Publications by authors named "Lorriana E Leard"

30 Publications

  • Page 1 of 1

Construct and Predictive Validity of Sarcopenia in Lung Transplant Candidates.

Ann Am Thorac Soc 2021 Feb 10. Epub 2021 Feb 10.

UC San Francisco, Pulmonary and Critical Care Medicine, San Francisco, California, United States.

Rationale: Sarcopenia is associated with disability and death. The optimal definition and clinical relevance of sarcopenia in lung transplantation remain unknown.

Objective: To assess the construct and predictive validity of sarcopenia definitions in lung transplant candidates.

Methods: In a multicenter prospective cohort of 424 lung transplant candidates, we evaluated limited (muscle mass only) and expanded (muscle mass and quality) sarcopenia definitions from the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), Foundation for the National Institutes of Health (FNIH), and a cohort-specific distribution-based lowest quartile definition. We assessed construct validity using associations with conceptually related factors. We evaluated the relationship between sarcopenia and frailty using generalized additive models. We also evaluated associations between sarcopenia definitions and key pre-transplant outcomes including disability (quantified by the Lung Transplant Valued Life Activities scale [range 0-3, higher scores = worse disability; minimally important difference: 0.3]) and waitlist delisting/death by multivariate linear and Cox regression, respectively.

Results: Sarcopenia prevalence ranged from 6-13% by definition used. The limited EWGSOP2 definition demonstrated the highest construct validity, followed by the expanded EWGSOP2 and both limited and expanded FNIH and lowest quartile definitions. Sarcopenia exhibited a linear association with the risk of frailty. The EWGSOP2 and expanded lowest quartile definitions were associated with disability, ranging from 0.20 to 0.25 higher LT-VLA scores. Sarcopenia was associated with increased risk of waitlist delisting or death by the limited and expanded lowest quartile definitions (HR: 3.8; 95%CI: 1.4, 9.9 and HR: 3.5; 95%CI: 1.1, 11.0, respectively) and the EWGSOP2 limited definition (HR 2.8; 95%CI: 0.9, 8.6) but not with the three other candidate definitions.

Conclusions: The prevalence and validity of sarcopenia vary by definition; the EWGSOP2 limited definition exhibited the broadest validity in lung transplant candidates. The linear relationship between low muscle mass and frailty highlights sarcopenia's contribution to frailty and also questions the clinical utility of a sarcopenia cut-point in advanced lung disease. The associations between sarcopenia and important pre-transplant outcomes support further investigation into using body composition for candidate risk stratification.
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http://dx.doi.org/10.1513/AnnalsATS.202007-796OCDOI Listing
February 2021

Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.

Am J Transplant 2020 Oct 20. Epub 2020 Oct 20.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.
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http://dx.doi.org/10.1111/ajt.16360DOI Listing
October 2020

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature.

Am J Transplant 2021 01 22;21(1):362-371. Epub 2020 Sep 22.

Department of Medicine, University of California, San Francisco, California, USA.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.
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http://dx.doi.org/10.1111/ajt.16293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009189PMC
January 2021

Primary graft dysfunction attenuates improvements in health-related quality of life after lung transplantation, but not disability or depression.

Am J Transplant 2021 02 5;21(2):815-824. Epub 2020 Sep 5.

Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine, University of California, San Francisco, California, USA.

Disability, depressive symptoms, and impaired health-related quality of life (HRQL) are common among patients with life-threatening respiratory compromise. We sought to determine if primary graft dysfunction (PGD), a syndrome of acute lung injury, attenuates improvements in patient-reported outcomes after transplantation. In a single-center prospective cohort, we assessed disability, depressive symptoms, and HRQL before and at 3- to 6-month intervals after lung transplantation. We estimated the magnitude of change in disability, depressive symptoms, and HRQL with hierarchical segmented linear mixed-effects models. Among 251 lung transplant recipients, 50 developed PGD Grade 3. Regardless of PGD severity, participants had improvements in disability and depressive symptoms, as well as generic-physical, generic-mental, respiratory-specific, and health-utility HRQL, exceeding 1- to 4-fold the minimally clinically important difference across all instruments. Participants with PGD Grade 3 had a lower magnitude of improvement in generic-physical HRQL and health-utility than in all other participants. Among participants with PGD Grade 3, prolonged mechanical ventilation was associated with greater attenuation of improvements. PGD remains a threat to the 2 primary aims of lung transplantation, extending survival and improving HRQL. Attenuation of improvement persists long after hospital discharge. Future studies should assess if interventions can mitigate the impact of PGD on patient-reported outcomes.
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http://dx.doi.org/10.1111/ajt.16257DOI Listing
February 2021

Cystic Fibrosis Lung Transplant Recipients Have Suppressed Airway Interferon Responses during Infection.

Cell Rep Med 2020 Jul;1(4)

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

Lung transplantation can be lifesaving in end-stage cystic fibrosis (CF), but long-term survival is limited by chronic lung allograft dysfunction (CLAD). Persistent upper airway (PsA) colonization can seed the allograft. While PsA infection is associated with CLAD in non-CF recipients, this association is less clear for CF recipients experiencing PsA recolonization. Here, we evaluate host and pathogen contributions to this phenomenon. In the context of PsA infection, brushings from the airways of CF recipients demonstrate type 1 interferon gene suppression. Airway epithelial cell (AEC) cultures demonstrate similar findings in the absence of pathogens or immune cells, contrasting with the pre-transplant CF AEC phenotype. Type 1 interferon promoters are relatively hypermethylated in CF AECs. CF subjects in this cohort have more mucoid PsA, while non-CF PsA subjects have decreased microbiome α diversity. Peri-transplant protocols may benefit from consideration of this host and microbiome equilibrium.
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http://dx.doi.org/10.1016/j.xcrm.2020.100055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402593PMC
July 2020

Frailty after lung transplantation is associated with impaired health-related quality of life and mortality.

Thorax 2020 08 6;75(8):669-678. Epub 2020 May 6.

Medicine, University of California San Francisco, San Francisco, California, USA.

Background: Lung transplantation and related medications are associated with pathobiological changes that can induce frailty, a state of decreased physiological reserve. Causes of persistent or emergent frailty after lung transplantation, and whether such transplant-related frailty is associated with key outcomes, are unknown.

Methods: Frailty and health-related quality of life (HRQL) were prospectively measured repeatedly for up to 3 years after lung transplantation. Frailty, quantified by the Short Physical Performance Battery (SPPB), was tested as a time-dependent binary and continuous predictor. The association of transplant-related frailty with HRQL and mortality was evaluated using mixed effects and Cox regression models, respectively, adjusting for age, sex, ethnicity, diagnosis, and for body mass index and lung function as time-dependent covariates. We tested the association between measures of body composition, malnutrition, renal dysfunction and immunosuppressants on the development of frailty using mixed effects models with time-dependent predictors and lagged frailty outcomes.

Results: Among 259 adults (56% male; mean age 55.9±12.3 years), transplant-related frailty was associated with lower HRQL. Frailty was also associated with a 2.5-fold higher mortality risk (HR 2.51; 95% CI 1.21 to 5.23). Further, each 1-point worsening in SPPB was associated, on average, with a 13% higher mortality risk (HR 1.13; 95% CI 1.04 to 1.23). Secondarily, we found that sarcopenia, underweight and obesity, malnutrition, and renal dysfunction were associated with the development of frailty after transplant.

Conclusions: Transplant-related frailty is associated with lower HRQL and higher mortality in lung recipients. Abnormal body composition, malnutrition and renal dysfunction may contribute to the development of frailty after transplant. Confirming the role of these potential contributors and developing interventions to mitigate frailty may improve lung transplant success.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023537PMC
August 2020

Improvements in frailty contribute to substantial improvements in quality of life after lung transplantation in patients with cystic fibrosis.

Pediatr Pulmonol 2020 06 1;55(6):1406-1413. Epub 2020 Apr 1.

Department of Medicine, University of California San Francisco, San Francisco, California.

Background: While lung transplantation (LTx) improves health-related quality of life (HRQL) in cystic fibrosis (CF), the determinants of this improvement are unknown. In other populations, frailty-a syndrome of vulnerability to physiologic stressors-is associated with disability and poor HRQL. We hypothesized that improvements in frailty would be associated with improved disability and HRQL in adults with CF undergoing LTx.

Methods: In a single-center prospective cohort study from 2010 to 2017, assessments of frailty, disability, and HRQL were performed before and at 3- and 6-months after LTx. We assessed frailty by the short physical performance battery (SPPB). We assessed disability with the Lung Transplant Valued Life Activities scale (LT-VLA) and HRQL by the Medical Outcomes Study Short Form Physical and Mental Component Summary scales (SF12-PCS, -MCS), the Airway Questionnaire 20-Revised (AQ20R), and the Euroqol 5D (EQ5D). We tested the association of concurrent changes in frailty and lung function on disability and HRQL by linear mixed-effects models adjusted for sex and body mass index.

Results: Among 23 participants with CF, improvements in frailty and lung function were independently associated with improved disability and some HRQL measures. For example, each 1-point improvement in SPPB or 200 mL improvement in FEV1 was associated with improved LT-VLA disability by 0.14 (95%CI: 0.08-0.20) and 0.07 (95%CI: 0.05-0.09) points and improved EQ5D by 0.05 (95%CI: 0.03 to 0.07) and 0.02 (95%CI: 0.01-0.03) points, respectively.

Conclusion: Improvement in frailty is a novel determinant of improved disability and HRQL in adults with CF undergoing LTx.
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http://dx.doi.org/10.1002/ppul.24747DOI Listing
June 2020

Tacrolimus trough monitoring guided by mass spectrometry without accounting for assay differences is associated with acute kidney injury in lung transplant recipients.

Am J Health Syst Pharm 2019 12;76(24):2019-2027

Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA.

Purpose: Tacrolimus is a nephrotoxic immunosuppressant historically monitored via enzyme-based immunoassay (IA). After 2011, the 2 largest laboratory companies in the United States implemented tacrolimus quantification by liquid chromatography-mass spectrometry (LC-MS); this method excludes metabolites, potentially resulting in lower quantified drug concentrations. We sought to determine if tacrolimus therapeutic drug monitoring via LC-MS, as performed using trough targets originally derived from IA values, influences clinical outcomes.

Methods: In a single-center retrospective cohort study of lung transplant recipients, risks of acute kidney injury, acute renal failure, and new-onset diabetes after transplantation, as well as chronic lung allograft dysfunction-free survival, were compared in 82 subjects monitored by LC-MS and 102 subjects monitored by IA using Cox proportional hazard models adjusted for age, sex, baseline renal function, and race.

Results: LC-MS-based monitoring was associated with a greater risk of acute kidney injury (adjusted hazard ratio, 1.65; 95% confidence interval, 1.02-2.67). No statistically significant differences in risks of acute renal failure and new-onset diabetes after transplantation were observed.

Conclusion: Although LC-MS provides a more accurate representation of the blood concentration of the parent compound tacrolimus exclusive of metabolite, established cut points for tacrolimus dosing may need to be adjusted to account for the increased risk of renal injury.
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http://dx.doi.org/10.1093/ajhp/zxz243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170730PMC
December 2019

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

Am J Respir Cell Mol Biol 2020 03;62(3):364-372

Department of Medicine.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.
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http://dx.doi.org/10.1165/rcmb.2019-0140OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055700PMC
March 2020

Frailty trajectories in adult lung transplantation: A cohort study.

J Heart Lung Transplant 2019 07 18;38(7):699-707. Epub 2019 Mar 18.

Departments of Medicine.

Background: Frailty is common in adults with advanced lung disease and is associated with death before and after lung transplantation. We aimed to determine whether frailty changes from before to after the lung transplant.

Methods: In a single-center, prospective cohort study among adults undergoing lung transplantation from 2010 to 2017, we assessed frailty by the Short Physical Performance Battery (SPPB; higher scores reflect less frailty) and Fried Frailty Phenotype (FFP; higher scores reflect greater frailty) before and repeatedly up to 36 months after transplant. We tested for changes in frailty scores over time using segmented mixed effects models, adjusting for age, sex, and diagnosis. We quantified the proportion of subjects transitioning between frailty states (frail vs not frail) from before to after the transplant.

Results: In 246 subjects, changes in frailty occurred within the first 6 post-operative months and remained stable thereafter. The overall change in frailty was attributable to improvements among those subjects who were frail before transplant. They experienced a 5.1-point improvement in SPPB (95% confidence interval [CI] 4.6-5.7) and a 1.8-point improvement in FFP (95% CI -2.1 to -1.6) during the early period. Frailty by SPPB and FFP did not change in those who were not frail before transplant. Approximately 84% of survivors who were frail before transplant became not frail after transplant.

Conclusions: Pre-operative frailty resolves in many patients after lung transplantation. Because a large proportion of frailty may be attributable to advanced lung disease, frailty alone should not be an absolute contraindication to transplantation.
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http://dx.doi.org/10.1016/j.healun.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612595PMC
July 2019

Management and clinical outcomes after lung transplantation in patients with pre-transplant Mycobacterium abscessus infection: A single center experience.

Transpl Infect Dis 2019 Jun 16;21(3):e13084. Epub 2019 Apr 16.

Department of Medicine, University of California, San Francisco.

Background: Preoperative Mycobacterium abscessus infection is often considered a contraindication to lung transplantation because of its association with poor outcomes after transplant. Detailed strategies for bridging to transplant, post-operative management, and data regarding outcomes are lacking.

Methods: We reviewed outcomes in subjects with M abscessus infection who underwent lung transplantation between 2010 and 2018 at the University of California San Francisco. M abscessus infection was defined by American Thoracic Society (ATS) criteria. Data collected included age, FEV , BMI, LAS, antibiotic regimens, and other management decisions. Time to chronic lung allograft dysfunction (CLAD) and survival were also assessed.

Results: Of 387 lung transplant recipients, seven were infected with M abscessus at the time of listing. All received multiple antibiotics before transplant. While all subjects converted to smear negative for acid-fast bacilli before listing, five of the seven remained culture-positive at the time of transplant. After transplant, subjects received a median of 6 months of a multi-antibiotic regimen. One subject developed a post-operative M abscessus soft tissue infection that was treated medically. Six of the seven subjects survived the observation period; one died unrelated to M abscessus. Time to CLAD and survival were similar to a contemporary comparator group of CF transplant recipients.

Conclusion: Lung transplant recipients with M abscessus infection have a low incidence of recurrent infection, excellent survival, and freedom from CLAD when an aggressive management and surveillance strategy is utilized. Given these findings, M abscessus infection may not be considered a contraindication to lung transplantation.
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http://dx.doi.org/10.1111/tid.13084DOI Listing
June 2019

Gene signatures common to allograft rejection are associated with lymphocytic bronchitis.

Clin Transplant 2019 05 27;33(5):e13515. Epub 2019 Mar 27.

Medical Service, Veterans Affairs Health Care System, San Francisco, California.

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.
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http://dx.doi.org/10.1111/ctr.13515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545574PMC
May 2019

Pirfenidone-Induced Sarcoid-Like Reaction: A Novel Complication.

Chest 2018 10;154(4):e89-e92

Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA.

Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia. Prognosis is poor with a median survival <3 years. Pirfenidone is one of two US Food and Drug Administration-approved medications that slow disease progression. We describe the development of lymphadenopathy or a sarcoid-like reaction following initiation of pirfenidone, a complication not previously reported.
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http://dx.doi.org/10.1016/j.chest.2018.03.048DOI Listing
October 2018

Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study.

Am J Transplant 2018 09 15;18(9):2285-2294. Epub 2018 May 15.

Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, MO, USA.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.
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http://dx.doi.org/10.1111/ajt.14893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117197PMC
September 2018

Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 Apr;16(4):412-441

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.
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http://dx.doi.org/10.6004/jnccn.2018.0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476336PMC
April 2018

Improvement in patient-reported outcomes after lung transplantation is not impacted by the use of extracorporeal membrane oxygenation as a bridge to transplantation.

J Thorac Cardiovasc Surg 2018 07 22;156(1):440-448.e2. Epub 2018 Feb 22.

Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco School of Medicine, San Francisco, Calif.

Objective: Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation. The impact of preoperative ECMO on health-related quality of life (HRQL) and depressive symptoms after lung transplantation remains unknown, however.

Methods: In a single-center prospective cohort study, we assessed HRQL and depressive symptoms before and at 3, 6, and 12 months after lung transplantation using the Short Form 12 Physical and Mental Component Scores (SF12-PCS and SF12-MCS), Airway Questionnaire 20-Revised (AQ20R), EuroQol 5D (EQ5D), and Geriatric Depression Scale (GDS). Changes in HRQL were quantified by segmented linear mixed-effects models controlling for age, sex, diagnosis, preoperative forced expiratory volume in 1 second, 6-minute walk distance, and Lung Allocation Score. We compared changes in HRQL among subjects bridged with ECMO, subjects hospitalized but not on ECMO, and subjects called in for transplantation as outpatients.

Results: Out of 189 subjects, 17 were bridged to transplantation with ECMO. In all groups, improvements in HRQL following lung transplantation exceeded the minimally clinically important difference using the SF12-PCS, AQ20R, EQ5D, and GDS. HRQL defined by SF12-MCS did not change after transplantation. Improvements were generally similar among the groups, except for EQ5D, which showed a trend toward less benefit in the outpatients, possibly due to their better HRQL before lung transplantation.

Conclusions: Subjects ill enough to require ECMO as a bridge to lung transplantation appear to achieve similar improvements in HRQL and depressive symptoms as those who do not. It is reassuring to both providers and patients that lung transplantation provides substantial improvements in HRQL, even for those patients who are critically ill in the run up to transplantation.
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http://dx.doi.org/10.1016/j.jtcvs.2018.01.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013366PMC
July 2018

Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts.

Transplantation 2016 10;100(10):2090-8

1 Medical Service, Veterans Affairs Medical Center, San Francisco, CA. 2 Department of Medicine, University of California, San Francisco, San Francisco, CA. 3 Department of Surgery, University of California, San Francisco, San Francisco, CA. 4 Department of Radiology, University of California, San Francisco, San Francisco, CA. 5 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.

Background: Acute cellular rejection is a major cause of morbidity after lung transplantation. Because regulatory T (Treg) cells limit rejection of solid organs, we hypothesized that donor-reactive Treg increase after transplantation with development of partial tolerance and decrease relative to conventional CD4 (Tconv) and CD8 T cells during acute cellular rejection.

Methods: To test these hypotheses, we prospectively collected 177 peripheral blood mononuclear cell specimens from 39 lung transplant recipients at the time of transplantation and during bronchoscopic assessments for acute cellular rejection. We quantified the proportion of Treg, CD4 Tconv, and CD8 T cells proliferating in response to donor-derived, stimulated B cells. We used generalized estimating equation-adjusted regression to compare donor-reactive T cell frequencies with acute cellular rejection pathology.

Results: An average of 16.5 ± 9.0% of pretransplantation peripheral blood mononuclear cell Treg cell were donor-reactive, compared with 3.8% ± 2.9% of CD4 Tconv and 3.4 ± 2.6% of CD8 T cells. These values were largely unchanged after transplantation. Donor-reactive CD4 Tconv and CD8 T cell frequencies both increased 1.5-fold (95% confidence interval [95% CI], 1.3-1.6; P < 0.001 and 95% CI, 1.2-1.6; P = 0.007, respectively) during grade A2 rejection compared with no rejection. Surprisingly, donor-reactive Treg frequencies increased by 1.7-fold (95% CI, 1.4-1.8; P < 0.001).

Conclusions: Contrary to prediction, overall proportions of donor-reactive Treg cells are similar before and after transplantation and increase during grade A2 rejection. This suggests how A2 rejection can be self-limiting. The observed increases over high baseline proportions in donor-reactive Treg were insufficient to prevent acute lung allograft rejection.
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http://dx.doi.org/10.1097/TP.0000000000001191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030122PMC
October 2016

Acquired acanthosis nigricans with tripe palms in a patient with interstitial lung disease.

JAAD Case Rep 2016 Jan 3;2(1):59-62. Epub 2016 Feb 3.

Department of Dermatology, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1016/j.jdcr.2015.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809450PMC
January 2016

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation.

Am J Respir Crit Care Med 2015 Dec;192(11):1325-34

4 Department of Medicine.

Rationale: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation.

Objectives: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates.

Methods: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively.

Measurements And Main Results: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB.

Conclusions: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.
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http://dx.doi.org/10.1164/rccm.201506-1150OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731703PMC
December 2015

Clinical outcomes of lung transplant recipients with telomerase mutations.

J Heart Lung Transplant 2015 Oct 11;34(10):1318-24. Epub 2015 May 11.

Division of Pulmonary and Critical Care Medicine, University of California, San Francisco Medical Center, San Francisco, California.

Background: Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations.

Methods: Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations.

Results: The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive.

Conclusions: The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations.
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http://dx.doi.org/10.1016/j.healun.2015.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382798PMC
October 2015

Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines.

J Natl Compr Canc Netw 2015 Jan;13(1):23-34; quiz 34

From University of Washington/Seattle Cancer Care Alliance; University of Michigan Comprehensive Cancer Center; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; University of Alabama at Birmingham Comprehensive Cancer Center; The University of Texas MD Anderson Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Dana-Farber/Brigham and Women's Cancer Center; Moffitt Cancer Center; Fox Chase Cancer Center; Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Stanford Comprehensive Cancer Center; UC San Diego Moores Cancer Center; Vanderbilt-Ingram Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Huntsman Cancer Institute at the University of Utah; Roswell Park Cancer Institute; City of Hope Comprehensive Cancer Center; University of Colorado Cancer Center; Massachusetts General Hospital Cancer Center; Duke Cancer Institute; Memorial Sloan Kettering Cancer Center; and National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide recommendations for selecting individuals for lung cancer screening, and for evaluation and follow-up of nodules found during screening, and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights focus on the major updates to the 2015 NCCN Guidelines for Lung Cancer Screening, which include a revision to the recommendation from category 2B to 2A for one of the high-risk groups eligible for lung cancer screening. For low-dose CT of the lung, the recommended slice width was revised in the table on "Low-Dose Computed Tomography Acquisition, Storage, Interpretation, and Nodule Reporting."
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http://dx.doi.org/10.6004/jnccn.2015.0006DOI Listing
January 2015

Rhinovirus and other respiratory viruses exert different effects on lung allograft function that are not mediated through acute rejection.

Clin Transplant 2013 Jan-Feb;27(1):E64-71. Epub 2012 Dec 30.

Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Background: Community acquired respiratory virus (CARV) infections in lung transplant recipients (LTR) have been associated with adverse outcomes, including acute rejection (AR) and decline in allograft function, in some but not in all studies.

Methods: Spirometry and transbronchial biopsy results of LTR diagnosed with CARV infection over a two-yr period were extracted from clinical records. Primary outcomes, studied at 1-2.5 months postinfection, were as follows: (i) incidence of biopsy-proven AR (grade >A0) and (ii) allograft function, defined by forced expiratory volume in one s (FEV(1)). A reference group of biopsies (n = 526) collected during the study period established the baseline incidence of AR. Rhinovirus (RV) and non-rhinovirus (non-RV) infections were analyzed as subgroups.

Results: Eighty-seven cases of CARV infection were identified in 59 subjects. Incidences of AR were similar in the post-CARV and reference groups and did not differ significantly after RV vs. non-RV infection. Allograft function declined significantly after non-RV infection, but not after RV infection.

Conclusions: In LTR, CARV infections other than RV are associated with allograft dysfunction at 1-2.5 months after infection. However, CARVs do not appear associated with AR at this time point. The impact of specific CARVs on lung allografts, including the development of chronic allograft rejection, merits further study.
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http://dx.doi.org/10.1111/ctr.12054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558613PMC
July 2013

Rapidly progressive pulmonary venoocclusive disease in young women taking oral contraceptives.

J Heart Lung Transplant 2012 Sep;31(9):1031-6

Department of Pathology, University of California San Francisco, San Francisco, CA 94143-0102, USA.

Pulmonary venoocclusive disease (PVOD) is a rare cause of pulmonary hypertension characterized by a progressive clinical course and poor outcomes if not treated by early lung transplantation. The pathogenesis of PVOD remains poorly understood. We report PVOD that developed in 2 young women soon after the initiation of oral contraceptives (OCs). The first patient is a 14-year-old girl, with no medical history, who started taking an OC 3 weeks before the onset of symptoms. The second patient is an 18-year-old girl, diagnosed 2 years previously with systemic lupus erythematosus and lupus anticoagulant, who started taking an OC 4 months before the onset of symptoms. Both patients required lung transplantation. Radiographic and histopathologic findings in both patients showed features of PVOD. Only 1 prior patient with PVOD and a handful of unclassified patients with pulmonary hypertension in association with OCs have been documented. The importance of PVOD as the basis of pulmonary hypertension in patients with connective tissue disease has been recently proposed, as well as the role of thrombogenesis, in the development of PVOD. The temporal sequence in these 2 patients suggests the thrombogenic action of OCs may contribute to the development of PVOD, with or without underlying connective tissue disease.
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http://dx.doi.org/10.1016/j.healun.2012.05.007DOI Listing
September 2012

Use of sublingual tacrolimus in lung transplant recipients.

J Heart Lung Transplant 2012 Feb 16;31(2):127-32. Epub 2011 Dec 16.

Department of Clinical Pharmacy, University of California, San Francisco, California 94143-0622, USA.

Background: In lung transplant recipients (LTRs), tacrolimus is often utilized as a core component of immunosuppressive regimens. Although tacrolimus can be delivered orally or intravenously, oral tacrolimus is associated with fewer adverse effects. Various reports have suggested that sublingual tacrolimus may be used as an alternative to oral tacrolimus; however, information regarding converting between routes is limited. We aimed to identify a dose conversion ratio between oral and sublingual tacrolimus in LTRs.

Methods: We identified adult LTRs at the University of California, San Francisco, who transitioned between oral and sublingual tacrolimus between 2005 and 2010 (n = 34). For tacrolimus, we obtained steady-state blood concentrations and total daily doses before and after the route conversion. Blood concentrations divided by daily doses were calculated for each route. The conversion ratio was then defined as: (blood concentration(sublingual)/daily dose(sublingual))/(blood concentration(oral)/daily dose(oral)). This ratio was tested in inpatient vs outpatient settings and in the presence of impaired gastric emptying. Adverse effects, including nephrotoxicity, hepatotoxicity and anaphylaxis, were evaluated.

Results: The conversion ratio of sublingual to oral tacrolimus was 0.46 ± 0.20 (mean ± SD). The ratio was not associated with hospital setting (p = 0.82) or with impaired gastric emptying (p = 0.31). When comparing sublingual to oral tacrolimus administration, there were no differences in serum creatinine, liver function tests or anaphylaxis.

Conclusions: Tacrolimus administered sublingually at approximately half of the oral dose achieves therapeutic blood concentrations and is safe in LTRs. Delivery via the sublingual route using this conversion ratio may aid clinicians in maintaining therapeutic tacrolimus blood concentrations while avoiding the need for intravenous administration.
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http://dx.doi.org/10.1016/j.healun.2011.10.015DOI Listing
February 2012

An analysis of potential risk factors for early complications from fiberoptic bronchoscopy in lung transplant recipients.

Transpl Int 2012 Feb 12;25(2):172-8. Epub 2011 Dec 12.

Department of Medicine, Division of Pulmonary and Critical Care, University of California, San Francisco, CA 94143-0903, USA.

Several reviews exist describing the safety of bronchoscopy in lung transplant recipients. However, the incidence of bronchoscopic complications in lung transplant recipients in relation to trainee involvement, and clinical characteristics such as pre-transplant diagnosis and transplant type, has not been described. We performed a retrospective cohort study of all lung transplant recipients undergoing flexible fiberoptic bronchoscopy (n = 259) at the University of California, San Francisco, between January, 2003, and June, 2009. Complications included bleeding, pneumothorax, aspiration, oversedation, and hypoxemia. From 2003 to 2009, 3734 flexible fiberoptic bronchoscopies were performed, including 2111 (57%) with transbronchial biopsies. Trainees were involved in 2102 bronchoscopies (56%), including 1046 transbronchial biopsies (49.5%). Complications occurred in 27 bronchoscopies [0.7% (95% Confidence Interval [CI]: 0.4-1.0)], with 10 involving a trainee (37%). Twenty (74%) occurred during bronchoscopies with transbronchial biopsies. Six of these involved a trainee, while 14 involved an attending alone (P = 0.03). We did not find differences in pre-transplant diagnosis, transplant type, lung, or renal function between subjects who suffered a complication and those who did not (P ≥ 0.30). The involvement of trainees, pre-transplant diagnosis, and transplant type do not significantly impact the rate of bronchoscopic complications in lung transplant recipients.
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http://dx.doi.org/10.1111/j.1432-2277.2011.01392.xDOI Listing
February 2012

Supratherapeutic anticoagulation from low-molecular-weight heparin in lung transplant recipients.

J Heart Lung Transplant 2010 Sep 8;29(9):1009-13. Epub 2010 Jun 8.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA.

Background: Venous thromboembolism (VTE) is common after lung transplantation. Enoxaparin is an approved therapy for VTE and anti-factor Xa level can be used to monitor enoxaparin activity. Some studies have demonstrated elevated anti-factor Xa levels are associated with an increased risk of hemorrhage. Having identified a high incidence of supratherapeutic anti-factor Xa levels in lung transplant recipients, we aimed to elucidate the relationship between enoxaparin dose and anti-factor Xa level in this patient population.

Methods: We identified post-lung transplantation patients with VTE receiving therapeutic enoxaparin who had anti-factor Xa level measured. Standard enoxaparin dosing was defined as 0.9 to 1.1 mg/kg. After identifying a high incidence of supratherapeutic anti-factor Xa levels, we implemented "non-standard" dosing of 0.8 mg/kg. Multivariate linear regression analysis was used to examine the association between enoxaparin dose and anti-factor Xa level; age, body mass index (BMI) and creatinine clearance were included as covariates.

Results: In the cohort, 18 patients received standard and 8 patients received non-standard enoxaparin dosing. Twelve of 18 patients (67%; 95% confidence interval [CI]: 43% to 91%) receiving standard dosing had supratherapeutic anti-factor Xa levels vs 0 of 8 patients (0%; 95% CI: 0% to 37%) receiving lower non-standard dosing (p = 0.002). Anti-factor Xa levels were significantly different between the two groups; the mean anti-factor Xa level was 1.3 IU/ml (95% CI: 1.06 to 1.53) in the standard group vs 0.79 IU/ml (95% CI: 0.67 to 0.91) in the non-standard group (p = 0.008). After controlling for covariates, for each 0.1-mg/kg increase in enoxaparin, the mean anti-factor Xa level increased by 0.18 IU/ml (95% CI: 0.05 to 0.31; p = 0.011; model r(2) = 0.53).

Conclusions: Standard dosing of enoxaparin in lung transplant recipients is associated with a high incidence of supratherapeutic anti-Xa levels. Further study will be required to correlate this finding with risk of hemorrhage.
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http://dx.doi.org/10.1016/j.healun.2010.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045833PMC
September 2010

Lung transplantation in patients with connective tissue disorders and esophageal dysmotility.

Dis Esophagus 2008 2;21(7):650-5. Epub 2008 May 2.

Department of Surgery, University of California, San Francisco, CA 94143-0790, USA.

Lung and esophageal dysfunction are common in patients with connective tissue disease (CTD). Recent reports have suggested a link between pathologic gastroesophageal reflux and bronchiolitis obliterans syndrome (BOS) after lung transplant. Because patients with CTD have a high incidence of esophageal dysmotility and reflux, this group may be at increased risk of allograft dysfunction after lung transplantation. Little is known about antireflux surgery in these patients. Our aims were to describe: (i) the esophageal motility and reflux profile of patients with CTD referred for lung transplantation; and (ii) the safety and outcomes of laparoscopic fundoplication in this group. A retrospective review of 26 patients with CTD referred for lung transplantation between July 2003 and June 2007 at a single center. Esophageal studies included manometry and ambulatory 24-h pH monitoring. Twenty-three patients had esophageal manometry and ambulatory 24-h pH monitoring. Nineteen patients (83%) had pathologic distal reflux and 7 (30%) also had pathologic proximal reflux. Eighteen patients (78%) had impaired or absent peristalsis. Eleven of 26 patients underwent lung transplantation. Ten patients are alive at a median follow-up of 26 months (range 3-45) and one has bronchiolitis obliterans syndrome-1. Six patients had a laparoscopic fundoplication, 1 before transplantation and 5 after. All fundoplication patients are alive at median follow-up of 25 months (range 19-45). In conclusion, esophageal dysmotility and reflux are common in CTD patients referred for lung transplant. For this group, laparoscopic fundoplication is safe in experienced hands.
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http://dx.doi.org/10.1111/j.1442-2050.2008.00828.xDOI Listing
March 2009

Fatal diffuse alveolar damage in two lung transplant patients treated with cetuximab.

J Heart Lung Transplant 2007 Dec;26(12):1340-4

Division of Pulmonary and Critical Care Medicine, University of California at San Francisco, San Francisco, California 94143-0111, USA.

Organ transplant recipients are at increased risk for aggressive cutaneous squamous cell carcinomas (cSCC) that recur and metastasize despite treatment with surgery, radiation, or both. Therapies targeting the epidermal growth factor receptor (EGFR) are being explored as treatments for metastatic cSCC. We describe our experience with two single-lung transplant patients who developed metastatic cSCC; failed surgical resection, radiation or chemoradiation therapy; and were ultimately treated with an EGFR inhibitor, cetuximab. Both patients died shortly after initiation of cetuximab due to diffuse alveolar damage, suggesting that EGFR inhibitors should be used with extreme caution in lung transplant recipients.
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http://dx.doi.org/10.1016/j.healun.2007.09.019DOI Listing
December 2007

Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation.

J Thorac Cardiovasc Surg 2007 Apr 22;133(4):1078-84. Epub 2007 Feb 22.

University of California San Francisco, Department of Surgery, San Francisco, Calif, USA.

Objectives: The association between gastroesophageal reflux disease and idiopathic pulmonary fibrosis has not been fully characterized. The aims of this study were to determine in patients with idiopathic pulmonary fibrosis (1) the prevalence of reflux symptoms, (2) the esophageal manometric profile, and (3) the prevalence of proximal and distal esophageal reflux.

Methods: Between May 1999 and March 2006, 30 patients with idiopathic pulmonary fibrosis were referred to the Swallowing Center at the University of California San Francisco. Each patient underwent a structured symptom assessment, esophageal manometry, and 24-hour dual sensor ambulatory pH monitoring.

Results: Twenty (67%) patients had abnormal esophageal reflux. Typical reflux symptoms, although more common in those with reflux, were not reliable as a screening test (sensitivity 65%, specificity 71%). Sixty-five percent of patients with abnormal reflux had a hypotensive lower esophageal sphincter. Abnormal esophageal peristalsis was more common among those with reflux (50% vs 10%; P = .03). In 9 (30%) patients, acid refluxed into the proximal esophagus for over 1% of the study time.

Conclusions: A majority of patients with idiopathic pulmonary fibrosis have pathologic reflux. Symptoms do not distinguish between those with and without reflux. In these patients, reflux is associated with a hypotensive lower esophageal sphincter and abnormal esophageal peristalsis, and often extends into the proximal esophagus.
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http://dx.doi.org/10.1016/j.jtcvs.2006.09.085DOI Listing
April 2007

Mesothelial cell proliferation and apoptosis.

Respirology 2004 Aug;9(3):292-9

Lung Biology Center, San Francisco General Hospital, University of California San Francisco, California, USA.

Mesothelial cells line the pleural and peritoneal surfaces, where under normal conditions they proliferate and undergo cell death at a slow rate, thereby maintaining a constant number of cells. These tightly regulated processes are disrupted in malignancy. By developing a better understanding of the mechanisms that regulate cell proliferation and apoptosis in mesothelial and mesothelioma cells, we may be able to develop more effective therapeutic agents that target specific steps in these pathways to induce apoptosis more efficiently. This paper reviews our current knowledge of the signaling pathways involved in the regulation of mesothelial cell proliferation and apoptosis. The latest advancements in identifying proteins that play key roles in the resistance to apoptosis are highlighted.
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http://dx.doi.org/10.1111/j.1440-1843.2004.00602.xDOI Listing
August 2004