Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

Granuloma annulare on the palms.

We present the case of a 72-year-old man with a one-week history of a red rash on the palms of both hands. A 4mm punch biopsy revealed interstitial granulomatous inflammation within the dermis and a colloidal iron stain showed increased dermal acid mucin. Immunohistochemical staining for CD68 confirmed the presence of abundant histiocytes within the dermis. The clinical and pathological correlation was consistent with the diagnosis of interstitial granuloma annulare. Exclusive involvement of the palms is a rare presentation and serves as a reminder for practitioners to keep granuloma annulare in their differential diagnosis when observing palmar plaques.

Results of XPAND II: A Multicenter, Prospective, Continued-Access Clinical Trial Using the AeroForm Tissue Expander for Two-Stage Breast Reconstruction.

BACKGROUND: XPAND II was a prospective, multicenter, single-arm, open-label, continued-access study designed to confirm the results from the XPAND study, a multicenter, prospective, randomized study for breast reconstruction. The AeroForm device received clearance from the U.S. Food and Drug Administration in December 2016 based on the results of the pivotal XPAND trial, which compared the AeroForm to saline expanders. METHODS: Fifty women were treated in the XPAND II study and implanted with the AeroForm device (86 devices). The study endpoint was successful completion of the second-stage surgery, and secondary endpoints were days to complete expansion and reconstruction, and patient/physician satisfaction. Following implantation, women were administered 10-cc doses of carbon dioxide at home up to three times daily. When adequate expansion was achieved, the expanders were exchanged for standard breast implants. RESULTS: The primary endpoint (successful exchange to standard breast implant, precluding non-device-related failures) is 100 percent. All-cause interim success is 95 percent, with three subjects (four breasts) failing primary exchange because of non-device-related reasons. Median time to complete expansion was 21 days (range, 5 to 117 days). Median time to complete the reconstruction was 112 days (range, 55 to 329 days). Ninety-six percent of the subjects were very or moderately satisfied with the AeroForm expansion process. CONCLUSIONS: Results of the XPAND II continued access study confirm and improve on previous results from the randomized trial (XPAND). These results validate that the AeroForm patient-controlled, needle-free carbon dioxide tissue expander is safe and effective for two-stage breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Carbon Dioxide-Based versus Saline Tissue Expansion for Breast Reconstruction: Results of the XPAND Prospective, Randomized Clinical Trial.

BACKGROUND: AeroForm is a new type of remote-controlled, needle-free, carbon dioxide-based expander involving a potentially faster method of tissue expansion. Results are presented here from the AirXpanders Patient Activated Controlled Tissue Expander pivotal trial comparing AeroForm to saline tissue expanders. METHODS: Women undergoing two-stage breast reconstruction were randomized at 17 U.S. sites in this U.S. Food and Drug Administration-approved investigational device exemption trial. Expansion in the investigational arm was performed by the patient in 10-cc increments up to 30 cc/day of carbon dioxide and in the control arm by the physician with periodic bolus injections of saline. Safety endpoints, expansion and reconstruction times, pain, and satisfaction were assessed. RESULTS: One hundred fifty women were treated: 98 with carbon dioxide expanders (n = 168) and 52 with saline expanders (n = 88). The treatment success rate (all breasts exchanged successfully excluding non-device-related failures) was 96.1 percent for carbon dioxide and 98.8 percent for saline. Median time to full expansion and completion of the second-stage operation was 21.0 and 108.5 days (carbon dioxide) versus 46.0 and 136.5 days (saline), respectively, with a similar rate of overall complications. Ease of use for the carbon dioxide expander was rated high by patients (98 percent) and physicians (90 percent). CONCLUSIONS: The AirXpanders Patient Activated Controlled Tissue Expander trial results demonstrate that a carbon dioxide-based expander is an effective method of tissue expansion with a similar overall adverse event rate compared to saline expanders, and provides a more convenient and expedient expansion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Carbon Dioxide versus Saline Tissue Expanders: Does It Matter?

BACKGROUND: Implant-based breast reconstruction is the most common reconstructive technique in the United States. Despite its popularity, saline-based tissue expansion still has its limitations, including lengthy expansion times, large uncomfortable bolus dosing, and frequent percutaneous injections/expansion visits. Ideally, a novel technology would eliminate frequent, percutaneous saline injections and allow patients to perform expansion at home, reducing the disruptive experience of current tissue expansion. METHODS: Within the past 6 years, the AeroForm tissue expander system has used remotely activated carbon dioxide release as the fill medium instead of saline, eliminating many limitations of traditional tissue expanders. In this article, the authors first review the relevant literature concerning carbon dioxide-based tissue expansion in animal and human models. The authors then analyze the similarities and differences between two groundbreaking human trials (i.e., Patient Activated Controlled Expansion and AirXpanders Patient Activated Controlled Tissue Expander) with carbon dioxide-based expanders and discuss the risks and benefits associated with this new technology. RESULTS: At their site, the authors have enrolled 34 patients using 36 experimental devices in total, and have found significantly shorter expansion and overall reconstruction times in the patient-controlled tissue expander group. CONCLUSIONS: The authors believe that carbon dioxide-based devices may play a significant role in the future of implant-based breast reconstruction, and may be widely applicable to other areas of plastic surgery that also involve tissue expansion.

Association between preoperative measurements and resection weight in patients undergoing reduction mammaplasty.

Current guidelines used to predict appropriate resection weight for patients undergoing reduction mammaplasty are typically based on relatively nondescript patient characteristics and are most often inaccurate. The determination of patient measurements that correlate with resection weight could enable appropriate resection weight to be predicted more precisely and on an individualized basis. To better elucidate this, data from 348 patients undergoing bilateral reduction mammaplasty (696 breasts) between October 2001 and March 2009 were reviewed retrospectively. The association between resection weight and sternal notch to nipple distance (SNN), inframammary fold to nipple distance (IMFN), and body mass index (BMI) was assessed. Regression analysis demonstrated a strong correlation between resection weight and SNN distance (r = 0.672, P < 0.001), IMFN distance (r = 0.467, P < 0.001), and BMI (r = 0.510, P < 0.001). The strongest correlation was observed after incorporating all 3 parameters (r = 0.740, P < 0.001). This enabled the calculation of a formula to predict resection weight: Predicted weight = 40.0(SNN) + 24.7(IMFN) + 17.7(BMI) - 1443 In conclusion, resection weight correlates strongly with SNN, IMFN, and BMI in patients undergoing reduction mammaplasty. When considered together, resection weight can be predicted with a strong degree of accuracy.

Early preclinical studies of discriminable sedative and hallucinogenic drug effects.

RATIONALE: One important technique in behavioral pharmacology is to train laboratory animals to discriminate between a psychoactive drug effect and a nondrug condition. Tests with different drugs have identified several categories of drugs that have different discriminable effects. OBJECTIVES: The two authors describe and discuss the early research on discriminable effects of sedative and hallucinogenic drugs and their acquaintance with each other at Yale University prior to their early and frequent publications on discriminable drug effects. Herb Barry studied sedative drugs primarily and Jim Appel studied hallucinogenic drugs. RESULTS: Sedative drugs include ethyl alcohol, barbiturates, and benzodiazepines. Their discriminable effects are largely attributable to the activation of an inhibitory neurotransmitter, gamma-amino butyric acid. Alcohol has the most pervasive effect in accordance with the high dose required to alter behavior. Hallucinogenic drugs include lysergic acid diethylamide and mescaline. They increase the activity of the neurotransmitter 5-hydroxytryptamine and, perhaps, dopamine in the central nervous system (CNS). In spite of their relatively low concentrations in the brain, both of these neurotransmitters have many important behavioral effects. CONCLUSIONS: Various sedative drugs cause a discriminable decrease in the function of the CNS. Different types of sedatives can be discriminated from each other. Indole and phenylethylamine hallucinogens have potent discriminative stimulus properties, which are related to the actions of biogenic amine neurotransmitters in the CNS.

Aprotinin's effect on blood product transfusion in off-pump bilateral lung transplantation.

In lung transplants necessitating cardiopulmonary bypass (CPB), aprotinin has been shown to decrease transfusion requirements. More recently, off-pump transplantation has become the standard of care. The efficacy of aprotinin use in this population has yet to be definitively examined. We completed a retrospective review of all adult OP-BOLTs performed between January 2000 and January 2006 at a single university center (n=215). Aprotinin use was determined by the attending anesthesiologist or surgeon. It was administered at the time of induction. The primary outcome was total blood products utilized in terms of units transfused during postoperative days 0, 1 and 2. One-hundred and one patients received aprotinin and 114 did not. An overall analysis of all of the patients in this study demonstrated a trend towards statistical significance for reduced total blood product transfusion for the aprotinin group compared to the non-aprotinin group (P=0.13). A subgroup analysis was performed in relation to each diagnosis. The use of aprotinin was associated with a significant reduction in peri-operative total blood products transfused in COPD patients (P=0.03) undergoing OP-BOLT. Subgroup analysis demonstrated that the use of aprotinin in the COPD population did result in a statistically significant decrease in total blood products transfused, specifically the total number of units of packed red blood cells given. These findings suggest that aprotinin administration should be considered for all patients undergoing OP-BOLT to reduce exposure to blood products and potential immune sensitization and infectious complications.

Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation.

BACKGROUND: Lung transplant survival is limited by the development of bronchiolitis obliterans syndrome (BOS). The strongest risk factor for BOS is acute rejection (AR). We have previously shown that rabbit anti-thymocyte globulin (RATG) induction therapy is associated with a decrease in early AR. Thus, we hypothesized that RATG induction would translate to reduced BOS and improved long-term graft survival. METHODS: Forty-four lung recipients were prospectively randomized to receive conventional immunosuppression with RATG induction (RATG group) or conventional immunosuppression alone (control group). End-points included graft survival, early and total acute rejection, BOS and treatment complications. RESULTS: There was no difference in graft survival between the groups at 8 years (RATG: 36%; control: 23%; p = 0.48). The RATG group had fewer early rejections compared with the control group (5% vs 41%; p = 0.01). However, the overall rejection incidence did not differ (RATG: 62%; control: 68%; p = 0.52). There was a trend toward a delay in BOS onset among RATG subjects compared with control subjects (2,376 days vs 1,108 days; log rank, p = 0.15). There was no difference in the incidence of infections, but the RATG group had a higher rate of malignancies. CONCLUSIONS: Our results suggest that alternative approaches to anti-thymocyte induction should be pursued to reduce BOS and prolong allograft survival.

Characterization of the innate immune response to chronic aspiration in a novel rodent model.

BACKGROUND: Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung. METHODS: Gastric fluid or normal saline was instilled into the left lung of rats (n = 48) weekly for 4, 8, 12, or 16 weeks (n = 6 each group). Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined. RESULTS: Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated) lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline. CONCLUSION: This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.

Effect of an anti-C5a monoclonal antibody indicates a prominent role for anaphylatoxin in pulmonary xenograft dysfunction.

BACKGROUND: In contrast to renal or cardiac xenografts, the inhibition of complement using cobra venom factor (CVF) accelerates pulmonary xenograft failure. By activating C3/C5 convertase, CVF depletes complement while additionally generating C5a and other anaphylatoxins, to which pulmonary xenografts may be uniquely susceptible. The current study investigates the role of C5a in pulmonary xenograft failure in baboons. METHODS: Left orthotopic pulmonary xenografts using swine lungs expressing human CD46 were performed in baboons receiving: I) no other treatment (n=4), II) immunodepletion (n=5), and III) immunodepletion plus a single dose of mouse anti-human C5a monoclonal antibody (anti-C5a, 0.6 mg/kg administered intravenously) (n=3). The extent to which anti-C5a inhibits baboon C5a was assessed in vitro using a hemolytic reaction involving baboon serum and porcine red blood cells and by ELISA. RESULTS: Baboons in Group III exhibited significantly prolonged xenograft survival (mean=722+/-121 min, P=0.02) compared to baboons in Group I (mean=202+/-24 min) and Group II (mean=276+/-79 min). Furthermore, baboons in Groups I and II experienced pronounced hemodynamic compromise requiring inotropic support whereas those in Group III remained hemodynamically stable throughout experimentation without the need for additional pharmacologic intervention. CONCLUSIONS: These findings indicate that C5a exacerbates pulmonary xenograft injury and compromises recipient hemodynamic status. Moreover, blockade of anaphylatoxins, such as C5a, offers a promising approach for future investigations aimed at preventing pulmonary xenograft injury in baboons.

Role of flow cytometry to define unacceptable HLA antigens in lung transplant recipients with HLA-specific antibodies.

BACKGROUND: Antidonor HLA-specific antibodies have been associated with hyperacute rejection and primary graft failure in lung transplant recipients. Thus, transplant candidates with HLA-specific antibodies generally undergo prospective crossmatching to exclude donors with unacceptable HLA antigens. However, the need to perform a prospective crossmatch limits the donor pool and is associated with increased waiting list times and mortality. A virtual crossmatch strategy using flow cytometry, which enables precise determination of HLA-specific antibody specificity, was compared to prospective crossmatching in sensitized lung transplant candidates. METHODS: In all, 341 lung transplant recipients were analyzed retrospectively (April 1992 to July 2003). Sixteen patients with HLA-specific antibodies underwent transplantation based on flow cytometric determination of antibody specificity and 10 underwent prospective crossmatching. RESULTS: Freedom from bronchiolitis obliterans syndrome (BOS) at three years was similar in those undergoing a virtual crossmatch, those undergoing prospective crossmatching, and those without HLA-specific antibodies (80.4% +/- 13.4, 85.7% +/- 13.2, and 73.8% +/- 2.8, respectively, P = 0.88). Three-year survival was also comparable (87.5% +/- 8.3, 70.0% +/- 14.5, and 78.5% +/- 2.4, respectively, P = 0.31). Elimination of prospective crossmatching for sensitized patients was associated with a significant decrease in time on the waiting list (P < 0.01) and in waiting list mortality (P < 0.05). All 16 patients undergoing a virtual crossmatch had negative retrospective crossmatches. CONCLUSIONS: By carefully determining the specificity of HLA-specific antibodies, flow cytometry methodologies enable the prediction of negative crossmatch results with up to 100% accuracy, enabling the determination of appropriateness of donors. Using this virtual crossmatch strategy, crossmatching can be safely omitted prior to lung transplantation, thereby decreasing waiting list time and mortality rates for candidates with HLA-specific antibodies.

Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation.

OBJECTIVE: Emerging clinical evidence suggests that gastroesophageal reflux disease is associated with pulmonary allograft dysfunction. In this study, we used a model of rat lung transplantation to test the hypothesis that chronic aspiration of gastric contents accelerates pulmonary allograft dysfunction. METHODS: We evaluated the effects of chronic aspiration on pulmonary isografts (strain F344) and pulmonary allografts (strain WKY to strain F344). Chronic aspiration consisted of 0.5 mL/kg of filtered gastric contents injected weekly into the left lung for 4 to 8 weeks beginning 1 week after transplantation. Seven days after the last aspiration, animals were killed, and grafts were evaluated grossly and by histologic and immunochemical analyses, including Masson trichrome staining for collagen and immunostaining for CD68+ and CD8+ cells. Serum cytokine concentrations were determined by bead-based immunoassays or enzyme-linked immunosorbent assay. RESULTS: Allografts without aspiration (n = 12) demonstrated a relatively normal architecture with diffuse International Society for Heart and Lung Transplantation grade 3 acute rejection; occasional grade 4 rejection was noted. In contrast, allografts with chronic aspiration (n = 7) demonstrated severe grade 4 acute rejection with significant monocyte infiltration, fibrosis, and loss of normal alveolar anatomy. Grossly, 8 (67%) of 12 allografts without aspiration seemed to inflate and perfuse normally, whereas all allografts exposed to chronic aspiration were firm and shrunken, without the ability to ventilate (P = .013; Fisher exact test). Aspiration was associated with increases in graft-infiltrating macrophages and CD8+ T cells and higher levels of serum transforming growth factor beta. CONCLUSIONS: Chronic aspiration of gastric contents promotes accelerated allograft failure and may promote a profibrotic environment.

Improved results treating lung allograft failure with venovenous extracorporeal membrane oxygenation.

BACKGROUND: Primary graft failure remains a significant source of mortality after lung transplantation. Extracorporeal membrane oxygenation (ECMO) provides treatment for affected recipients. We hypothesized that venovenous membrane oxygenation provides a safer alternative than venoarterial support for lung recipients suffering from primary graft failure. METHODS: We conducted an analysis of 522 patients who underwent lung transplantation from April 1992 to July 2004. Twenty-three (4.5%) patients required membrane oxygenation secondary to primary graft failure unresponsive to conventional treatment. Of these recipients, 15 (65%) were treated with venoarterial, while 8 (35%) underwent venovenous membrane oxygenation. RESULTS: Median days to initiation and duration of membrane oxygenation did not differ between groups. Eight of 15 patients (53%) from the venoarterial group were successfully weaned from life support, with one surviving greater than 45 days. This lone long-term survivor required retransplantation 4 days after initial transplant. In contrast, all venovenous patients were weaned from support, with 7 of 8 surviving greater than 30 days. The 30-day survival for venovenous recipients (88%) approximates that of all lung recipients at our center (94%, p = 0.42). Noted complications for ECMO patients included renal failure (n = 16), neurologic catastrophes (n = 8), sepsis (n = 5), and hemorrhage (n = 10). The venoarterial recipients suffered 30 of 39 total complications. Most of the complications for venovenous recipients involved renal failure, but by hospital discharge these patients demonstrated a mean creatinine of 0.9 mg/dL. CONCLUSIONS: For lung recipients with primary graft failure, venovenous membrane oxygenation provides better outcomes, with fewer complications, than venoarterial membrane oxygenation.

Antireflux surgery in the setting of lung transplantation: strategies for treating gastroesophageal reflux disease in a high-risk population.

In lung transplant recipients, GERD is associated with increased incidence of acute rejection, earlier onset of chronic rejection, and higher mortality. Surgical treatment of GERD in lung recipients seems to prevent early allograft dysfunction and improve overall survival. A total (360 degrees) fundoplication is shown to be a safe and effective method for treating GERD in lung transplant recipients and is the authors' procedure of choice, in most cases, for this high-risk patient population. The principal goal should be to minimize reflux of enteric contents that may lead to micro- or macroaspiration events in this complicated group of patients. Perioperative care should involve a multidisciplinary approach, including physicians and other health care providers familiar with the complexities of lung transplant recipients.

Hepatitis B core antibody positive donors as a safe and effective therapeutic option to increase available organs for lung transplantation.

BACKGROUND: The use of hepatitis B core antibody (HBcAb+) and hepatitis C antibody (HCV Ab+) positive donors represents one strategy to increase available donor organs, but this remains controversial because of concern for viral transmission to recipients. We hypothesized that isolated HBcAb+ donors represent minimal risk of viral transmission in vaccinated lung transplant (LTx) recipients. METHODS: A retrospective study was performed of LTx recipients who received HBcAb+ or HCV Ab+ pulmonary allografts. We analyzed liver function studies, viral hepatitis screening tests, quantitative polymerase chain reaction for hepatitis B viral DNA (HBV DNA) and hepatitis C viral RNA (HCV RNA), freedom from bronchiolitis obliterans syndrome, acute rejection, and survival. RESULTS: Between April 1992 and August 2003, 456 LTx operations were performed. Twenty-nine patients (HB group) received HBcAb+ allograft transplants with a median posttransplant follow-up of 24.5 months. Three critically ill patients (HC group) received HCV Ab+ allografts with a median follow-up of 21.5 months. One-year survival for the HB group is 83% versus 82% for all patients who received non-HB organs (P=0.36). No patient in the HB group developed clinical liver disease because of viral hepatitis, and all patients alive (n=21) at follow-up are, to date, HBV DNA and/or HBcAb negative. All patients in the HC group tested HCV RNA positive; one patient died of liver failure at 22 months. CONCLUSIONS: Risk of viral transmission with HCV Ab+ allografts seems high after LTx. However, the use of HBcAb+ pulmonary allografts in recipients with prior hepatitis B vaccination seems to be a safe and effective strategy to increase organ availability.

Utility of peritransplant and rescue intravenous immunoglobulin and extracorporeal immunoadsorption in lung transplant recipients sensitized to HLA antigens.

The role of anti-human leukocyte antigen (HLA) antibodies in lung transplantation is not fully clear. The presence of pretransplant third-party anti-HLA antibodies or the development of de novo anti-HLA antibodies has been associated with acute posttransplant complications, bronchiolitis obliterans syndrome (BOS), and early mortality in some studies. However, little has been reported regarding the utility of desensitization therapy in sensitized lung transplant recipients. For approximately 3 years, desensitization therapy consisting of intravenous immunoglobulin (IVIG) and, in most instances, extracorporeal immunoadsorption (ECI) has been administered peritransplant to lung transplant recipients at our institution with third-party anti-HLA antibodies or as rescue therapy to those who develop de novo anti-HLA antibodies. Notably, the administration of peritransplant desensitization therapy to these patients has been associated with improvement in several clinical parameters, including acute rejection and BOS. Furthermore, administration of rescue IVIG with or without ECI has been associated with an overall improvement in the rate of pulmonary function decline. Our experience suggests that desensitization therapy may be beneficial for lung transplant recipients with pretransplant or de novo anti-HLA antibodies. We discuss the appropriateness and clinical impact of IVIG and ECI in sensitized lung transplant recipients as well as cellular mechanisms that may contribute.

Increasing the selectivity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol: complete substitution with methanandamide.

In an attempt to increase the selectivity of the discriminative stimulus effects of Delta9-tetrahydrocannabinol (THC), rats were trained to discriminate 3.2 mg/kg of this compound from a group of "other" drugs consisting of morphine (3.2 mg/kg), PCP (2.5 mg/kg), and vehicle. Acquisition of the Delta9-THC-other discrimination was rapid (38 days) and did not differ significantly from that of a group of "control" animals trained to discriminate Delta9-THC (3.2 mg/kg) from its vehicle (33 days). In substitution (generalization) tests, a high dose of anandamide, which also severely decreased response rate, substituted partially in both the control and the Delta9-THC-other group; (R)-methanandamide, an analog of anandamide which is metabolized more slowly, substituted completely for Delta9-THC in the control, and partially in the Delta9-THC-other group; neither pentobarbital nor diazepam substituted completely for Delta9-THC under any experimental condition. Regardless of the level of Delta9-THC lever responding, all drugs except diazepam substituted less in the Delta9-THC-other than in the control group. For this reason, the Delta9-THC-other training procedure might be described as being more selective than the commonly used drug-no drug procedure.

J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease.

BACKGROUND: Chronic allograft dysfunction limits the long-term success of lung transplantation. Increasing evidence suggests nonimmune mediated injury such as due to reflux contributes to the development of bronchiolitis obliterans syndrome. We have previously demonstrated that fundoplication can reverse bronchiolitis obliterans syndrome in some lung transplant recipients with reflux. We hypothesized that treatment of reflux with early fundoplication would prevent bronchiolitis obliterans syndrome and improve survival. METHODS: A retrospective analysis of 457 patients who underwent lung transplantation from April 1992 through July 2003 was conducted. Patients were stratified into four groups: no history of reflux, history of reflux, history of reflux and early (< 90 days) fundoplication and history of reflux and late fundoplication. RESULTS: Incidence of postoperative reflux was 76% (127 of 167 patients) in pH confirmed subgroups. In 14 patients with early fundoplication, actuarial survival was 100% at 1 and 3 years when compared with those with reflux and no intervention (92% +/- 3.3, 76% +/- 5.8; p < 0.02). Further, those who underwent early fundoplication had improved freedom from bronchiolitis obliterans syndrome at 1 and 3 years (100%, 100%) when compared with no fundoplication in patients with reflux (96% +/- 2.5, 60% +/- 7.5; p < 0.01). CONCLUSIONS: Reflux is a frequent medical complication after lung transplantation. Although the number of patients undergoing early fundoplication is small, our results suggest early aggressive surgical treatment of reflux results in improved rates of bronchiolitis obliterans syndrome and survival. Further research into the mechanisms and treatment of nonalloimmune mediated lung allograft injury is needed to reduce rates of chronic lung failure.