Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.

Randomized Trial of Pleural Fluid Drainage Frequency in Patients with Malignant Pleural Effusions. The ASAP Trial.

RATIONALE: Patients with malignant pleural effusions have significant dyspnea and shortened life expectancy. Indwelling pleural catheters allow patients to drain pleural fluid at home and can lead to autopleurodesis. The optimal drainage frequency to achieve autopleurodesis and freedom from catheter has not been determined. OBJECTIVES: To determine whether an aggressive daily drainage strategy is superior to the current standard every other day drainage of pleural fluid in achieving autopleurodesis. METHODS: Patients were randomized to either an aggressive drainage (daily drainage; n = 73) or standard drainage (every other day drainage; n = 76) of pleural fluid via a tunneled pleural catheter. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of autopleurodesis following the placement of the indwelling pleural catheters. The rate of autopleurodesis, defined as complete or partial response based on symptomatic and radiographic changes, was greater in the aggressive drainage arm than the standard drainage arm (47% vs. 24%, respectively; P = 0.003). Median time to autopleurodesis was shorter in the aggressive arm (54 d; 95% confidence interval, 34-83) as compared with the standard arm (90 d; 95% confidence interval, 70 to nonestimable). Rate of adverse events, quality of life, and patient satisfaction were not significantly different between the two arms. CONCLUSIONS: Among patients with malignant pleural effusion, daily drainage of pleural fluid via an indwelling pleural catheter led to a higher rate of autopleurodesis and faster time to liberty from catheter. Clinical trial registered with www.clinicaltrials.gov (NCT 00978939).

Lung Cancer Screening in the Community Setting.

BACKGROUND: Lung cancer has high incidence and high mortality burden, particularly because it is typically diagnosed in later stages. The National Lung Screening Trial demonstrated a lung cancer-specific mortality benefit in high-risk current and former smokers with yearly low-dose chest computed tomography (CT). Lung cancer screening is thus recommended, but it is unclear whether the results of the National Lung Screening Trial can be replicated in community settings. METHODS: A retrospective review was performed of the lung screening program over its first 5 years, 2012 to 2016. Patients' demographics, initial screening results, follow-up, and management results were analyzed in relation to the National Lung Screening Trial results. Annual adherence was defined as returning for imaging within 1 year + 90 days. RESULTS: A total of 1,241 persons underwent initial screening over the 5-year period; 78.6% of findings were benign, and only annual repeat low-dose chest CT was recommended. A total of 29 cancers were identified in 26 participants (2%), of which 72% were stage I. The annual adherence rate to repeat imaging after a low-risk baseline scan was 37%, and the any follow-up rate was 51% despite programmatic efforts to follow screening recommendations. When positive findings required more intensive evaluation, most commonly by repeat chest CT scan, adherence was 88%. A total of 1.1% of all participants had invasive biopsies for benign results. Complications of biopsy were minimal. CONCLUSIONS: This review demonstrates that a community-based program can approximate the results of the National Lung Screening Trial in detecting early lung cancers. Further study of the adherence phenomenon is essential.

Surgery for aortic root aneurysm in children: a 21-year experience in 50 patients.

BACKGROUND: Ascending aortic aneurysms are unusual in children and have received little attention to develop guidelines for management. This study reviewed our experience with 50 children who have undergone aortic root replacement for ascending aortic aneurysm. METHODS: A retrospective clinical review was conducted using hospital charts and office records. Patients or their physicians were contacted for follow-up and recent echocardiograms were obtained and reviewed. RESULTS: There was no operative or hospital mortality. Twenty-six children had aortic root replacement with a composite graft, 10 patients had replacement with a homograft aortic root, and 14 patients had a David II valve-sparing procedure. Factors related to late morbidity and mortality were analyzed. Long-term results were excellent in the 26 children receiving a composite graft. Twenty-three of these children were New York Heart Association class I (19) or II (4) at study closure. There were 3 late deaths (11, 16, and 17 years postoperative). Seven of 10 children receiving a homograft aortic root are long-term survivors and all 14 children having a valve-sparing procedure are alive. Generally, late results with the David II remodeling procedure have been good although 3 patients developed late aortic insufficiency and two required valve replacement. CONCLUSIONS: Aortic root replacement in children with aneurysms has low operative risk and good long-term results. Composite grafts in particular carry a low risk of endocarditis, thromboembolism, and hemorrhagic events. Homografts are suitable for small patients but lack durability. Late results with the David II remodeling valve-sparing procedure in children have been compromised by late root dilatation.

Pharmacological preconditioning ameliorates neurological injury in a model of spinal cord ischemia.

BACKGROUND: Pharmacological openers of mitochondrial ATP-sensitive potassium (mitoKATP) channels have been shown to mimic ischemic preconditioning (IPC) in both the brain and myocardium. We hypothesized that similar endogenous mechanisms exist in the spinal cord and that diazoxide, a potent mitoKATP opener, could reduce neurologic injury after aortic cross-clamping in a model of spinal cord ischemia. METHODS: The infra-renal aorta was cross-clamped in 45 male New Zealand white rabbits for 20 minutes. Control animals received no pretreatment. Diazoxide-treated animals were dosed (5 mg/kg) 15 minutes before cross-clamp. A third group underwent 5 minutes of IPC 30 minutes before cross-clamp. Two groups received KATP antagonists, 5-hydroxydecanoic acid (5-HD, 20 mg/kg) or glibenclamide (1.0 mg/kg), before diazoxide administration. Systemic hypotension was induced in a final group with excess isoflurane. Tarlov Scoring was used to assess neurologic function at 24 and 48 hours, after which, the spinal cords were procured for histopathological analysis. RESULTS: Tarlov scoring demonstrated marked improvement in the Diazoxide group compared with control at 24 hours (p < 0.02) and 48 hours (p < 0.009). Moreover, no further neurologic injury occurred in this group at 7 days. IPC-treated animals showed neurologic improvement but were not significantly different from controls. Further, administration of glibenclamide was effective in antagonizing diazoxide's protective effect. CONCLUSIONS: Administration of diazoxide resulted in significant improvement in neurologic outcome in this model. This protective effect improved outcome at both early and late time points. Further, the antagonistic effect of glibenclamide implicates diazoxide's ATP-dependent potassium channel agonism as the mechanism of protection. Overall, this study suggests that diazoxide may be useful in the prevention of neurologic injury after thoracic aneurysm surgery.

Application of haptic feedback to robotic surgery.

Robotic surgical systems have greatly contributed to the advancement of minimally invasive endoscopic surgery. However, current robotic systems do not provide tactile or haptic feedback to the operating surgeon. Under certain circumstances, particularly with the manipulation of delicate tissues and suture materials, this may prove to be a significant irritation. We hypothesize that haptic feedback, in the form of sensory substitution, facilitates the performance of surgical knot tying. This preliminary study describes evidence that visual sensory substitution permits the surgeon to apply more consistent, precise, and greater tensions to fine suture materials without breakage during robot-assisted knot tying.

Thoracoscopic detection of occult indeterminate pulmonary nodules using bronchoscopic pleural dye marking.

BACKGROUND: The annual incidence of a small indeterminate pulmonary nodule (IPN) on computed tomography (CT) scan remains high. While traditional paradigms exist, the integration of new technologies into these diagnostic and treatment algorithms can result in alternative, potentially more efficient methods of managing these findings. METHODS: We report on an alternative diagnostic and therapeutic strategy for the management of an IPN. This approach combines electromagnetic navigational bronchoscopy (ENB) with an updated approach to placement of a pleural dye marker. This technique lends itself to a minimally invasive wedge resection via either video-assisted thoracoscopic surgery (VATS) or a robotic approach. RESULTS: Subsequent to alterations in the procedure, a cohort of 22 patients with an IPN was reviewed. Navigation was possible in 21 out of 22 patients with one patient excluded based on airway anatomy. The remaining 21 patients underwent ENB with pleural dye marking followed by minimally invasive wedge resection. The median size of the nodules was 13.4 mm (range: 7-29). There were no complications from the ENB procedure. Indigo carmine dye was used in ten patients. Methylene blue was used in the remaining 11 patients. In 81% of cases, the visceral pleural marker was visible at the time of surgery. In one patient, there was diffuse staining of the parietal pleura. In three additional patients, no dye was identified within the hemithorax. In all cases where dye marker was present on the visceral pleural surface, it was in proximity to the IPN and part of the excised specimen. CONCLUSIONS: ENB with pleural dye marking can provide a safe and effective method to localize an IPN and can allow for subsequent minimally invasive resection. Depending on the characteristics and location of the nodule, this method may allow more rapid identification intraoperatively.

Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers.

BACKGROUND: Survival outcomes of never smokers with non-small cell lung cancer (NSCLC) who undergo surgery are poorly characterized. This investigation compared surgical outcomes of never and current smokers with NSCLC. METHODS: This investigation was a single-institution retrospective study of never and current smokers with NSCLC from 1975 to 2004. From an analytic cohort of 4,546 patients with NSCLC, we identified 724 never smokers and 3,822 current smokers. Overall, 1,142 patients underwent surgery with curative intent. For survival analysis by smoking status, hazard ratios (HRs) were estimated using Cox proportional hazard modeling and then further adjusted by other covariates. RESULTS: Never smokers were significantly more likely than current smokers to be women (P < .01), older (P < .01), and to have adenocarcinoma (P < .01) and bronchioloalveolar carcinoma (P < .01). No statistically significant differences existed in stage distribution at presentation for the analytic cohort (P = .35) or for the subgroup undergoing surgery (P = .24). The strongest risk factors of mortality among patients with NSCLC who underwent surgery were advanced stage (adjusted hazard ratio, 3.43; 95% CI, 2.32-5.07; P < .01) and elevated American Society of Anesthesiologists classification (adjusted hazard ratio, 2.18; 95% CI, 1.40-3.40; P < .01). The minor trend toward an elevated risk of death on univariate analysis for current vs never smokers in the surgically treated group (hazard ratio, 1.20; 95% CI, 0.98-1.46; P = .07) was completely eliminated when the model was adjusted for covariates (P = .97). CONCLUSIONS: Our findings suggest that smoking status at time of lung cancer diagnosis has little impact on the long-term survival of patients with NSCLC, especially after curative surgery. Despite different etiologies between lung cancer in never and current smokers the prognosis is equally dismal.

Aortic valve replacement in a diseased bicuspid valve eleven years after transplantation.

Cardiac allotransplantation is subject to a number of chronic complications that may limit graft survival. These include allograft coronary artery disease, renal dysfunction, hypertension, and malignancy, which are largely due to the immuno-modulatory and adverse effects of transplant medications. Reoperation for native allograft disease progression is a rarer phenomenon. We report a case of aortic valve replacement for bicuspid aortic valve stenosis that occurred in a patient more than ten years after cardiac transplantation.

Recurrence after neoadjuvant chemoradiation and surgery for esophageal cancer: does the pattern of recurrence differ for patients with complete response and those with partial or no response?

OBJECTIVE: We hypothesized that most relapses in patients with esophageal cancer having neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields. METHODS: Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who had esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years. RESULTS: Of 267 patients, 82 (30.7%) showed complete response to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) showing partial response or no response, respectively. Recurrence developed in 84 patients (patients with complete response 18/82, 21.4%; patients with partial response 39/108, 36.1%; patients with no response 27/77, 35.1%; P = .055, respectively). Most patients had recurrences at distant sites (65/84;77.4%) regardless of pathologic response, and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for patients with partial response or no response, but was longer for patients with complete response with distant recurrence, whose median disease-free survival was 27.3 months (P = .008). By multivariate analysis, no other factor except for pathologic response to neoadjuvant therapy was associated with disease recurrence or death. Patients with partial response or no response were 1.97 and 2.23 times more likely to have recurrence than patients with complete response (P = .024 and P = .012, respectively). CONCLUSIONS: Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathologic response. Fewer patients achieving complete response had recurrences, and distant recurrences in these patients manifest later than in patients showing partial response and those showing no response. Only pathologic response is significantly associated with disease recurrence, suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.

Use of video-assisted thoracic surgery for lobectomy in the elderly results in fewer complications.

BACKGROUND: The purpose of this study was to determine if the utilization of video-assisted thoracic surgery (VATS) for lobectomy for clinical stage I non-small cell lung cancer in elderly patients results in decreased complications compared with lobectomy by thoracotomy (THOR). METHODS: A retrospective, matched case-control study was performed evaluating the perioperative outcomes after lobectomy by VATS versus THOR performed in elderly patients (age > or = 70 years) at a single institution. All complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (http://ctep.cancer.gov/reporting/ctc.html). RESULTS: Between May 1, 2002 and December 31, 2005 333 patients (245 THOR, 88 VATS) 70 years old or greater underwent lobectomy for clinical stage I non-small cell lung cancer. After matching based on age, gender, presence of comorbid conditions, and preoperative clinical stage, there were 82 patients in each group. Patients had similar preoperative characteristics. A VATS approach resulted in a significantly lower rate of complications compared with THOR (28% vs 45%, p = 0.04) and a shorter median length of stay (5 days, range 2 to 20 vs 6 days, range 2 to 27, p < 0.001). No patients undergoing VATS lobectomy had higher than grade 2 complications, whereas 7% of complications in the THOR group were grade 3 or higher. There were no perioperative deaths in the VATS patients compared with an in-hospital mortality rate of 3.6% (3 of 82) for THOR patients. CONCLUSIONS: A VATS approach to lobectomy for clinical stage I non-small cell lung cancer in the elderly was associated with fewer and overall reduced severity of complications as well as a shorter hospital stay compared with thoracotomy.

Heterotopic abdominal heart transplantation: a pilot study.

The increasingly severe shortage of donor hearts has prompted a liberalization of what is considered an acceptable donor heart. The use of marginally acceptable organs has increased in recent years. Although these marginal donors have proved effective, there still remains a tremendous shortage of donors to treat the large number of patients who are candidates for cardiac transplantation. Further use of marginal donors is limited by the requirement to assume immediate and full support of the circulation. New strategies are required to increase donor organ use even further. The authors developed a model of heterotopic abdominal heart transplant (HAHT) to investigate the possibility of using marginal donor hearts to expand the donor pool for cardiac transplantation. The authors' goal was to show that HAHT was technically feasible and could potentially function as auxiliary circulatory support in the setting of low cardiac output. The hemodynamic and metabolic consequences of a HAHT were investigated in a pilot study that provides proof of concept and lays the groundwork for future investigations.

Results of aortic valve-sparing operations: experience with remodeling and reimplantation procedures in 65 patients.

BACKGROUND: Valve-sparing operations for aortic root aneurysms are increasing in frequency, but techniques and results are still in evolution. We reviewed our experience with 65 patients (adults and children) who had this operation at our institution to determine early and late outcomes. METHODS: A retrospective clinical review was undertaken using hospital records, clinical and echocardiographic, computed tomography, magnetic resonance imaging data, and telephone interviews with patients and their physicians. RESULTS: Between July 1994 and December 2002, 65 patients (46 adults and 19 children) underwent a valve-sparing operation for aortic root aneurysm. Forty-four of the patients had the Marfan syndrome; the remaining 21 had either a nonspecific connective tissue disorder (14 patients) or a miscellaneous disease process such as Ehlers-Danlos syndrome (7 patients). Fifty-eight (89%) had a David II (remodeling) procedure and 7 had a David I (reimplantation) procedure. The DePaulis "Valsalva graft" was used in six of the David I patients. There were no operative or hospital deaths; only one late death occurred in an adult due to salmonella meningitis. Overall, survival was 100% at one year and 98% at 3 and 5 years. Ten patients (7 adults and 3 children) developed significant late aortic insufficiency (AI). Nine of these patients had a David II procedure and in 8 of these cases, AI was secondary to significant late annular dilatation. One of the 10 patients developed late AI 8.2 years after a David I procedure; his AI was secondary to aortic leaflet extension and prolapse. Six of the 10 patients who developed significant late AI required aortic valve replacement (4 adults and 2 children). Freedom from late aortic valve replacement (AVR) in this series of 65 patients was 91% at 3 and 84% at 5 years. At the close of this study, 58 patients were New York Heart Association (NYHA) class I and 6 were NYHA class II; no patients were class III or IV. There were no episodes of endocarditis or clinically significant thromboembolism. CONCLUSIONS: Valve-sparing operations provide satisfactory results for many patients with an aortic root aneurysm, but the David II remodeling procedure has a greater risk of late annular dilatation and AI. The David I reimplantation procedure utilizing the DePaulis Valsalva graft may obviate this problem.

Effect of bronchial artery blood flow on cardiopulmonary bypass-induced lung injury.

Cardiovascular surgery requiring cardiopulmonary bypass (CPB) is frequently complicated by postoperative lung injury. Bronchial artery (BA) blood flow has been hypothesized to attenuate this injury. The purpose of the present study was to determine the effect of BA blood flow on CPB-induced lung injury in anesthetized pigs. In eight pigs (BA ligated) the BA was ligated, whereas in six pigs (BA patent) the BA was identified but left intact. Warm (37 degrees C) CPB was then performed in all pigs with complete occlusion of the pulmonary artery and deflated lungs to maximize lung injury. BA ligation significantly exacerbated nearly all aspects of pulmonary function beginning at 5 min post-CPB. At 25 min, BA-ligated pigs had a lower arterial Po(2) at a fraction of inspired oxygen of 1.0 (52 +/- 5 vs. 312 +/- 58 mmHg) and greater peak tracheal pressure (39 +/- 6 vs. 15 +/- 4 mmHg), pulmonary vascular resistance (11 +/- 1 vs. 6 +/- 1 mmHg x l(-1) x min), plasma TNF-alpha (1.2 +/- 0.60 vs. 0.59 +/- 0.092 ng/ml), extravascular lung water (11.7 +/- 1.2 vs. 7.7 +/- 0.5 ml/g blood-free dry weight), and pulmonary vascular protein permeability, as assessed by a decreased reflection coefficient for albumin (sigma(alb); 0.53 +/- 0.1 vs. 0.82 +/- 0.05). There was a negative correlation (R = 0.95, P < 0.001) between sigma(alb) and the 25-min plasma TNF-alpha concentration. These results suggest that a severe decrease in BA blood flow during and after warm CPB causes increased pulmonary vascular permeability, edema formation, cytokine production, and severe arterial hypoxemia secondary to intrapulmonary shunt.