1b (50 microg m(-2) on days 2, 6 and 10) were injected subcutaneously after each MTX dose. At the end of MTX treatment the IFNs were continued as maintenance therapy until disease progression. Seven partial responses were observed among 24 patients evaluable for response (response rate 29%, 95% confidence interval 13-51%). Median duration of response was 10 months (range 3-24 months). Median survival was 17 months and 1-year and 2-year survival rates 62% and 31% respectively. The toxicity of the chemo-immunotherapy was acceptable. Treatment was stopped in one patient who developed grade IV neurological toxicity. MTX dose reductions were rare (two patients with grade 1-2 renal toxicity). The combination of high dose MTX and IFN-alpha and IFN-gamma is active against malignant pleural mesothelioma and well-tolerated. The survival rates are encouraging.

Tumour response and radiation-induced lung injury in patients with recurrent small cell lung cancer treated with radiotherapy and concomitant interferon-alpha.

The aim of this study was to determine whether either natural or recombinant interferon (IFN)-alpha can improve the response to radiotherapy (RT) in patients with small cell lung cancer (SCLC), and to assess the role of IFN in radiation-induced lung injury. All patients had previously participated in a randomised trial of chemotherapy alone or in combination with IFN-alpha in three arms (arm O: no IFN, arm I: natural IFN-alpha, arm II: recombinant IFN-alpha). Patients with locally progressive disease in the lungs following chemotherapy were treated with RT and they continued with their concomitant IFN-alpha. The RT dose was 50 Gy. Radiation-induced lung injury was assessed by lung function tests, computed tomography and bronchoalveolar lavage fluid (BALF) analysis which included cell findings, Interleukin (IL)-1 alpha/-1 beta expression by alveolar macrophages and surfactant components. Seventeen patients were entered in the study, 16 of whom were evaluable. Response rates in Arms O, I and II were 50, 67 and 50%, respectively. Median survival was 18.5, 7 and 23 months respectively, and 1-year survival was 67, 29 and 75% respectively. Long-term survival as assessed by 2- and 3-year survival rates was 29% in patients receiving natural IFN-alpha as compared to 17% in patients not receiving IFN (not statistically significant findings). Every patient had abnormal results when assessed for radiation-induced lung injury. No statistically significant difference was found in toxicity between the treatment arms. A high surfactant protein (SP)-A/phospholipid ratio and a high level of SP-A in BALF before RT was associated with a high degree of radiation-induced lung injury measured by lung function tests and computed tomography in all arms of the study. Thus, we could not show that the combination of IFN-alpha and RT induced more lung toxicity than RT alone as we did in our previous study. The role of high SP-A/phospholipid ratios and high SP-A levels in BALF before RT as predictors of the development of lung injury after RT needs to be determined in the future.

Concomitant chemotherapy and IFN-alpha for small cell lung cancer: a randomized multicenter phase III study.

Patients with any stage of small cell lung cancer were given low-dose interferon-alpha (IFN-alpha) from the first day of treatment as long as possible irrespective of changes in treatment dictated by disease progression. All patients received 6 cycles of the chemotherapy (CT): cisplatin 70 mg/m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1, 2, 3 every 28 days. Seventy-eight patients were assigned to arm 1: CT alone, 75 patients to arm 2: CT + natural IFN-alpha (3 MU three times a week i.m.), and 66 patients to arm 3: CT + recombinant IFN alpha-2a (3 MU three times a week i.m.). There was no difference in median survival between the arms (10.2 months, 10.0 months, 10.1 months, respectively), p = 0.32. The 2-year survival rates were 15%, 3%, and 11%, respectively. Grade 3 and 4 leukopenia occurred more frequently in the IFN arms than in the CT alone arm and resulted in dose reductions. Antibodies occasionally developed to recombinant IFN. We conclude that IFN-alpha can be administered concomitantly with chemotherapy but is probably better kept for maintenance therapy so that optimal full doses of induction CT can be given.

Amplitude variation in static-charge-sensitive bed signal increased in obstructive airways disease.

The relationship between oesophageal pressure variation and amplitude variation in the static-charge-sensitive bed (SCSB) ballistocardiogram suggests that changes in intrathoracic pressure can be detected using the SCSB method. We investigated whether amplitude variation in the static-charge-sensitive bed ballistocardiogram (SAV) is related to severity of airway obstruction in patients with asthma and chronic obstructive pulmonary disease. The ability of SAV to detect an increase in airway obstruction induced by histamine challenge was also tested. Twenty-six patients suffering from asthma and 12 patients with chronic obstructive pulmonary disease (COPD) were enrolled in the study. SAV, amplitude from the SCSB ballistocardiogram, respiratory amplitude from the SCSB respiratory wave form and heart rate from the electrocardiogram (ECG) were computed using analysing software (Biorec, Helsinki, Finland) during a 7-min supine rest. SAV was related to forced expiratory volume in one second (FEV1) immediately after signal recording. Asthma patients participated in a standardized histamine challenge test to reveal the effect of acute bronchoconstriction on SAV. An inverse relationship existed between baseline FEV1 and SAV in asthma and COPD. In the histamine inhalation test, FEV1 fell by 0.7 +/- 0.3 l or 26% +/- 11% (P < 0.0001) and SAV increased by 12% +/- 5% (P < 0.0001) in 12 asthma patients. The fall in FEV1 induced by histamine followed regularly and correlated significantly with the rise in SAV (n = 24, r = -0.58, P = 0.002). Changes in respiratory amplitude or heart rate did not explain changes in SAV. SAV may not separate the upper airway obstruction from the bronchial obstruction but it is related to severity of airway obstruction. The clinically significant increase in airway obstruction induced by histamine inhalation increases amplitude variation in SCSB.

Paclitaxel (Taxol) and carboplatin followed by concomitant paclitaxel, cisplatin and radiotherapy for inoperable stage III NSCLC.

We assessed the efficacy and toxicity of low-dose paclitaxel (Taxol) given combined with carboplatin before radiotherapy, and with cisplatin concomitantly with radiotherapy, in 27 patients with previously untreated inoperable stage IIA/IIIB non-small cell lung cancer. The induction chemotherapy consisted of paclitaxel 135 mg/m2 given over 1 h on day 1 and carboplatin 200 mg/m2 on day 2 repeated every 3 weeks for three cycles. Patients free of progression after induction chemotherapy received megavoltage radiation (56 Gy, 2 Gy/fraction) along with paclitaxel (30 mg/m2/1 h) and cisplatin (30 mg/m2/1 h) given 2-4 h before irradiation on days, 1, 2, 3, 22, 23 and 24. A combination of antero-posterior and oblique treatment fields was used to limit the dose to the spinal cord and to the left side of the heart to 36 Gy. The overall response rate was 78% (complete response, 19%). With a median follow-up of 19 months the median survival is 12 months, the estimated 2-year survival rate is 36%, and all patients with a complete response survived for at least 12 months after starting treatment. A total of 17 deaths occurred with metastases predominantly in the brain. Major acute toxicities (> grade 3) during induction chemotherapy included leuko-/neutropenia (n = 5/27, 19%), and during chemoradiotherapy leuko-/neutropenia (n = 10/23, 43%), thrombocytopenia (n = 1, 4%), oesophagitis (n = 3, 13%) and pneumonitis (n = 7, 30%). No toxic deaths occurred. Marked renal toxicity was not observed. We conclude that this chemoradiotherapy regimen is effective and well-tolerated, and should be further evaluated in a randomised phase III trial.

Ganciclovir prophylaxis after lung and heart-lung transplantation.

Cytomegalovirus (CMV) infection causes both acute and chronic allograft damage. The aim of this study was to analyze the utility of ganciclovir in preventing CMV infection in pulmonary allografts. Thirty five consecutive lung (LTX) and heart-lung (HLTX) transplant patients were studied from 1990 to 1996. CMV prophylaxis was started in January 1995. Recipients with CMV-positive serology received ganciclovir on postoperative days (POD) 7-28. Acyclovir was given on POD 29-90. Recipients with CMV-negative serology received ganciclovir on POD 7-90 if the serology of the donor was positive. CMV was demonstrated by rapid cell vial culture and/or detecting CMV-specific antigens in bronchoalveolar lavage (BAL) samples. The time point of the first BAL fluid specimen exhibiting CMV was estimated using the Life Table method. BAL samples of all the recipients without ganciclovir treatment became positive for CMV, whereas two of the 11 patients with ganciclovir administration remained negative. Ganciclovir significantly (P < 0.05) delayed but did not absolutely prevent CMV infection after LTX and HLTX.