A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma.

The International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) has recently proposed a new lung adenocarcinoma classification. We investigated whether nuclear features can stratify prognostic subsets. Slides of 485 stage I lung adenocarcinoma patients were reviewed. We evaluated nuclear diameter, nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, prominence of nucleoli, intranuclear inclusions, mitotic count/10 high-power fields (HPFs) or 2.4 mm(2), and atypical mitoses. Tumors were classified into histologic subtypes according to the IASLC/ATS/ERS classification and grouped by architectural grade into low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic predominant), intermediate (papillary or acinar), and high (micropapillary or solid). Log-rank tests and Cox regression models evaluated the ability of clinicopathologic factors to predict recurrence-free probability. In univariate analyses, nuclear diameter (P=0.007), nuclear atypia (P=0.006), mitotic count (P<0.001), and atypical mitoses (P<0.001) were significant predictors of recurrence. The recurrence-free probability of patients with high mitotic count (≥5/10 HPF: n=175) was the lowest (5-year recurrence-free probability=73%), followed by intermediate (2-4/10 HPF: n=106, 80%), and low (0-1/10 HPF: n=204, 91%, P<0.001). Combined architectural/mitotic grading system stratified patient outcomes (P<0.001): low grade (low architectural grade with any mitotic count and intermediate architectural grade with low mitotic count: n=201, 5-year recurrence-free probability=92%), intermediate grade (intermediate architectural grade with intermediate-high mitotic counts: n=206, 78%), and high grade (high architectural grade with any mitotic count: n=78, 68%). The advantage of adding mitotic count to architectural grade is in stratifying patients with intermediate architectural grade into two prognostically distinct categories (P=0.001). After adjusting for clinicopathologic factors including sex, stage, pleural/lymphovascular invasion, and necrosis, mitotic count was not an independent predictor of recurrence (P=0.178). However, patients with the high architectural/mitotic grade remained at significantly increased risk of recurrence (high vs low: P=0.005) after adjusting for clinical factors. We proposed this combined architectural/mitotic grade for lung adenocarcinoma as a practical method that can be applied in routine practice.

Value of routine timed barium esophagram follow-up in achalasia after myotomy.

OBJECTIVES: The value of routine timed barium esophagram (TBE) in longitudinal follow-up of achalasia after Heller myotomy is unknown. We prospectively prescribed a yearly follow-up TBE. Purposes were to characterize esophageal emptying over time after myotomy, identify preoperative TBE measures associated with follow-up TBE, and characterize follow-up TBE over time in relationship to reintervention. METHODS: From March 1995 to April 2013, 635 patients underwent Heller myotomy for achalasia; 559 had at least 1 follow-up TBE. Temporal trends of 1335 follow-up TBEs in all nonreintervention and reintervention patients were assessed. Multivariable longitudinal analysis identified preoperative TBE measures associated with follow-up TBE. RESULTS: On average, TBE height and width at 1 and 5 minutes decreased approximately 50% and 60%, respectively, at first postoperative follow-up, and remained stable or slightly decreased for up to 5 years. Wider TBE width at 5 minutes was associated with greater follow-up TBE height and width at 1 minute. Of 118 patients undergoing reintervention, 64 (57%) had only 1 reintervention, with follow-up TBE returning to that of nonreintervention patients. Patients whose follow-up TBE remained abnormal underwent a further reintervention, some normalizing on subsequent TBE, and some not. CONCLUSIONS: Follow-up TBE is valuable postmyotomy, particularly if there is substantial esophageal dilatation preoperatively. Follow-up TBE reassures patients with stable or decreasing TBE measures, permitting decreased follow-up intensity. Reintervention should not be considered a myotomy failure, because a successful, single, nonsurgical reintervention often results in long-term successful palliation. More than 1 reintervention requires intensification of TBE follow-up, facilitating treatment planning.

Surgical Management of Sternoclavicular Joint Infections.

BACKGROUND: Infections of the sternoclavicular joint (SCJ) respond poorly to nonoperative management and typically require resection. We examined presenting characteristics and outcomes after surgical management of SCJ infections, reviewing a 20-year single-institution experience. METHODS: From January 1992 to December 2012, 40 patients (age, 57 ± 12 years; 70% male) underwent resection of an infected SCJ. Sternal infections after cardiac surgery were excluded. Clinical features, microbiology, recurrence, survival, and functional impairment were assessed. Infection was documented by the surgeon, and supported by tissue culture. Clinical presentation and treatment course were obtained by review of medical records. The functional assessment was determined by phone interviews using the validated QuickDASH outcome measure. Mortality data were gathered from the medical record. RESULTS: Pain was the presenting symptom in 93% of patients. Staphylococcal species were isolated in 73% of tissue specimens. Fifteen patients (37%) underwent primary closure and 25 patients (63%) underwent closure by secondary intention with application of negative-pressure wound therapy. There were four recurrences (10%), one after primary closure and three in the secondary intention group. No deaths occurred within 30 days of operation, and 5-year survival was 67%. Functional assessment using the QuickDASH outcome measure revealed minimal loss in upper extremity function after the procedure (preoperative score, 10 ± 3; postoperative score, 19 ± 6.8; n = 11). There was no difference in functional outcome comparing primary closure versus secondary intention (19 ± 4.4 versus 20 ± 8.2; p = 0.64). CONCLUSIONS: Septic arthritis of the SCJ is routinely managed surgically at many centers. We report that primary closure with a muscle flap can achieve similar outcomes to secondary intention in selected patients. Furthermore, patients experienced minimal functional impairment at long-term follow-up.

Lung transplantation for multifocal lung adenocarcinoma (multifocal lung carcinoma).

Lung transplantation is an acceptable treatment option in highly selected patients with lung limited AIS or MIA. Aside from the cancer diagnosis, ideal candidates should not possess any absolute or relative contraindications to lung transplantation as described by the ISHLT. Confirmation of lung-limited disease and AIS/MIA with lepidic histology and the absence of carcinoma metastatic to mediastinal lymph nodes will optimize outcomes. Those patients with multifocal minimally invasive lung ACA and respiratory insufficiency from severe bronchorrhea may enjoy the best palliation of their disease and have high enough LAS to facilitate transplantation. The role of targeted therapies for those patients with EGFR or ALK-activating mutations and might favorably AIS/MIA has yet to be determined and impact survival and augment (or supplant) lung transplantation for these patients.

Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma.

PURPOSE: In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biologic and clinical relevance. EXPERIMENTAL DESIGN: In a training and validation set of patients with early-stage (I-III) lung ADC (n = 1,209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models. RESULTS: MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS [HR = 1.78; 95% confidence interval (CI), 1.26-2.50; P < 0.01] and RFS (HR = 1.67; 95% CI, 1.21-2.27; P < 0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P = 0.001). CONCLUSIONS: MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.

High SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: supportive evidence to reclassify pleomorphic as nonepithelioid histology.

BACKGROUND: We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as nonepithelioid (biphasic/sarcomatoid) histology because of its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM. METHODS: Clinical data were collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0). RESULTS: The median overall survival of epithelioid tumors with high SUVmax (n = 12) was significantly shorter (7.1 months) than that of epithelioid tumors with low SUVmax (n = 54, 18.9 months, p < 0.001) and comparable to nonepithelioid tumors (n = 12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n = 9) had marginally higher SUVmax (mean ± SD: 10.6 ± 5.9) than epithelioid nonpleomorphic subtype (n = 57, 6.5 ± 3.2, p = 0.050), and were comparable to that of nonepithelioid tumors (n = 12, 9.1 ± 4.8). Among the epithelioid tumors with high SUVmax (n = 12), 50% (n = 6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low SUVmax (n = 54), 6% (n = 3) showed epithelioid pleomorphic subtypes (p = 0.001). A positive correlation between mitotic count and SUVmax was observed (r = 0.30, p = 0.010). CONCLUSIONS: Pleomorphic subtype of epithelioid MPM showed higher SUVmax than the epithelioid nonpleomorphic subtype and was similar to nonepithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as nonepithelioid.

Pre-clinical mouse models of primary and metastatic pleural cancers of the lung and breast and the use of bioluminescent imaging to monitor pleural tumor burden.

Malignant pleural disease (MPD) results in an estimated 150,000 cases of malignant pleural effusions (MPE) annually. The most common malignancies associated with MPD are primary malignant pleural mesothelioma (MPM) and metastatic lung cancer, breast cancer, and lymphoma. MPM is a rare, regionally aggressive malignancy whose incidence is increasing secondarily to the latency of disease progression. MPD is characteristic of advanced-stage pleural disease and portends a grave clinical prognosis with a median survival between 3 and 12 months. Preclinical investigations conducted in flank and intraperitoneal tumor models do not fully recapitulate the pleural tumor microenvironment, and the results are not directly translatable to the clinical setting. The protocol described herein provides a mouse model of MPM and MPD from nonhematogenous tumors, resulting in reproducible tumor location, tumor progression, animal survival, and histopathology. Pleural tumor growth in this model resembles the regionally aggressive clinical course and tumor microenvironment of human pleural cancers and provides an optimal animal model to investigate MPD biology and therapies.

Recovery and Biodistribution of Ex Vivo Expanded Human Erythroblasts Injected into NOD/SCID/IL2Rγ mice.

Ex vivo expanded erythroblasts (EBs) may serve as advanced transfusion products provided that lodgment occurs in the macrophage-niche of the marrow permitting maturation. EBs expanded from adult and cord blood expressed the receptors (CXCR4, VLA-4, and P-selectin ligand 1) necessary for interaction with macrophages. However, 4-days following transfusion to intact NOD/SCID/IL2Rγ(null) mice, CD235a(pos) EBs were observed inside CD235a(neg) splenic cells suggesting that they underwent phagocytosis. When splenectomized and intact NOD/SCID/IL2Rγ(null) mice were transfused using retrovirally labeled human EBs, human cells were visualized by bioluminescence imaging only in splenectomized animals. Four days after injection, human CD235a(pos) cells were detected in marrow and liver of splenectomized mice but only in spleen of controls. Human CD235a(pos) erythrocytes in blood remained low in all cases. These studies establish splenectomized NOD/SCID/IL2Rγ(null) mice as a suitable model for tracking and quantification of human EBs in vivo.

Prognostic immune markers in non-small cell lung cancer.

Tumor-associated immune responses have polarized effects in regulating tumor growth. Although a clear association has been shown between the tumor immune response and clinical outcome in colorectal and ovarian cancers, the role of immune markers for stratifying prognosis in non-small cell lung cancer (NSCLC) is less defined. Herein, we review the prognostic significance of published immune markers in the tumor microenvironment and peripheral blood of NSCLC patients. To identify prognostic immune genes, we reviewed all published gene-profiling studies in NSCLC and delineated the significance of immune genes by doing subanalysis on the microarray database of the NIH Director's Challenge study. This first comprehensive review of prognostic immune markers provides a foundation for further investigating immune responses in NSCLC.

Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters.

INTRODUCTION: Despite increasing use of tunneled pleural catheters (TPCs), their efficacy as a definitive procedure for achieving palliation or spontaneous pleurodesis (SP) in the management of malignant pleural effusion (MPE) remains unclear. In the largest TPC series to date, we evaluate the efficacy for palliation and review the rate and predictors of SP. METHODS: Retrospective review of 418 TPCs (355 patients) over 2 years (September 2007-September 2009) was performed. Palliation was deemed successful when the patient did not require any other subsequent effusion-directed drainage procedure. SP was defined as satisfying the following criteria: (a) TPC removal without need for further effusion-directed intervention during the patient's lifespan and (b) no evidence of effusion reaccumulation by clinical and radiographic evidence at 1-month postremoval follow-up. RESULTS: After TPC placement, no subsequent effusion-directed procedure was required for 380 of 418 (91%). SP was achieved after only 26% of TPCs (110 of 418), in which the median time to catheter removal was 44 days. Neither demographics nor primary tumor type predicted SP. In patients selected for TPC placement in the operating room, SP occurred in 36% (39 of 107), with 45% in loculated MPE (13 of 29, p = 0.014). Complications occurred after 20 TPCs (4.8%), with none occurring after bedside placement. CONCLUSION: TPC placement is safe and provides durable palliation, most often obviating the need for subsequent procedures in MPE patients. TPC, however, remains suboptimal at achieving pleurodesis.

Expression signature developed from a complex series of mouse models accurately predicts human breast cancer survival.

PURPOSE: The capability of microarray platform to interrogate thousands of genes has led to the development of molecular diagnostic tools for cancer patients. Although large-scale comparative studies on clinical samples are often limited by the access of human tissues, expression profiling databases of various human cancer types are publicly available for researchers. Given that mouse models have been instrumental to our current understanding of cancer progression, we aimed to test the hypothesis that novel gene signatures possessing predictability in clinical outcome can be derived by coupling genomic analyses in mouse models of cancer with publicly available human cancer data sets. EXPERIMENTAL DESIGN: We established a complex series of syngeneic metastatic animal models using a murine breast cancer cell line. Tumor RNA was hybridized on Affymetrix MouseGenome-430A2.0 GeneChips. With the use of Venn logic, gene signatures that represent metastatic competency were derived and tested against publicly available human breast and lung cancer data sets. RESULTS: Survival analyses showed that the spontaneous metastasis gene signature was significantly associated with metastasis-free and overall survival (P < 0.0005). Consequently, the six-gene model was determined and showed statistical predictability in predicting survival in breast cancer patients. In addition, the model was able to stratify poor from good prognosis for lung cancer patients in most data sets analyzed. CONCLUSIONS: Together, our data support that novel gene signature derived from mouse models of cancer can be used for predicting human cancer outcome. Our approaches set precedence that similar strategies may be used to decipher novel gene signatures for clinical utility.

Therapeutic sentinel lymph node imaging.

Improving existing means of sentinel lymph node identification in non-small cell lung cancer will allow for molecular detection of occult micrometastases that may cause recurrence in early stage non-small cell lung cancer. Furthermore, targeted application of chemical and biological cytotoxic agents can potentially improve outcomes in patients with lymph node (LN) metastases. "Therapeutic Sentinel Lymph Node Imaging" incorporates these modalities into a single agent thereby identifying which LNs harbor tumor cells and simultaneously eradicating metastatic disease. In this review, we summarize the novel preclinical agents for identification and treatment of tumor bearing LNs and discuss their potential for clinical translation.

Launching a novel preclinical infrastructure: comparative oncology trials consortium directed therapeutic targeting of TNFalpha to cancer vasculature.

BACKGROUND: Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. METHODOLOGY/PRINCIPAL FINDINGS: Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to alphaV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5x10(12) transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). CONCLUSIONS/SIGNIFICANCE: The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies.