Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Lung transplantation in a recipient with novel 2009 H1N1 influenza: lessons learned.

Immunosuppressed patients are at an increased risk for severe disease from influenza A (H1N1). We report a case of a patient who died of septic complications from H1N1 acquired at the time of single lung transplant.

Allograft entrapment after lung transplantation: a simple solution using a pleurocutaneous catheter.

BACKGROUND: Chronic pleural effusion following lung transplantation (LTx) is often responsible for respiratory insufficiency and can lead to lung entrapment. Decortication carries considerable morbidity, and extended use of tube thoracostomy is not practical. We have utilized an indwelling pleurocutaneous catheter in the setting of intractable post-transplant effusion and have reviewed our experience to determine whether this strategy: 1) facilitates resolution of effusion, and 2) adequately palliates lung entrapment. METHODS: Twelve PleurX (Denver Biomedical, Golden, CO, USA) catheters were placed in 9 LTx patients (6 unilateral, 3 bilateral) for refractory pleural effusions after standard tube thoracostomy drainage failed (12/12). Two-thirds of the patients (8/12) also had concomitant lung entrapment. RESULTS: There was no operative mortality. Median time from LTx to catheter placement was 79 days (range 21-769). Catheter use achieved the desired outcome in 11/12 placements. Catheters remained in place for a median of 86 days (range 35-190). Direct catheter-related complications included hemothorax (1) and empyema (1). CONCLUSION: Use of an indwelling pleurocutaneous catheter effectively achieves its intended goals of pleurodesis and management of entrapped lungs after LTx.

Open window thoracostomy: modern update of an ancient operation.

INTRODUCTION: In modern day thoracic surgical practice, better understanding of the pathophysiology of intrathoracic infections, improved antibiotic therapy and advancements in thoracic surgical techniques have decreased the use of procedures such as open window thoracostomy (OWT). Despite this, there are occasions where OWT cannot be avoided, and it is of interest where its current utility lies. To determine the current efficacy of OWT, we reviewed our recent experience with a focus on the indications, timing of surgery, effectiveness in clearing infection, patient survival, and timing of closure. METHODS: After Institutional Review Board approval, charts of 78 patients were reviewed. Dates reviewed were from 1/1/1998 to 1/1/2008. Patients were predominantly male (66 %) with a median age 58 years. Median time from initial diagnosis to OWT was 70 days (range 1 to 720 days). RESULTS: Primary indication for surgery was empyema in 75 (96 %), and most patients had previous thoracic surgery. The most frequent causes of empyema were post-pneumonectomy (n = 25), post-pneumonic (n = 14), and post-lobectomy (n = 9). Bronchopleural fistulae were present in 29 (37 %) cases. Lung cancer was diagnosed in 34 (45 %) patients, and 24 underwent perioperative radiation therapy. Patient survival at 1 month, 6 months, 1 year and 5 years was 94 %, 82 %, 74 % and 60 %, respectively, with an in-hospital mortality of 6.4 %. Infection was controlled in nearly all patients (n = 72). Fifteen (19 %) patients underwent surgical closure for OWT; in 2 (2.6 %), OWT closed spontaneously. CONCLUSIONS: Currently, open window thoracostomy is used to treat complex empyema incurred from pulmonary resection, cancer and/or infection in patients that cannot be managed by more conservative strategies. Overall mortality and morbidity rates are acceptable in this debilitated patient group.

Lung transplantation: past, present, and future.

Lung transplantation (LTx) is an established therapy for end-stage lung disease (ESLD). Survival after LTx is limited by infection and rejection, particularly bronchiolitis obliterans syndrome (BOS). New techniques with the potential to increase donor lung supply and prevent rejection continue to evolve. These developments hold promise for improved outcomes for a greater number of patients.

Challenges in the diagnosis and management of Nocardia infections in lung transplant recipients.

BACKGROUND: Nocardia infection occurs in 2.1-3.5% of lung transplant recipients, and may involve cavitary nodular pulmonary lesions, soft tissue infection, or other sites of dissemination. Nocardiosis can pose challenging clinical problems in the areas of diagnosis and treatment. Diagnostic delays may occur, and adverse reactions to therapy are common. This study reviews clinical and epidemiological aspects of nocardiosis in lung transplant recipients, with special attention to pitfalls in management. Clinicians should be alert for these possibilities in order to institute prompt therapy and to achieve successful outcomes. METHODS: A retrospective cohort study was conducted of 577 lung transplant recipients from January 1991 to May 2007. Demographics, reason for transplant, recent rejection, time from transplantation, site of infection, hypogammaglobulinemia, and/or neutropenia shortly before onset, Pneumocystis jiroveci prophylaxis, Nocardia species, radiographic findings, extrapulmonary lesions, nature and duration of treatment, adverse reactions, and outcomes were recorded. RESULT: Nocardia infection occurred in 1.9% (11/577). Mean onset was 14.3 months after transplant (range 1.5-39 months). N. asteroides was isolated in 55% (6/11). Emphysema was the most common reason for transplant (7/11, 64%). Six patients were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis. Three patients had immune globulin G levels <400 mg/dL and 2 were neutropenic in the 3 months preceding diagnosis. Diagnosis was made by bronchoalveolar lavage (55%), skin abscess culture (18%), open lung biopsy (9%), pleural fluid (9%), and sputum culture (9%). Definitive diagnosis required a median of 9 days and a mean of 13.6 days (range 3-35 days) from the time of diagnostic sampling. Soft tissue lesions occurred in 3 and central nervous system involvement in 1 patient. Adverse reactions to therapy occurred in 9/10 (90%) of patients for whom information was available. Nocardia-related mortality occurred in 2/11 patients (18%). CONCLUSIONS: Nocardiosis occurred in 1.9% of lung transplant recipients and was associated with a mean of nearly 2 weeks to diagnosis and frequent adverse effects on therapy. TMP-SMX prophylaxis on a thrice weekly basis did not prevent all episodes of nocardiosis. Despite utilization of protocol bronchoscopies with cultures for Nocardia, this organism remains a source of clinical complexity in the lung transplant population.

Assessment of a pathophysiology-directed treatment for symptomatic epiphrenic diverticulum.

Epiphrenic diverticulum is a rare disease associated with distal esophageal obstruction and a weakened muscularis propria. We have adhered to an operative strategy of excision (diverticulectomy), repair of esophageal wall, and relief of functional and mechanical obstruction. We sought to assess this pathophysiology-directed treatment strategy. From 1987 to 2005, 44 patients underwent surgery for epiphrenic diverticulum. Diverticulectomy, repair, and relief of distal obstruction was performed in 35 (80%) and esophagectomy in nine (10%). Outcome (symptoms, diet, subsequent therapies and morbidity) was assessed by follow-up. Forty of 44 patients had preoperatively identifiable esophageal obstruction (91%). Distal obstruction was functional in 32 patients and mechanical in 24; these conditions coexisted in 16. After surgery, there were no in-hospital deaths; 15 patients experienced 22 in-hospital complications. Survival was 90% at 5 years and 72% at 10 years. Symptoms improved in most patients (P = 0.0004), except for gastroesophageal reflux; new symptoms of gastroesophageal reflux occurred in 9/27 (33%) without this symptom preoperatively. Diet was less restricted postoperatively (P < 0.0001). Of 35 patients undergoing diverticulectomy, three (8.6%) required dilatation and two (6%) reoperation; 6/9 esophagectomy patients required dilatations. Preoperative assessment must include evaluation for mechanical obstruction. Adherence to a pathophysiology-directed operative strategy is safe and will improve the symptoms of most patients, with little need for reintervention. However, occasional patients will experience new symptoms, particularly reflux. Esophagectomy is the alternative for patients who are not candidates for diverticulectomy, repair of esophageal wall, and relief of distal obstruction.

Can treatment of P. vivax lead to a unexpected appearance of falciparum malaria?

Of 994 patients admitted to the Bangkok Hospital for Tropical Diseases for P. vivax malaria, 104 (10.5%) experienced appearance of Plasmodiumfalciparum following drug treatment for P. vivax . In all patients, P. falciparum parasites were not found by microscopic examination upon admission. The mean time for P. falciparum appearance was 12.6 days after the commencement of chloroquine treatment. Patients experiencing appearance of P. falciparum had significantly lower hematocrit, and greater initial P. vivax parasite counts. We use a mathematical model to explore the consequences of chloroquine treatment of such mixed infections. Both clinical results and features of the model suggest that such "hidden infections" may be quite common, and that the appearance of P. falciparum may be stimulated by treatment of P. vivax.

G-protein expression and intimal hyperplasia after arterial injury: a role for Galpha(i) proteins.

PURPOSE: Guanine nucleotide binding protein (G-protein) coupled receptors are involved in smooth muscle cell proliferation, but the role of G-proteins in arterial intimal hyperplasia has not been defined. This study examines the expression of G-proteins in the developing intimal hyperplasia after balloon injury of the rat carotid artery and specifically tests the hypothesis that the pertussis toxin sensitive G(i) G-protein subunit plays a role in the initiation of intimal hyperplasia. METHODS: In vitro responses to serum stimulation (10% fetal bovine serum) were examined in the presence and absence of pertussis toxin (PTx). After a standard balloon injury in male Sprague-Dawley rats, the expression of G-protein subunits (alpha(o), alpha(i), alpha(q), alpha(s), and betagamma) was determined by means of Western blotting in the first 28 days. Thereafter, a second set of animals was allocated to control and PTx-treated (a Galpha(i) inhibitor; 500 ng/mL in an externally applied 30% pluronic gel) groups. Smooth muscle cell proliferation was estimated by means of thymidine analogue 5-bromo-2' deoxyuridine incorporation 2 days after injury, and vessel dimensions were determined by means of videomorphometry 14 days after injury. RESULTS: There was inhibition of DNA synthesis and smooth muscle cell proliferation in response to serum with an IC(50) of 100 ng/mL. Three days after balloon injury, there was an increase in Galpha(i3) expression, which decreased at days 7, 14, and 28, compared with the uninjured carotid. Galpha(q) expression increased in a time-dependent manner. There was a marked time-dependent increase in Gbetagamma in the 28 days. Galpha(i2) and Galpha(s) isoforms (45 and 52 kDa) did not change significantly with time. There was no major change in Galpha(i1) and Galpha(o) in the study period. At 14 days, PTx treatment reduced intimal hyperplasia by 52% (63 +/- 4 microm vs. 30 +/- 5 microm, control vs. PTx; P <.001). Medial smooth muscle cell proliferation at day 2 was decreased in the PTx group, compared with that in the gel-coated group (15% +/- 2% and 26% +/- 3%; P = .02). CONCLUSION: After balloon injury, there is a time-dependent increase in G-protein expression, which is subunit specific. Activation of PTx sensitive G-proteins (Galpha(i)) is involved during the initiation of intimal hyperplasia after arterial injury, and their inhibition results in a decrease in early medial cell proliferation. This acute interruption of G(i) signaling produces a long-term decrease in intimal hyperplasia.

Retrovirally mediated expression of decorin by macrovascular endothelial cells. Effects on cellular migration and fibronectin fibrillogenesis in vitro.

Decorin is a member of the widely expressed family of small leucine-rich proteoglycans. In addition to a primary role as a modulator of extracellular matrix protein fibrillogenesis, decorin can inhibit the cellular response to growth factors. Decorin expression is induced in endothelial cells during angiogenesis, but not when migration and proliferation are stimulated. Thus, decorin may support the formation of the fibrillar pericellular matrix that stabilizes the differentiated endothelial phenotype during the later stages of angiogenesis. Therefore, we tested whether constitutive decorin expression alone could modify endothelial cell migration and proliferation or affect pericellular matrix formation. To this end, replication-defective retroviral vectors were used to stably express bovine decorin, which was detected by Northern and Western blotting. The migration of endothelial cells that express decorin is significantly inhibited in both monolayer outgrowth and microchemotaxis chamber assays. The inhibition of cell migration by decorin was not accompanied by decreased proliferation. In addition, endothelial cells that express decorin assemble an extensive fibrillar fibronectin matrix more rapidly than control cells as assessed by immunocytochemical and fibronectin fibrillogenesis assays. These observations suggest that cell migration may be modulated by the influence of decorin on the assembly of the cell-associated extracellular matrix.

Effect of platelet-derived growth factor receptor-alpha and -beta blockade on flow-induced neointimal formation in endothelialized baboon vascular grafts.

The growth of neointima and neointimal smooth muscle cells in baboon polytetrafluoroethylene grafts is regulated by blood flow. Because neointimal smooth muscle cells express both platelet-derived growth factor receptor-alpha and -beta (PDGFR-alpha and -beta), we designed this study to test the hypothesis that inhibiting either PDGFR-alpha or PDGFR-beta with a specific mouse/human chimeric antibody will modulate flow-induced neointimal formation. Bilateral aortoiliac grafts and distal femoral arteriovenous fistulae were placed in 17 baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, normalizing flow through the ipsilateral graft while maintaining high flow in the contralateral graft. The experimental groups received a blocking antibody to PDGFR-alpha (Ab-PDGFR-alpha; 10 mg/kg; n=5) or PDGFR-beta (Ab-PDGFR-beta; 10 mg/kg; n=6) by pulsed intravenous administration 30 minutes before ligation and at 4, 8, 15, and 22 days after ligation. Controls received carrier medium alone (n=8). Serum antibody concentrations were followed. Grafts were harvested after 28 days and analyzed by videomorphometry. Serum Ab-PDGFR-alpha concentrations fell rapidly after day 7 to 0, whereas serum Ab-PDGFR-beta concentrations were maintained at the target levels (>50 microg/mL). Compared with controls (3.7+/-0.3), the ratio of the intimal areas (normalized flow/high flow) was significantly reduced in Ab-PDGFR-beta (1.2+/-0.2, P<0.01) but not in Ab-PDGFR-alpha (2.2+/-0.4). Ab-PDGFR-alpha decreased significantly the overall smooth muscle cell nuclear density of the neointima (P<0.01) compared with either the control or Ab-PDGFR-beta treated groups. PDGFR-beta is necessary for flow-induced neointimal formation in prosthetic grafts. Targeting PDGFR-beta may be an effective pharmacological strategy for suppressing graft neointimal development.

Inhibition of vascular smooth muscle cell migration by elevation of extracellular potassium concentration.

The effect of potassium on the migration of vascular smooth muscle cells was analyzed in media made with extracellular potassium concentrations of 3, 4, 5, and 6 mmol/L. The migration of cultured porcine coronary artery cells was stimulated with platelet-derived growth factor (PDGF)-BB. In the first study, cells were exposed to PDGF-BB at concentrations of 0, 10, or 20 ng/mL for 5 hours with the use of a Boyden chamber. Cells were quiescent overnight in 0.5% fetal bovine serum in Dulbecco's modified Eagle's medium with an extracellular potassium concentration of 4 mmol/L. With increasing potassium concentration, migration was significantly inhibited (P<0. 02, 2-way ANOVA). In the cells exposed to 10 ng/mL PDGF-BB, migration ranged from 500+/-86% to 294+/-44% (value in wells with 0 ng/mL PDGF-BB and 4 mmol/L potassium concentration=100%) in medium containing 3 to 6 mmol/L extracellular potassium concentration (P<0. 03). Long-term potassium exposure was investigated in cells grown in 5% serum in Dulbecco's modified Eagle's medium with an extracellular potassium concentration of 3, 4, 5, or 6 mmol/L for 3 to 4 weeks. Migration was assessed with 0 or 20 ng/mL PDGF-BB. Migration was significantly inhibited by the elevation of extracellular potassium concentration (P<0.01, 2-way ANOVA). With 20 ng/mL PDGF-BB, the migration rates ranged from 152+/-11% in medium with 3 mmol/L potassium to 69+/-5% in 6 mmol/L potassium (P<0.01). Increases in extracellular potassium concentration within the physiological range significantly and directly inhibit vascular smooth muscle cell migration.

Review and recent progress: the mathematical modeling of mixed species Plasmodium infections.

Mathematical modeling serves numerous uses in biology, notably in the exploration of phenomena that are difficult to observe empirically. Here, I review recent progress in modeling the blood-stage dynamics of mixed-species Plasmodium infections, namely P. malariae-P. falciparum and P. vivax- P. falciparum mixed infections. Modeling reproduces features of such infections found in nature including the asymmetry of parasite blood-stage densities, inter-specific suppression, and parasite asexual-form recrudescence following long-standing sub-patency. Several findings which merit clinical attention are presented: the ability of P. malariae and P. vivax to reduce the peak parasitemia of co-infecting P. falciparum, and the potential recrudescence of a low-level P. falciparum infection following a P. malariae infection or P. vivax infection or relapse. The action of antimalarial drugs is discussed, highlighting some potential complications in treating mixed-species malaria infections. Most notably, if a mixed-species infection is misdiagnosed as a single-species P. vivax infection, treatment can lead to the dangerous appearance of "hidden" P. falciparum.

Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery.

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerosis as well as intimal hyperplasia after vascular injury. We used Fischer rat smooth muscle cells (SMCs) overexpressing MMP-9 to determine the role of MMP-9 in migration and proliferation as well as in vessel remodeling after balloon denudation. Fischer rat SMCs were stably transfected with a cDNA for rat MMP-9 under the control of a tetracycline-regulatable promoter. In this system, MMP-9 was overexpressed in the absence, but not in the presence, of tetracycline. In vitro SMC migration was determined using a collagen invasion assay as well as a Boyden chamber assay. In vivo migration was determined by measuring the invasion into the medial and intimal layers of transduced SMCs seeded on the outside of the artery. Transduced SMCs were also seeded on the luminal surface, and the effect of local MMP-9 overexpression on vascular structure was measured morphometrically at intervals up to 28 days. MMP-9 overexpression enhanced SMC migration in both the collagen invasion assay and Boyden chamber in vitro, increased SMC migration into an arterial matrix in vivo, and altered vessel remodeling by increasing the vessel circumference, thinning the vessel wall and decreasing intimal matrix content. These results demonstrate that MMP-9 enhances vascular SMC migration in vitro and in vivo and alters postinjury vascular remodeling.

Blood-stage dynamics and clinical implications of mixed Plasmodium vivax-Plasmodium falciparum infections.

We present a mathematical model of the blood-stage dynamics of mixed Plasmodium vivax-Plasmodium falciparum malaria infections in humans. The model reproduces features of such infections found in nature and suggests several phenomena that may merit clinical attention, including the potential recrudescence of a long-standing, low-level P. falciparum infection following a P. vivax infection or relapse and the capacity of an existing P. vivax infection to reduce the peak parasitemia of a P. falciparum superinfection. We simulate the administration of antimalarial drugs, and illustrate some potential complications in treating mixed-species malaria infections. Notably, our model indicates that when a mixed-species infection is misdiagnosed as a single-species P. vivax infection, treatment for P. vivax can lead to a surge in P. falciparum parasitemia.

The blood-stage dynamics of mixed Plasmodium malariae-Plasmodium falciparum infections.

We present the first mathematical model of the within-host dynamics of a mixed-species malaria infection in a human: the blood-stage population dynamics of a dual infection with Plasmodium malariae and Plasmodium falciparum. Our results reproduce several important features of such infections in nature, including the asymmetry of species asexual-form densities, inter-specific suppression through interactions with the human immune system, and seasonal alternations in species prevalence. Most importantly, our results suggest that an existing P. malariae infection can reduce the peak parasitemia of a subsequent P. falciparum superinfection by as much as 50%. This result integrates numerous empirical observations and supports the hypothesis that clinical outcomes of P. falciparum infections may be influenced by the presence of a congener.

Hidden Plasmodium falciparum infections.

Mixed infection of P. vivax and P. falciparum malaria frequently recorded in field survey. However mixed infection was frequently misdiagnosed as single infection due to low parasite density, difficult species identification and procedure error of microscopic examination. Our previous report showed high rates (32-33%) of P vivax infection following treatment of previously assumed to be only P. falciparum infection. In a study of 992 patients with initial presentation with P. falciparum, we found that 104 (10.5%) of patients had P. falciparum appearing during 28 days in the hospital (ranged 1-28 days) following chloroquine treatment for P. vivax. The potential for P. falciparum appearing following elimination of P. vivax must be considered in malaria treatment.