Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder(☠).

Reduction of immunosuppression (RI) is commonly used to treat posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients. We investigated the efficacy, safety and predictors of response to RI in adult patients with PTLD. Sixty-seven patients were managed with RI alone and 30 patients were treated with surgical excision followed by adjuvant RI. The response rate to RI alone was 45% (complete response-37%, partial response-8%). The relapse rate in complete responders was 17%. Adjuvant RI resulted in a 27% relapse rate. The acute rejection rate following RI-containing strategies was 32% and a second transplant was feasible without relapse of PTLD. The median survival was 44 months in patients treated with RI alone and 9.5 months in patients who remained on full immunosuppression (p = 0.07). Bulky disease, advanced stage and older age predicted lack of response to RI. Survival analysis demonstrated predictors of poor outcome-age, dyspnea, B symptoms, LDH level, hepatitis C, bone marrow and liver involvement. Patients with none or one of these factors had a 3-year overall survival of 100% and 79%, respectively. These findings support the use of RI alone in low-risk PTLD and suggest factors that predict response and survival.

The effect of recipient's age on lung transplant outcome.

Selection criteria for organ transplantation have evolved over time. Age has been revisited periodically. We studied the outcome of lung transplant adjusted by age in a single center transplant population. We matched the 42 lung graft recipients older than 60 years transplanted by July 1999 to younger controls by lung disease, transplant era within 2 years, type of transplant and gender. The female to male ratios were 17/25 among the older cohort (median age 61.6 years), and 15/27 (median age 51.9 years) among the matched younger. Survival analysis demonstrated a significant difference: at 1 year, 60% versus 86%, and at 5 years, 37% versus 57%, for older and younger, respectively, p=0.005. Excess annual mortality, calculated with the declining exponential approximation to life expectancy (DEALE), showed an older/younger ratio of 1.9. Eleven deaths occurred within 6 months among the older patients, 10 due to infection. After 6 months, there were 20 more deaths, 6 due to malignancy, 5 to Bronchiolitis Obliterans Syndrome (BOS), 3 to infection and 6 to other causes. Among the younger there were 6 deaths within 6 months and 12 more thereafter; among the latter, 8 were due to BOS. Despite stringent selection, lung transplant recipients older than 60 years show increased mortality even after adjusting for their expected higher age-related mortality.

The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D.

Gastro-esophageal reflux and related pulmonary bile acid aspiration were prospectively investigated as possible contributors to postlung transplant bronchiolitis obliterans syndrome (BOS). We also studied the impact of aspiration on pulmonary surfactant collectin proteins SP-A and SP-D and on surfactant phospholipids--all important components of innate immunity in the lung. Proximal and distal esophageal 24-h pH testing and broncho-alveolar lavage fluid (BALF) bile acid assays were performed prospectively at 3-month posttransplant in 50 patients. BALF was also assayed for SP-A, SP-D and phospholipids expressed as ratio to total lipids: phosphatidylcholine; dipalmitoylphosphatidylcholine; phosphatidylglycerol (PG); phosphatidylinositol; sphingomyelin (SM) and lysophosphatidylcholine. Actuarial freedom from BOS was assessed. Freedom from BOS was reduced in patients with abnormal (proximal and/or distal) esophageal pH findings or BALF bile acids (Log-rank Mantel-Cox p < 0.05). Abnormal pH findings were observed in 72% (8 of 11) of patients with bile acids detected within the BALF. BALF with high levels of bile acids also had significantly lower SP-A, SP-D, dipalmitoylphosphatidylcholine; PG and higher SM levels (Mann-Whitney, p < 0.05). Duodeno-gastro-esophageal reflux and consequent aspiration is a risk factor for the development of BOS postlung transplant. Bile acid aspiration is associated with impaired lung allograft innate immunity manifest by reduced surfactant collectins and altered phospholipids.

Association of clinical risk factors with functional status following lung transplantation.

A fundamental goal of lung transplantation is the regaining of functional capacity, yet little is known about what factors are associated with the achievement of this goal. The aim of this study is to test the association of clinical risk factors with functional status 1 year following lung transplantation. We conducted a cohort study of 321 lung transplants and assessed functionality by the distance achieved during a standard 6-min walk test (6MWT). Preoperative recipient risk factors were evaluated for association with functional status and adjusted for confounding using multivariable linear regression models. In these multivariable analyses, recipient female gender (p<0.001), recipient pretransplant body mass index (BMI) of greater than 27 kg/m2 (p=0.017) and shorter pretransplant 6MWT distances (p=0.006) were independently associated with shorter distances achieved during 6MWT after lung transplant, while cystic fibrosis (CF) (p=0.003), and bilateral lung transplant (p=0.014) were independently associated with longer distances achieved. Approximately 51% of the variance in 6MWT distance was explained by these risk factors in the linear regression models (R2=0.51). These findings may have implications in patient counseling, selection, procedure choice, and may lead to interventions aimed at improving the functional outcomes of lung transplantation.

Impact of lung transplant operation on bronchiolitis obliterans syndrome in patients with chronic obstructive pulmonary disease.

Previous studies suggest that bilateral (BLT) compared with single lung transplantation (SLT) for patients with chronic obstructive pulmonary disease (COPD) results in improved long-term survival. The effect of transplant operation on bronchiolitis obliterans syndrome (BOS) is unknown. A retrospective study of all lung transplant recipients with pre-transplant diagnoses of COPD at the University of Toronto and at Duke University was performed. Data collected were age, gender, date and type of transplant, acute rejection, survival, presence and time of BOS. 221 (bilateral n = 101, single n = 120) patients met our criteria. Patients with BLT were younger (53.0 vs. 55.3 years; p = 0.034), more likely to be male (56.3% vs. 42.4%; p = 0.039) and more likely to be transplanted at the University of Toronto (79.6% vs. 16.1%; p < 0.001). Freedom from BOS was similar at 1 year post-transplant. However, BLT recipients were more commonly free from BOS 3 years (57.4% vs. 50.7%) and 5 years (44.5% vs. 17.9%) post-transplant (p = 0.024). Survival of BLT was better than SLT recipients at 3 and 5 years post-transplant (BLT vs. SLT: 67.5% vs. 61.1% and 60.7% vs. 34.1%, respectively; p = 0.018). Similar trends on survival were observed after development of BOS. BLT results in lower rates of BOS in patients with COPD that are eligible for both SLT and BLT.

Bacteremia in lung transplant recipients in the current era.

Current trends in the epidemiology, outcome and variables influencing mortality in bacteremic lung transplant recipients have not been fully described. We prospectively studied bacteremias in lung transplant recipients in a multicenter study between 2000-2004. Bacteremia was documented in 56 lung transplant recipients, an average of 172 days after transplantation. Multiple antibiotic resistance was documented in 48% of the isolates; these included 57% of the Gram-negative and 38% of the Gram-positive bacteria. Pulmonary infection was the most common source of resistant gram-negative bacteremias. Mortality rate at 28 days after the onset of bacteremia was 25% (14/56). Mechanical ventilation and abnormal mental status correlated independently with higher mortality (p < 0.05 for both variables). Bacteremia remains a significant complication in lung transplant recipients and is associated with considerable mortality. Recognition of variables portending a high risk for antibiotic resistance and for poor outcome has implications relevant for optimizing antibiotic prescription and for improving outcomes in lung transplant recipients.

Laparoscopic antireflux surgery in the lung transplant population.

BACKGROUND: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. METHODS: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. RESULTS: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). CONCLUSIONS: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.

Prognostic value of serum carcinoembryonic antigen levels in patients who undergo lung transplantation.

BACKGROUND: Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance. MATERIALS AND METHODS: We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmenger's syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other. RESULTS: After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmenger's syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001). CONCLUSIONS: CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Methemoglobinemia after infusion of ifosfamide chemotherapy: first report of a potentially serious adverse reaction related to ifosfamide.

Acute formation of methemoglobin is a life-threatening condition caused by multiple medications. In this article we report the first case of methemoglobinemia in a patient with metastatic uterine leiomyosarcoma, after infusion of ifosfamide chemotherapy. The patient recovered after prompt diagnosis and treatment of the condition. A mechanism for the formation of methemoglobin as a result of the ifosfamide infusion is offered.

Anastomotic infections in lung transplant recipients.

OBJECTIVES: Anastomotic infections are an uncommon but potentially devastating complication after lung transplantation. The incidence, microbiology, predisposing factors, and clinical outcomes of anastomotic infections have not been well described. METHODS: We performed a retrospective chart review of the first 283 lung or heart-lung transplant recipients performed at Duke University Medical Center and identified all cases of anastomotic infection. RESULTS: Fifteen patients (5.3%) developed anastomotic infections. Aspergillus caused infection in six patients, Candida in eight patients and Staphylococcus aureus in one patient. Bilateral or right lung transplantation and the use of induction immunosuppression with monoclonoal or polyclonal antibodies are associated with a higher incidence of anastomotic infections. All patients with fungal anastomotic infections were treated with a combination of systemic and inhaled antifungal agents. All patients had improvement of their anastomotic sites after treatment and no patients developed anastomotic dehiscence. CONCLUSIONS: Anastomotic infection is an infrequent complication after lung transplantation, and is caused predominately by fungal pathogens. In contrast to previous reports, anastomotic dehiscence did not occur in any patient in our series. Treatment with the combination of inhaled and systemic antimicrobial agents may have favorably affected clinical outcomes.

Partial liquid ventilation.

Mortality from the adult respiratory distress syndrome (ARDS) and the infant respiratory distress syndrome remains high despite numerous interventions and modalities. Perfluorocarbons (PFC) are inert liquids that can dissolve large amounts of oxygen and carbon dioxide and can be used as respiratory media. Partial liquid ventilation uses PFC to partially fill the lungs of patients with ARDS to improve gas exchange and support them. Studies in animals and humans (mostly neonates) using perflubron, which is currently the only PFC approved for clinical use, have shown that they are safe and effective in improving oxygenation. In this article the rationale of the technique, its historical background, and animal and clinical data to date are reviewed.

Rapidly growing mycobacterial lung infection in association with esophageal disorders.

Esophageal or other swallowing disorders complicated by lipoid pneumonia are reported to be associated with pulmonary infections caused by rapidly growing mycobacteria. Herein we describe a 63-year-old woman with achalasia of the esophagus complicated by lung infection with Mycobacterium chelonae and a 47-year-old man in whom long-term ingestion of mineral oil was complicated by lipoid pneumonia and M. fortuitum lung infection. A MEDLINE search of English language publications from 1966 to 1997 revealed 18 cases of lung infections caused by rapidly growing mycobacteria in patients with esophageal disorders. Of these 18 patients and our 2 patients, 11 were men and 9 were women (mean age, 50 years). Achalasia was present in 11 patients, and 6 had lipoid pneumonia without evidence of esophageal disorders. Three patients had lipoid pneumonia caused by lipoid ingestion in the setting of achalasia or another swallowing disorder. In 14 patients, lung infection was caused by M. fortuitum; in 5, M. chelonae; and in 1, a non-M. fortuitum rapidly growing mycobacterial infection. The most common clinical feature was fever, and the most common roentgenologic abnormality was the presence of unilateral or bilateral and patchy or dense infiltrates. The sputum was the most common source of isolation of rapidly growing mycobacteria. Achalasia and lipoid pneumonia are important risk factors for the development of lung infections caused by rapidly growing mycobacteria. Treatment of the esophageal disease might prevent occurrence of and facilitate recovery from these infections.

The relationship between latex skin prick test responses and clinical allergic responses.

BACKGROUND: Allergic responses to latex have been reported more frequently in the past 5 years. Although commercial skin prick test solutions are available and can be used in the diagnosis of latex allergy in some countries, the characteristics of patients sensitized to latex relative to their skin test responses have not been reported. OBJECTIVE: The purpose of this study is to relate the clinical characteristics of patients with latex sensitivity to the size of their latex skin prick test response. METHODS: A retrospective review of patients who were attending a hospital-based allergy and asthma clinic and who had positive skin test responses to a commercial latex skin test solution was undertaken. RESULTS: Of 47 patients who had skin test responses to latex, 36 had a mean wheal diameter at least 3 mm greater than the negative control (diluent). Sixty-eight percent were health care workers. There was a positive association between the size of skin test response and severity of latex-induced symptoms (p < 0.001). A history of banana sensitivity was also associated with larger skin test responses (p < 0.05). CONCLUSION: The size of the skin prick test response to latex solution that is commercially available in Canada reflects the severity of latex-induced clinical allergic responses.

On the Mechanism of Action of the Antitumor Drug cis-Platin (cis-DDP) and its Second Generation Derivatives.

The present article attempts to summarise the elements of the mechanism of action of the antitumor drug cis -Platin presented the last few years. Highlights on the discovery, of the drug and the development of it's second generation derivatives are presented, as well as the ways that cis -DDP reacts with biomolecules as DNA and proteins and their models e.g. nucleosides, nucleotides. Also the hydrolysis data are presented for cis -DDP and its' inactive congener trans -DDP, as well as for the second generation drug carboplatin. Finally, usefull conclusions are given from this work, pointing out the unanswered questions about the action of cis -DDP as well as its differences in action, in comparison with trans -DDP.