EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery.

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

Surgical outcome of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy.

OBJECTIVES: Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous operation. We retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. METHODS: We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small-cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without a prior ipsilateral lobectomy. RESULTS: Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min, and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. CONCLUSIONS: Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy.

Mediastinal and Hilar Lymph Node Metastases from Renal Cell Carcinoma with Concomitant Lung Carcinoma: A Rare Case with Unique Diagnostic Challenges.

A 75-year-old man presented to our hospital 1 year after partial renal resection for clear cell carcinoma. A right lower lobe lung nodule noted at the time of surgery had increased to 3.0 cm in diameter and was confirmed as squamous cell lung carcinoma by bronchoscopic cytology. Computed tomography had also revealed paratracheal lymph node swelling. He underwent right lower lobectomy with lymph node dissection by video-assisted thoracic surgery. Pathological examination confirmed squamous cell carcinoma of the lung but diagnosed the right hilar and mediastinal lymph node metastases as clear cell carcinoma.

Clinical Features of Patients With Second Primary Lung Cancer After Head and Neck Cancer.

BACKGROUND: In survivors of head and neck cancer (HNC), second primary lung cancer (SPLC) often develop as a result of a common risk factor, that is, smoking. A multicenter experience was reviewed to evaluate how the history of a diagnosis of HNC affects the outcomes of patients undergoing pulmonary resection for SPLC. METHODS: A multicenter retrospective analysis of patients hospitalized between January 2012 and December 2018 was performed. From a cohort of 4521 patients undergoing therapeutic pulmonary resection for primary non-small cell lung cancer, 100 patients with a previous history of HNC (HNC group) were identified. These patients were compared with a control group consisting of 200 patients without an HNC history from the same cohort pair-matched with operating facility, age, sex, and pathologic stage of lung cancer. RESULTS: At the time of surgery for SPLC, the HNC group showed malnutrition with a lower prognostic nutritional index compared with the control group (P < .001). The HNC group was determined to have postoperative complications more frequently (P = .02). The 5-year overall survival rates in the HNC and control groups were 59.0% and 83.2%, respectively (P < .001). Statistically, HNC history, lower prognostic nutritional index, squamous cell lung cancer, and TNM stage were identified to be independently associated with poor survival. CONCLUSIONS: Patients with SPLC after primary HNC often present with malnutrition and are predisposed to postoperative complications and poor survival after pulmonary resection.

Use of uniportal video-assisted thoracic surgery combined with a posterior approach to resect a dumbbell-shaped mediastinal granular cell tumor: A case report.

INTRODUCTION: A dumbbell-shaped mediastinal granular cell tumor has never been reported, and there have been no reports of dumbbell-shaped tumors resected with a combination of uniportal video-assisted thoracic surgery and the posterior approach. PRESENTATION OF CASE: An 18-year-old woman was diagnosed with a mediastinal dumbbell-shaped granular cell tumor by computed tomography. Complete resection was achieved via a posterior approach combined with the uniportal video-assisted thoracic surgery. First, a T3 left hemilaminectomy was performed in the prone position and the tumor located inside the intervertebral foramen was removed as far as possible. Next, the patient was repositioned to the right lateral decubitus position, a 2.5-cm skin incision was made on the 4th intercostal posterior axillary line, and resection of the residual tumor was performed. Pathological diagnosis of the resected tumor revealed a benign granular cell tumor. The patient recovered post-surgery and no tumor was reported in the 4-month follow-up magnetic resonance imaging. DISCUSSION: This is the first reported case of a mediastinal dumbbell-shaped granular cell tumor and its successful resection using a combined posterior and uniportal video-assisted thoracic surgery approach. CONCLUSION: This is a potentially safe and effective procedure for mediastinal granular cell tumors, with outstanding cosmetic advantages.

Quality of life after partial lung resection with uniportal versus 3-port video-assisted thoracoscopic surgery: a prospective randomized controlled study.

PURPOSE: The effect of uniportal video-assisted thoracoscopic surgery (uni-VATS) versus that of conventional VATS on postoperative quality of life (QOL) is unclear. This prospective randomized controlled study compared uni-VATS and conventional 3-port VATS in terms of QOL and patient satisfaction. METHODS: The subjects of this study were 84 patients with pulmonary nodules or bullous formation, randomized to undergo uniportal or conventional 3-port video-assisted thoracoscopic partial lung resection. The primary endpoint was postoperative pain, assessed using a numeric rating scale on postoperative day (POD) 1. RESULTS: No differences were found in the numeric rating scale on POD 1 after uni-VATS and conventional 3-port VATS. There were also no differences in blood loss, operative time, complication rate, surgical margin, analgesic requirement, vital capacity (VC), forced expiratory volume in 1 s (FEV1), the 6-min walk test (6MWT), C-reactive protein (CRP) levels, white blood cell count (WBC), or duration of chest tube drainage and hospital stay. Differences were found in the numeric rating scale on days 2, 3, 5, and 10 and in the patient satisfaction score on PODs 5 and 10. CONCLUSIONS: Uni-VATS is associated with less chest pain and better patient satisfaction in the short term but without differences in complication rates or surgical margins from the lesions. CLINICAL TRIAL REGISTRY NUMBER: University Hospital Medical Information Network Clinical Trial Registry (UMIN000015340 http://www.umin.ac.jp/english/ ).

Resected case of stage IV pleomorphic carcinoma of the lung with long-term survival.

BACKGROUND: No established treatments for pulmonary pleomorphic carcinoma exist because of its rarity, and the prognosis is poorer than that of other non-small cell lung cancers. CASE REPORT: We present a case of stage IV pleomorphic carcinoma; the patient was a 66-year-old male. He was referred to our hospital because of a right adrenal hemorrhage and a lung tumor. A systemic examination revealed that the lung tumor was a primary lung cancer and that the adrenal hemorrhage was due to a metastatic cancer. We performed an adrenalectomy and resection of the lung tumor and obtained a diagnosis of pleomorphic carcinoma with adrenal metastasis. The patient has remained recurrence-free for 6 years since the surgery. CONCLUSIONS: We report a patient with stage IV pleomorphic carcinoma of the lung and an oligometastasis in whom a complete resection enabled a good outcome. Additional reports are needed to clarify definite prognostic factors and the optimal treatment for pleomorphic carcinoma.

A case of thoracic endometriosis-related pneumothorax in a menopausal woman.

Thoracic endometriosis-related pneumothorax (TERP) or thoracic endometriosis syndrome (TES) usually occurs in women of childbearing age and affects the right thorax. Menopausal and left-sided cases are rare. A case of left-sided TERP in a postmenopausal woman after adjuvant endocrine therapy for breast cancer is reported. A 51-year-old woman underwent video-assisted thoracic surgery for recurrent left pneumothorax. Immunohistological examination of the resected specimen from the apical bleb and a diaphragmatic blueberry spot demonstrated thoracic endometriosis. Even in the case of a left-sided pneumothorax in a menopausal woman, clinicians should be aware of the possibility of TERP.

Therapeutic Outcomes of 15 Postoperative Bronchopleural Fistulas Including Seven Endoscopic Interventions.

Therapeutic approaches to bronchopleural fistula (BPF) closure after lung resection are surgical or endoscopic interventions. We evaluated therapeutic outcomes to determine the optimal approach. We reviewed 15 patients who had developed BPF after lung resection for thoracic malignant diseases at our institution in the 10 years since 2008. The patients were 11 men and 4 women (mean age 68 years). We performed one pneumonectomy, 6 lobectomies, 7 segmentectomies, and one partial resection for malignant diseases. The median interval from lung resection to the BPF diagnosis was 46 days. The BPF-associated mortality rate was 26.7% (4/15). The rate of successful BPF closure was 66.6% (10/15). The endoscopic and surgical intervention success rates were 14.2% (1/7) and 69.2% (9/13), respectively (p<0.01). Of 5 patients who had failed BPF treatments, 4 died, and one transferred out without BPF closure. The therapeutic outcomes were related to preoperative comorbidities, performance status at the BPF diagnosis, time intervals from lung resection to BPF diagnosis, and presence of active pneumonia. The difference between endoscopic and surgical outcomes was nonsignificant, although the surgical intervention success rate was somewhat higher. The selection of endoscopic or surgical intervention for BPF does not significantly affect therapeutic outcomes.

Surgical outcomes in 13 patients with bronchopulmonary carcinoid tumors including one recurrent oncocytic carcinoid tumor.

INTRODUCTION: Bronchopulmonary carcinoids are low-grade tumors for which the standard treatment is surgical resection. We retrospectively evaluated the surgical outcomes. METHODS: Thirteen patients underwent surgical resection for them at our institution between January 2005 and December 2016. We collected their clinicopathologic data to evaluate surgical outcomes. RESULTS: The 13 patients comprised seven men and six women. Complete resection was performed in all cases. All the tumors were typical carcinoids, including one oncocytic carcinoid which showed highest fluorodeoxyglucose (FDG) uptake (SUVmax 45.7). The 5-year overall survival rates were 100%. The only patient with oncocytic carcinoid developed recurrence of liver metastasis 49 months after the primary lung resection. The metastasis showed low FDG uptake (SUVmax 2.8) and its histology was typical carcinoid and not oncocytic carcinoid. CONCLUSION: Surgical outcomes in our patients were favorable. In oncocytic carcinoid, metastatic site may have a radiologic and histologic appearance different from the primary tumor.

Restrictive ventilatory impairment is associated with poor outcome in patients with cT1aN0M0 peripheral squamous cell carcinoma of the lung.

BACKGROUND: Patients with squamous cell carcinoma (SqCC) of the lung sometimes have a comorbid pulmonary disease such as pulmonary emphysema or an interstitial lung disease (ILD), both of which negatively affect patient outcome. The aim of this study was to determine the outcome of patients in a multicenter database who underwent surgery for cT1aN0M0 peripheral SqCC lung cancer. METHODS: The medical records of a total of 228 eligible patients from seven institutions were reviewed to evaluate the impact of concomitant impaired pulmonary function and other clinicopathological factors on overall survival (OS) and relapse-free survival (RFS). RESULTS: Six patients with positive or unclear tumor margins were excluded. Of the 222 remaining study patients, 42 (18.9%) and 97 (43.7%) patients were found to have coexisting restrictive or obstructive ventilatory impairment, respectively. Over a median follow-up period of 30.6 months, the 5-year OS and RFS were 69.0% and 62.6%, respectively. By multivariate analysis, ILDs identified on high-resolution computed tomography (HRCT), pulmonary function test results indicating a restrictive ventilatory impairment, and wedge resection were found to be independent risk factors for poor OS. An increased level of serum squamous cell carcinoma antigen (SCC-Ag) (>1.5 ng/mL) and the same risk factors for poor OS were independent risk factors for recurrence. Among patients who underwent anatomical lung resection (lobectomy and segmentectomy, n=173), a restrictive ventilatory impairment was an independent risk factor for poor OS, and increased serum SCC-Ag level, ILDs on HRCT, and restrictive ventilatory impairment were independent risk factors for poor RFS by multivariate analysis. Factors such as visceral pleural invasion, and lymphatic or vascular invasion were not significantly associated with outcome. CONCLUSIONS: A restrictive ventilatory impairment negatively affects the outcome of patients with cT1aN0M0 peripheral SqCC lung cancer.

Feasibility Trial of Oral UFT after Platinum-based Adjuvant Chemotherapy in Patients with Resected Non-small Cell Lung Cancer.

We evaluated the feasibility of maintenance treatment using UFT (a combination of tegafur and uracil) after adjuvant platinum-based chemotherapy in patients with resected lung cancer. A prospective feasibility trial was conducted. Between 2010 and 2014, UFT was administered for 2 years sequentially after platinum-based adjuvant chemotherapy in 24 patients with resected Stage IIA-IIIA non-small cell lung cancer. The safety of UFT and the rate of treatment completion were then evaluated. The prior platinum-based chemotherapy regimens consisted of cisplatin+vinorelbine in 16 patients, carboplatin+paclitaxel in 5 and carboplatin+S-1 in one. During the subsequent UFT administration, a total of 3 patients required a dose reduction because of Grade 1 blood-stained sputum, Grade 2 numbness, and Grade 2 constipation, in one patient each. Eleven patients underwent the planned 2-year UFT administration, but 12 patients could not because of the recurrence of lung cancer in 5 patients, metachronous malignancy in one, and toxicities in 6. The completion rate for UFT administration was 64.7% (11/17). The most common type of toxicity was gastrointestinal toxicities. All of the toxicities were grade 1 or 2, and no severe toxicities were observed. UFT treatment after platinum-based chemotherapy was revealed to be feasible.

Long-term Outcomes of Patients With Ground-Glass Opacities Detected Using CT Scanning.

BACKGROUND: The long-term outcomes of follow-up care for ground-glass opacity (GGO) lesions need to be clarified. METHODS: Between 2000 and 2005, a total of 226 patients with pure or mixed GGO lesions ≤ 3 cm in size were registered. The CT findings and changes in the findings during the follow-up period and the outcomes of the 226 patients were subsequently reviewed. RESULTS: Overall, 124 patients underwent resections, 57 did not receive follow-up examinations after 68 months because of stable disease or disease reduction, and 45 are continuing to receive follow-up examinations. Thirty-nine patients exhibited tumor growth during the follow-up period. Among the patients with a ratio of the diameter of consolidation relative to the tumor diameter (CTR) > 0, all cases with tumor growth were identified within 3 years; meanwhile, > 3 years were required to identify tumor growth in 16% of the patients with a CTR of 0. Aggressive cancer occurred in 4% of patients with a CTR of 0 and in 70% of patients with a CTR > 25%. Aggressive cancer was observed in 46% of the patients whose CTR increased during the follow-up period and in 8% of the patients whose tumors increased in size. CONCLUSIONS: A higher CTR and an increase in CTR during follow-up were associated with invasive cancer. A follow-up period of 3 years is considered to be adequate for judging tumor growth in patients with a CTR > 0, whereas a longer follow-up period might be needed for patients with a CTR of 0.

Pulmonary metastasectomy from renal cell carcinoma including 3 cases with sarcomatoid component.

INTRODUCTION: Usefulness of complete metastasectomy against pulmonary metastases from renal cell carcinoma (RCC) is well known. We examined the efficacy of surgical resection of pulmonary metastases from RCC performed in Shikoku Cancer Center. METHOD: Between January 2004 and December 2014, 11 patients with pulmonary metastases from RCC underwent thoracic resection in our institution. We examined disease-free interval (DFI) and overall survival of these patients after pulmonary metastasectomy. RESULTS: Patients included 9 men and 2 women with a mean age of 63.2 years. The median number of metastases was 1 (range 1-6). Overall, 5 patients had a single metastasis (45.5%), 8 patients had unilateral metastases (72.7%), and 3 patients received immunotherapy or chemotherapy in the interval between radical nephrectomy and pulmonary metastasectomy. We performed complete pulmonary metastasectomy in these patients. The median observation period was 43 months (range 5-82), median DFI was 5 months (range 2-17), and 3-year overall survival rate was 86%. In the 3 patients who had primary or metastatic tumors with sarcomatoid (SA) component, their median DFI tended to be shorter than that of 8 patients without it (2 vs. 8 months, p = 0.07). CONCLUSION: The pulmonary metastasectomy for RCC is a treatment option, while the indication for RCC with SA component should be carefully considered.

Monitoring and management of lung cancer patients following curative-intent treatment: clinical utility of 2-deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography/computed tomography.

A large number of studies have demonstrated that 2-deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) is superior to conventional modalities for the diagnosis of lung cancer and the evaluation of the extent of the disease. However, the efficacy of PET/CT in a follow-up surveillance setting following curative-intent treatments for lung cancer has not yet been established. We reviewed previous papers and evaluated the potential efficacy of PET-CT in the setting of follow-up surveillance. The following are our findings: 1) PET/CT is considered to be superior or equivalent to conventional modalities for the detection of local recurrence. However, inflammatory changes and fibrosis after treatments in local areas often result in false-positive findings; 2) the detection of asymptomatic distant metastasis is considered to be an advantage of PET/CT in a follow-up setting. However, it should be noted that detection of brain metastasis with PET/CT has some limitation, similar to its use in pretreatment staging; 3) additional radiation exposure and higher medical cost arising from the use of PET/CT should be taken into consideration, particularly in patients who might not have cancer after curative-intent treatment and are expected to have a long lifespan. The absence of any data regarding survival benefits and/or improvements in quality of life is another critical issue. In summary, PET/CT is considered to be more accurate and sensitive than conventional modalities for the detection of asymptomatic recurrence after curative-intent treatments. These advantages could modify subsequent management in patients with suspected recurrence and might contribute to the selection of appropriate treatments for recurrence. Therefore, PET/CT may be an alternative to conventional follow-up modalities. However, several important issues remain to be solved. PET/CT in a follow-up surveillance setting is generally not recommended in clinical practice at the moment.

Use of a vessel sealing system versus conventional electrocautery for lung parenchymal resection: a comparison of the clinicopathological outcomes in porcine lungs.

PURPOSE: LigaSure, a vessel sealing system, has been shown to have excellent hemostatic properties; however, its use for lung parenchymal resection has been limited. We herein examined the hemostatic properties and potential for inducing histological lung injury of the LigaSure system in non-anatomic pulmonary resection to estimate the feasibility of its clinical application. METHODS: Non-anatomic pulmonary wedge resections of the right cranial, middle, and caudal lobes were performed in four pigs using the LigaSure system (Group A) or electrocautery (Group B). In each resection, the resection time, blood loss, and weight of the resected lung were measured. The thermal effect on the lung tissue was examined by means of intraoperative thermography and histology. RESULTS: A total of 12 lung wedge resections were performed in each group. For an equivalent length of operation and weight of the resected lung parenchyma, Group A showed significantly lower blood loss and lower maximum and minimum temperatures of the lung tissue, as assessed by thermography, than Group B. The degree of thermal injury as estimated by a histological examination was lower in Group A than in Group B. CONCLUSION: Our study suggests that the LigaSure system may be superior to conventional electrocautery, indicating its clinical usefulness for non-anatomic pulmonary resection.

Preservation solution supplemented with biliverdin prevents lung cold ischaemia/reperfusion injury.

OBJECTIVES: Biliverdin (BV), one of the byproducts of heme catalysis through the heme oxygenase system, is a known scavenger of the reactive oxygen species. We hypothesized that adding BV to the perfusate and cold storage solution could protect rat lung grafts from oxidative injuries via its antioxidant efficacies. METHODS: Orthotopic left lung transplantation was performed in a syngenic Lewis-to-Lewis rat combination under 100% oxygen. Grafts were preserved in low-potassium dextran (LPD; Perfadex) at 4°C for 6 h with or without supplementation of 1 or 10 µM of BV into LPD. RESULTS: Prolonged cold storage and reperfusion resulted in a considerable deterioration of graft functions associated with massive apoptosis in the grafts after reperfusion. The untreated grafts exhibited the early up-regulations of mRNA for inflammatory mediators and an increase in a marker of lipid peroxidation, showing oxidative injuries. Although BV supplementation of LPD at a lower concentration (1 µM) did not improve the graft gas exchange, the grafts treated with BV (10 µM) showed a significant improvement of oxygenation and less inflammatory responses as well as reduced lipid peroxidation and apoptosis. Although the rapid activations of mitogen-activated protein kinases (MAPKs) were seen 30 min after reperfusion in the grafts stored in control LPD, BV treatment significantly reduced phosphorylated-MAPK protein expression. CONCLUSIONS: This study demonstrates that the exposure of the lung grafts to BV during cold storage can impart potent cytoprotective effects to lung cold ischaemia/reperfusion injury and significantly improve the lung graft function following extended cold preservation and transplantation by the mechanism of a reduction in oxidative injury and following inflammatory events.

Oral hydrogen water prevents chronic allograft nephropathy in rats.

Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation.

Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both.

BACKGROUND: Recent advances in novel medical gases, including hydrogen and carbon monoxide (CO), have demonstrated significant opportunities for therapeutic use. This study was designed to evaluate the effects of inhaled hydrogen or CO, or both, on cold ischemia/reperfusion (I/R) injury of the myocardium. METHODS: Syngeneic heterotopic heart transplantation was performed in rats after 6 or 18 hours of cold ischemia in Celsior solution. Survival, morphology, apoptosis and marker gene expression were assessed in the grafts after in vivo inhalation of hydrogen (1% to 3%), CO (50 to 250 ppm), both or neither. Both donors and recipients were treated for 1 hour before and 1 hour after reperfusion. RESULTS: After 6-hour cold ischemia, inhalation of hydrogen (>2%) or CO (250 ppm) alone attenuated myocardial injury. Prolonged cold ischemia for 18 hours resulted in severe myocardial injury, and treatment with hydrogen or CO alone failed to demonstrate significant protection. Dual treatment with hydrogen and CO significantly attenuated I/R graft injury, reducing the infarcted area and decreasing in serum troponin I and creatine phosphokinase (CPK). Hydrogen treatment alone significantly reduced malondialdehyde levels and serum high-mobility group box 1 protein levels as compared with air-treated controls. In contrast, CO only marginally prevented lipid peroxidation, but it suppressed I/R-induced mRNA upregulation for several pro-inflammatory mediators and reduced graft apoptosis. CONCLUSIONS: Combined therapy with hydrogen and CO demonstrated enhanced therapeutic efficacy via both anti-oxidant and anti-inflammatory mechanisms, and may be a clinically feasible approach for preventing cold I/R injury of the myocardium.