Preoperative respiratory intervention eliminated the operation cancelations of lobectomy surgery.

In Nagasaki University Hospital, the patients undergoing surgery with abnormal respiratory function have been automatically referred to specialized clinic by Medical Support Center (MSC) since July 2016 to reduce surgery cancellations due to insufficient preoperative evaluation. Whether the MSC system decreased post-hospital surgery cancellation, variance rate, or length of hospital stays in patients received "lobectomy" were retrospectively compared between Period A (n = 264, before MSC introduction) and Period B (n = 264, after MSC introduction). Four patients' operations were cancelled after hospitalization in Period A, while 0 patients in Period B (p < 0.05). The length of hospital stay, operation time, anesthesia time, and postoperative extubation oxygen administration time were all shorten in Period B significantly. "Period B", "operation time", and "postoperation oxygenation time" were independent factors for "hospital days", but chronic obstructive pulmonary disease or age were not. The preoperative intervention eliminated the operation cancellation. Preoperative MSC interventions may have contributed to the reduction in hospital days even for the patients with pulmonary dysfunction.

[Airway Complications after Lung Transplantation].

Lung transplantation is the only option for patients with end-stage pulmonary diseases. During recent years, satisfactory results in terms of long-term survival and quality of life have been achieved with improvements in perioperative management, surgical technique, and immunosuppression. Airway complications after lung transplantation are associated with significant morbidity and mortality. Common airway complications after lung transplantation include anastomotic granulation, airway stenosis, bronchomalacia, fistulas, and anastomotic infection. These airway complications often result in repeated hospitalisations and interventions. If bronchoscopic interventions are not effective, other alternatives like surgical intervention or re-transplantation become necessary. While numerous strategies for airway complications have been proven effective, there are still some issues that to be solved. Further research is necessary to reduce mortality and improve quality of life of these patients.

A randomized phase II study of S-1 monotherapy versus cisplatin with vinorelbine for completely resected stage II/IIIA non-small cell lung cancer: rationale and study protocol design for the LOGIK1702 study.

BACKGROUND: The current standard postoperative treatment for stage II-IIIA non-small cell lung cancer (NSCLC) is a regimen of platinum doublet adjuvant chemotherapy. These regimens, which are the same as for solid NSCLC tumors, often cause severe adverse reactions in the treated patients. Therefore, an effective treatment regimen with fewer side effects is needed. METHODS/DESIGN: The purpose of this study is to evaluate the effectiveness and safety of S-1 monotherapy (80 mg/m2 orally administrated twice daily, at day 1-14, 16 cycles) and cisplatin with vinorelbine combination therapy (cisplatin 80 mg/m2 at day 1,vinorelbine 25 mg/m2 at day 1, 8, 4 cycles) in patients with II/IIIA stage non-small-cell lung cancer who underwent a total resection. In addition, we will also evaluate the level of treatment side effects by assessing quality of life (QOL), work productivity and activity performance. The primary endpoint is a 2-year relapse free survival (RFS) and the second primary endpoints are 2-year overall survival (OS), rate of treatment completion, safety, work productivity and activity, and quality of adjusted life years (QALY). At the same time, we aim to obtain precise information required to perform future phase 3 randomized controlled trials. The study is designed to estimate the primary endpoint with accuracy determined as the width of its 95% confidence interval to be less than 20%. Recruitment started in May 2017 and is ongoing. DISCUSSION: This study has been conceived to establish a superior regimen for completely resected NSCLC based on efficacy, safety and QOL. TRIAL REGISTRATION: Registry number: UMIN000027435 . Registered May 22, 2017.

[Resection of Lung Cancer with Chest Wall Invasion Using Posterior Paramedian Incision].

We report a case of lung cancer with chest wall invasion resected with the posterior paramedian incision. A man in his 60s exhibited hemosputum and cough. Chest X-ray revealed a large mass below the right hilum. A 6.3 cm soft tissue mass with central cavity invading to the lower posterior chest wall was found on chest computed tomography( CT). The tumor was diagnosed as squamous cell carcinoma by transcutaneous lung biopsy( TCLB). Thoracoscopic hilar dissection of the right lower lobe with dissection of the mediastinal lymph nodes were preceded to the en-bloc resection of the invaded chest wall with less invasive manner by the posterior paramedian incision.

Ratio of C-reactive protein to albumin is a prognostic factor for operable non-small-cell lung cancer in elderly patients.

PURPOSE: The aim of this retrospective study was to evaluate inflammation-based scoring as a prognostic factor for operable non-small-cell lung cancer (NSCLC) in elderly patients. METHODS: We collected preoperative data from 108 patients aged above 80 years with NSCLC. Inflammation-based scoring systems, including the C-reactive protein to albumin ratio (CAR) and the Glasgow prognostic score (GPS), as well as other clinicopathological factors, were evaluated as potential prognostic factors. RESULTS: The median patient age was 82 (range 80-93) years and the 5-year overall and disease-specific survival rates were 49.7 and 73.9%, respectively. The cut-off value for CAR was calculated using a receiver operator characteristics analysis and patients were dichotomized accordingly. Patients with a low CAR had significantly higher overall survival than those with a high CAR (<0.028; 65.2% vs. ≥0.028; 31.0%, respectively; p < 0.01). In univariate analysis, female gender, a low Charlson comorbidity index of 0 or 1 and a low CAR were significantly identified in overall survival. On multivariate analysis, a low CAR (p = 0.03, hazard ratio: 2.13, 95% confidence interval 1.074-4.295) was identified as a significant prognostic factor. CONCLUSIONS: The preoperative CAR is a useful predictor of overall survival and could be a simple prognostic tool to help identify resectable NSCLC in elderly patients.

[Granuloma by Foreign Body Reaction to the Stapler Used for Partial Resection of the Lung].

A 66-year-old woman underwent right lower lobectomy and partial resection of the middle lobe for Stage I A double lung cancer. Five years after the operation, a routine computed tomography (CT) scan showed a mass on the staple line at the middle lobe. The mass was enlarged on CT scan after 6 months. A definitive diagnosis could not be made by bronchoscopic examination and fluoro-2-deoxy-glucose(FDG)/positron emission tomography( PET)-CT showed FDG uptake in the mass( early phase:SUVmax=3.24, late phase:SUVmax=4.31). Local recurrence of lung cancer was not completely denied, and right middle lobectomy was performed. Histopathologically, the resected specimen revealed granuloma with foreign body reaction. We should keep in mind the possibility of granuloma as differential diagnosis of lung cancer when using stapler.

Management of unexpected intraoperative bleeding during thoracoscopic pulmonary resection: a single institutional experience.

PURPOSE: Unexpected intraoperative bleeding during thoracoscopic surgery, necessitating emergency conversion to thoracotomy, is gradually being reported. We reviewed our experience of encountering unexpected bleeding during thoracoscopic surgery. METHODS: We defined "unexpected intraoperative bleeding" as the need for hemostatic procedures with angiorrhaphy, with or without a sealant. The location, cause, and management of injured vessels, and perioperative outcomes were investigated and compared with those for patients without injured vessels. RESULTS: Between 2007 and 2014, a total of 241 thoracoscopic anatomical pulmonary resections were performed at our hospital. Twenty (8.3 %) of these patients required hemostatic procedures with angiorrhaphy, with or without a sealant. The main injured vessels were the pulmonary artery (n = 13) and vein (n = 3) and the main causes of injury were related to technical issues with energy devices and staplers. There were no morbidities related to intraoperative bleeding. The operation time and blood loss were significantly greater in the patients with vessel injury than in those without vessel injury, but perioperative morbidities and the duration of chest tube insertion (4.5 vs. 3.5 days, average, p = 0.20) and postoperative hospital stay (12.7 vs. 11.0 days, average, p = 0.08) were not significantly different. CONCLUSIONS: The frequency of unexpected bleeding was relatively high in this series, but its management and outcomes were satisfactory in terms of safety.

[Anastomotic Airway Complications after Lung Transplantation].

Anastomotic airway complications still remain an important issue after lung transplantation. Most of the complications are stenosis and anastomotic leakage. Stent insertion is one option for the stenosis. We review the anastomotic airway complications and report our recent experience of stent insertion using 3-dimensional printed airway model.

Post-thoracotomy pain syndrome in the era of minimally invasive thoracic surgery.

Post-thoracotomy pain syndrome (PTPS) is defined as pain around the wound that persists for more than 2 months after surgery. Persistent pain not only increases the use of analgesics and their side effects but also causes many social problems, such as decreased activities of daily living, decreased quality of life, and increased medical costs. In particular, thoracic surgery is associated with a higher frequency and severity of chronic pain than is surgery for other diseases. The basic principles of postoperative pain treatment, not limited to thoracic surgery, are multimodal analgesic methods (using combinations of several drugs to minimize opioid use) and around-the-clock treatment (administering analgesics at a fixed time and in sufficient doses). Thoracic surgeons must always be aware of the following three points: acute severe postoperative pain is a major risk factor for chronic pain; neuropathic pain due to intercostal nerve injury is a major cause of postoperative pain after thoracic surgery, and its presence must not be overlooked from the acute stage; and analgesics must be administered in sufficient quantities according to dosage and volume. The frequency of PTPS has decreased compared with that in the standard thoracotomy era because of the development of analgesia and the widespread use of minimally invasive procedures such as thoracoscopic surgery and robot-assisted surgery. However, no consistently effective prevention or treatment strategies for PTPS have yet been established. In this review, we focus on PTPS in the era of minimally invasive surgery and discuss the role of thoracic surgeons in its management.

Curved Axillary Incision with Video-Assisted Thoracoscopic Surgery: An Alternative Approach for Teenage Female with Large Apical Chest Wall Tumor.

Primary chest wall tumors are rare, their common clinical features are not well known, and surgical resection remains the main treatment. Apical chest wall tumors require large skin incisions and dissection of the chest wall muscles, making it difficult to maintain cosmetic appearance, respiratory function, and support of the upper extremity. There are few treatment options and no studies have reported on thoracotomy that spares muscles and preserves cosmetic superiority. However, in benign chest wall tumors in young patients, it is necessary to consider radicality, cosmetic superiority, and muscle sparing. We used a combined axillary incision and thoracoscopic approach to treat a massive myxoid neurofibroma at the apical chest wall in a 14-year-old female and were able to preserve the chest wall, upper limb function, and cosmetic aspects. This report provides a detailed description of the combined axillary incision and thoracoscopic approach for apical chest wall tumors.

Designer umbilical cord-stem cells induce alveolar wall regeneration in pulmonary disease models.

Background: Researchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion. Objective: To develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment. Methods: dUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed. Results: Increased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin ß1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs. Conclusion: We developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.

Does the human leukocyte antigen's relatively homogeneous genetic background relate to better lung transplantation outcomes in Japan?

The outcomes of lung transplantation in Japan are better than in other countries; however, the reasons for this are unclear. While the genetic background of the Japanese may be relatively homogeneous compared with those of other countries, whether this genetic similarity is related to better lung transplantation outcomes is an interesting question. We reviewed the literature to define the relationship between genetic similarity and better lung transplantation outcomes. However, it is still difficult to directly describe the relationship between genetic background and lung transplantation outcomes. As another approach, racial match or mismatch lung transplantation helps investigate whether genetic background similarity contributes to better outcomes of lung transplantation. Some reports have evaluated the impact of donor/recipient race-matching, which does not sufficiently influence patient outcomes to factor into organ transplant offers. Matching is not beneficial for African American lung transplant recipients. This may indicate that other factors influence the outcomes of these transplants. However, to discuss racial mismatch transplantation, racial disparities in organ transplantation need to be understood because the outcomes of organ transplantation differ between recipients of different races regardless of mismatched or matched organ transplantation. This makes it difficult to understand the outcome of a racially matched or mismatched lung transplantation. Meanwhile, in cadaveric liver and kidney transplantations, there is no difference in the outcomes in Japan and in other countries. In conclusion, it remains difficult to determine whether similarity in genetic backgrounds is related to better lung transplantation outcomes in Japan.

Spontaneous pleural aspergillosis in an immunocompetent young adult treated with minimally invasive surgery.

Spontaneous cases of pleural aspergillosis in healthy adults are rare, and the optimal therapeutic approach has not been established. Here we report a rare case of spontaneous pleural aspergillosis in an otherwise healthy young adult. Two-stage surgery with decortication and cavernostomy, followed by systemic antifungal therapy, finally resulted in a successful resolution of his empyema without any serious complications. In young patients with good pulmonary compliance, less invasive procedures, such as thoracoscopic decortication and/or carvernotomy, is a potential treatment option.

A novel ex vivo lung cancer model based on bioengineered rat lungs.

Introduction: Two-dimensional cell cultures have contributed substantially to lung cancer research, but 3D cultures are gaining attention as a new, more efficient, and effective research model. A model reproducing the 3D characteristics and tumor microenvironment of the lungs in vivo, including the co-existence of healthy alveolar cells with lung cancer cells, is ideal. Here, we describe the creation of a successful ex vivo lung cancer model based on bioengineered lungs formed by decellularization and recellularization. Methods: Human cancer cells were directly implanted into a bioengineered rat lung, which was created with a decellularized rat lung scaffold reseeded with epithelial cells, endothelial cells and adipose-derived stem cells. Four human lung cancer cell lines (A549, PC-9, H1299, and PC-6) were applied to demonstrate forming cancer nodules on recellularized lungs and histopathological assessment were made among these models. MUC-1 expression analysis, RNA-seq analysis and drug response test were performed to demonstrate the superiority of this cancer model. Results: The morphology and MUC-1 expression of the model were like those of lung cancer in vivo. RNA sequencing revealed an elevated expression of genes related to epithelial-mesenchymal transition, hypoxia, and TNF-α signaling via NF-κB; but suppression of cell cycle-related genes including E2F. Drug response assays showed that gefitinib suppressed PC-9 cell proliferation equally well in the 3D lung cancer model as in 2D culture dishes, albeit over a smaller volume of cells, suggesting that fluctuations in gefitinib resistance genes such as JUN may affect drug sensitivity. Conclusions: A novel ex vivo lung cancer model was closely reproduced the 3D structure and microenvironment of the actual lungs, highlighting its possible use as a platform for lung cancer research and pathophysiological studies.

Adipose-Derived Mesenchymal Stem Cells Attenuate Immune Reactions Against Pig Decellularized Bronchi Engrafted into Rat Tracheal Defects.

Decellularized scaffolds are promising biomaterials for tissue and organ reconstruction; however, strategies to effectively suppress the host immune responses toward these implants, particularly those without chemical crosslinking, remain warranted. Administration of mesenchymal stem cells is effective against immune-mediated inflammatory disorders. Herein, we investigated the effect of isogeneic abdominal adipose-derived mesenchymal stem/stromal cells (ADMSCs) on xenogeneic biomaterial-induced immunoreactions. Peripheral bronchi from pigs, decellularized using a detergent enzymatic method, were engrafted onto tracheal defects of Brown Norway (BN) rats. BN rats were implanted with native pig bronchi (Xenograft group), decellularized pig bronchi (Decellularized Xenograft), or Decellularized Xenograft and ADMSCs (Decellularized Xenograft+ADMSC group). In the latter group, ADMSCs were injected intravenously immediately post implantation. Harvested graft implants were assessed histologically and immunohistochemically. We found that acute rejections were milder in the Decellularized Xenograft and Decellularized Xenograft+ADMSC groups than in the Xenograft group. Mild inflammatory cell infiltration and reduced collagen deposition were observed in the Decellularized Xenograft+ADMSC group. Additionally, ADMSC administration decreased CD8+ lymphocyte counts but increased CD163+ cell counts. In the Decellularized Xenograft+ADMSC group, serum levels of vascular endothelial growth factor and IL-10 were elevated and tissue deposition of IgM and IgG was low. The significant immunosuppressive effects of ADMSCs illustrate their potential use as immunosuppressive agents for xenogeneic biomaterial-based implants.

Timing of Mesenchymal Stromal Cell Therapy Defines its Immunosuppressive Effects in a Rat Lung Transplantation Model.

Cell therapy using mesenchymal stromal cells (MSCs) is being studied for its immunosuppressive effects. In organ transplantation, the amount of MSCs that accumulate in transplanted organs and other organs may differ depending on administration timing, which may impact their immunosuppressive effects. In vitro, adipose-derived mesenchymal stem cells (ADMSCs) suppress lymphocyte activation under cell-to-cell contact conditions. However, in vivo, it is controversial whether ADMSCs are more effective in accumulating in transplanted organs or in secondary lymphoid organs. Herein, we aimed to investigate whether the timing of ADMSC administration affects its immunosuppression ability in a rat lung transplantation model. In the transplantation study, rats were intramuscularly administered half the usual dose of tacrolimus (0.5 mg/kg) every 24 h after lung transplantation. ADMSCs (1 × 106) were administered via the jugular vein before (PreTx) or after (PostTx) transplantation. Cell tracking using quantum dots was performed. ADMSCs accumulated predominantly in the lung and liver; fewer ADMSCs were distributed in the grafted lung in the PreTx group than in the PostTx group. The rejection rate was remarkably low in the ADMSC-administered groups, particularly in the PostTx group. Serum tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin (IL)-6 levels showed a greater tendency to decrease in the PreTx group than in the PostTx group. The proportion of regulatory T cells in the grafted lung 10 days after transplantation was higher in the PostTx group than in the PreTx group. PostTx administration suppresses rejection better than PreTx administration, possibly due to regulatory T cell induction by ADMSCs accumulated in the transplanted lungs, suggesting a mechanism different from that in heart or kidney transplantation that PreTx administration is more effective than PostTx administration. These results could help establish cell therapy using MSCs in lung transplantation.

[A review of cases of surgery for acute empyema].

We retrospectively reviewed cases of acute empyema treated surgically in our hospital from April 2005 to April 2010. Patients comprised 10 men and 4 women, with a mean age of 62.5 years( range, 23~ 80 years). One case required open thoracotomy and decortication, and was in the organized phase at the time of operation( duration of symptoms before surgery, 44 days). The remaining 13 cases were in the fibropurulent phase at the time of operation and underwent video-assisted thoracoscopic surgery (VATS). In 6 of these 13 remaining cases, we performed mini-thoracotomy combined with the thoracoscopic operation due to the presence of severe intrathoracic adhesions. Median durations of postoperative drainage and postoperative stay were 5 days( range, 2~7 days) and 13.5 days( range, 6~17 days), respectively. Postoperative complications of subcutaneous abscess, drug-induced hepatitis, pseudomembranous enterocolitis and reexpansion pulmonary edema were observed in 1 case each, but all patients survived to discharge without perioperative deaths. VATS is a safe and effective method for the management of acute empyema, and is favorable to perform in the fibropurulent phase. Appropriate combination with mini-thoracotomy was useful in accomplishing surgery in cases with dense adhesion.

Successful pulmonary artery stenting for occlusion at a constructed pericardial conduit after right upper double sleeve lobectomy.

The patient was a 53-year-old man. His chief complaint was a cough and dyspnea on exertion. Computed tomography (CT) showed a 3-cm-diameter tumor in the right upper lobe with invasion from hilar lymph nodes to the superior vena cava, right main bronchus, and pulmonary artery. After being diagnosed with non-small cell lung cancer, the patient underwent preoperative induction radiochemotherapy. At surgery, right upper double sleeve lobe lobectomy was performed. The right main pulmonary artery was reconstructed using a pericardial conduit. CT 1 week after surgery showed impaired blood flow in the right pulmonary artery. A metal vascular stent was inserted into the narrow part of the constructed pulmonary artery in the hybrid operating room because thrombectomy was unsuccessful. After surgery, contrast CT showed that blood flow was maintained. The patient is currently well without any recurrence 3 years after surgery.

Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation.

BACKGROUND: Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. METHODS: Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. RESULTS: Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. CONCLUSIONS: Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.

Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models.

Malignant pleural mesothelioma (MPM) is a highly malignant disease that develops after asbestos exposure. Although the number of MPM cases is predicted to increase, no effective standard therapies have been established. The novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) enhances the effects of γ-radiation in human lung and prostate cancer cell lines and in animal models. In this study, we explored the radiosensitizing effect of SQAP and its mechanisms in MPM. The human MPM cell lines MSTO-211H and MESO-4 were implanted subcutaneously into the backs and thoracic cavities of immunodeficient KSN/Slc mice, then 2 mg/kg SQAP was intravenously administered with or without irradiation with a total body dose of 8 Gy. In both the orthotopic and ectopic xenograft murine models, the combination of irradiation plus SQAP delayed the implanted human MSTO-211H tumor growth. The analysis of the changes in the relative tumor volume of the MSTO-211H indicated a statistically significant difference after 8 Gy total body combined with 2 mg/kg SQAP, compared to both the untreated control (P = 0.0127) and the radiation treatment alone (P = 0.0171). After the treatment in each case, immunostaining of the harvested tumors revealed decreased cell proliferation, increased apoptosis and normalization of tumor blood vessels in the SQAP- and irradiation-treated group. Furthermore, hypoxia-inducible factor (HIF) 1 mRNA and protein expression were decreased, indicating reoxygenation in this group. In conclusion, SQAP improved hypoxic conditions in tumor tissue and may elicit a radiosensitizing effect in malignant mesothelioma models.