Development and External Validation of the Munich Sorafenib Evaluation Score for Hepatocellular Carcinoma.

INTRODUCTION: In recent years, increasing options for systemic HCC treatment have become available. The development of therapy-specific prognostic scores has been encouraged. Tailoring therapy to individual patients requires prognostic scores for treatment success in addition to the Barcelona-Clinic-Liver-Cancer (BCLC) classification. We have developed and validated a prognostic score for patients treated with sorafenib. METHODS: Prognostic factors identified in a multivariate analysis of 108 sorafenib patients were used to construct the Munich Sorafenib Evaluation (M-SE) score. M-SE and 9 established HCC prognostic systems were ranked according to concordance-index and AIC. External M-SE validation was performed in an independent HCC sorafenib cohort (n = 101) derived from the prospective multicenter randomized controlled SORAMIC trial. RESULTS: Ascites (p < 0.0001; HR 2.923), tumor burden ≥50% of the liver (p = 0.0033; HR 1.946), and GOT (p < 0.0001; HR 1.716) were identified as independent prognostic parameters. All three M-SE stages were characterized by significantly different survival times (p < 0.0001). M-SE stage-A patients had a median OS of 18.7 months (95% CI: 15.6-21.8); patients in stage B and C showed a significantly shorter survival of 5.7 (2.7-8.7) and 2.0 months (1.6-2.4), respectively. M-SE (c-index 0.70; AIC 621) outperformed all other prognostic systems. External validation in a prospective cohort confirmed its superior prognostic performance. CONCLUSION: The M-SE score allows classification of sorafenib patients in three distinct prognostic stages. Provided that M-SE successfully passes prospective validation, it can help to predict the outcome of patients evaluated for sorafenib treatment.

Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer.

The efficacy of cancer immunotherapy may be improved by increasing the number of circulating tumor-reactive T cells. The bone marrow is a priming site and reservoir for such T cells. The characteristics of bone marrow-derived tumor-reactive T cells are poorly understood in patients with non-small-cell lung cancer (NSCLC). To compare the responsiveness of tumor antigen-reactive T cells from the bone marrow with matched peripheral blood samples in patients with resectable NSCLC, we used flow cytometry, cytokine capture assays and enzyme-linked immunospot assays to examine the responsiveness of T cells to 14 tumor antigens in matched bone marrow and peripheral blood samples from patients with resectable NSCLC or benign tumors and tumor-free patients. T cells with reactivity to tumor antigens were detected in the bone marrow of 20 of 39 (51%) NSCLC patients. The panel of tumor antigens recognized by bone marrow-derived T cells was distinct from that recognized by peripheral blood-derived T cells in NSCLC patients. Unlike for peripheral blood T cells, the presence of tumor-reactive T cells in the bone marrow did not correlate with recurrence-free survival after curative intent resection of NSCLC. T cells with reactivity to tumor antigens are common in the bone marrow of patients with NSCLC. Tumor-reactive T cells of the bone marrow have the potential to significantly broaden the total repertoire of tumor-reactive T cells in the body. To clarify the role of tumor-reactive T cells of the bone marrow in T cell-based immunotherapy approaches, clinical studies are needed (ClinicalTrials.gov: NCT02515760).

A new bronchoscopic catheter for the transbronchial ablation of pulmonary nodules.

OBJECTIVES: With the objective of simultaneous bronchoscopic biopsy and ablation of malignant solitary pulmonary nodules, we have developed a flexible monopolar radiofrequency (RF) catheter that can be deployed through the working channel of most bronchoscopes. MATERIALS AND METHODS: Fresh tumor specimens were heated in a water bath to 37 °C, and the RF catheter was inserted into the tumors within the specimen. Temperature sensors were positioned 3 mm, 5 mm and 7 mm from the electrode to measure the temperature of the surrounding tissue every 1 s. The ablation was conducted by applying RF energy for 8 min. The ablated specimens were evaluated by cutting the tissue samples along the top of the device and measuring the ablation zones. RESULTS: Five ablations were performed in 3 specimens. All of the ablation zones had a major axis length (along the electrode axis) between 18.9 mm and 22.8 mm and a minor axis length (perpendicular to the major axis) between 13.3 mm and 18.0 mm. The temperature data showed that all of the temperature sensors detected 60 °C or higher. These results demonstrate that the RF catheter was capable of generating ablation zones that were locally contained in ex vivo human cancerous lung specimens and that incorporated the tumor tissues. CONCLUSION: We present the results of a benchtop study demonstrating the local control of ablation achieved using the RF device. This study suggests that the ex vivo ablation of lung malignancy with a new bronchoscopic RF catheter is feasible and that in vivo tumor ablation with this method in humans merits further study.

Sublobar Resection, Radiofrequency Ablation or Radiotherapy in Stage I Non-Small Cell Lung Cancer.

BACKGROUND: The best therapy for patients with stage I non-small cell lung cancer (NSCLC) who are medically unfit for lobectomy or prefer not to undergo surgery has not yet been demonstrated. OBJECTIVES: We analyzed data from our prospective database to evaluate the recurrence and survival rates and assess the extent to which the type of treatment explains outcome differences. METHODS: This study included 116 patients with histologically proven clinical stage I NSCLC who were treated with sublobar resection (SLR; n = 42), radiofrequency ablation (RFA; n = 25) or radiotherapy (RT; n = 49) between 2009 and 2013. The primary end point was the time to primary tumor recurrence (PR). Kaplan-Meier curves and Cox regression were used to compare the recurrence patterns and survivals after adjustments for potential confounders. RESULTS: The SLR patients were younger and exhibited better performance status. The RT patients had larger tumors. After adjusting for age and tumor size, there were differences between the different treatments in terms of the PR rate, but no differences were observed in overall (OS) or disease-free survival. The hazard ratio for PR comparing SLR versus RT adjusted for age and tumor size was 2.73 (95% confidence interval, CI, 0.72-10.27) and that for SLR versus RFA was 7.57 (95% CI 1.94-29.47). CONCLUSIONS: Our study suggests that SLR was associated with a higher primary tumor control rate compared to RFA or RT, although the OSs were not different. These results should be confirmed in prospective trials.

Development and validation of a risk score for predicting death after pneumonectomy.

Pneumonectomy is associated with significant postoperative mortality. This study was undertaken to develop and validate a risk model of mortality following pneumonectomy. We reviewed our prospective database and identified 774 pneumonectomies from a total of 7792 consecutive anatomical lung resections in the years 2003 to 2010 (rate of pneumonectomy: 9.9%). Based on data from 542 pneumonectomies between 2003 and 2007 (i.e., the "discovery set"), a penalized multivariable logistic regression analysis was performed to identify preoperative risk factors. A risk model was developed and validated in an independent data set of 232 pneumonectomies that were performed between 2008 and 2010 (i.e., the "validation set"). Of the 542 patients in the discovery set (DS), 35 patients (6.5%) died after pneumonectomy during the same admission. We developed a risk prediction model for in-hospital mortality following pneumonectomy; that model included age, current alcohol use, coronary artery disease, preoperative leukocyte count and palliative indication as possible risk factors. The risk model was subsequently successfully validated in an independent data set (n = 232) in which 18 patients (7.8%) died following pneumonectomy. For the validation set, the sensitivity of the model was 53.3% (DS: 54.3%), the specificity was 88.0% (DS: 87.4%), the positive predictive value was 26.7% (DS: 22.9%) and the negative predictive value was 95.8% (DS: 96.5%). The Brier score was 0.062 (DS: 0.054). The prediction model is statistically valid and clinically relevant.

Extended resection of a plasmocytoma of bone and an amyloidoma of the chest wall.

Solitary plasmocytoma of bone is a rare condition of plasma cell neoplasia that presents as a single lesion. Amyloidoma of the chest wall is an uncommon presentation of solitary tissue amyloid deposition in the absence of systemic light-chain amyloidosis. This report describes a patient with both uncommon conditions. The tumor originated from the spine and invaded the right lung. In this exceedingly rare case, radiotherapy and a two-step resection of the right lower lobe, full-thickness chest wall, diaphragm, and vertebral body of T9 provided local control of the tumor. Spondylodesis of T7 to T11 provided spine stability.

Metastatic adrenocortical carcinoma: results of 56 pulmonary metastasectomies in 24 patients.

BACKGROUND: Surgical resection is an important form of treatment for metastatic disease in patients with adrenocortical carcinoma (ACC). However, data about the results of this treatment are sparse. We reviewed our experience with the resection of pulmonary lesions metastatic from ACC as a means of evaluating such results. METHODS: A retrospective review of the database at a German national registry for ACC identified 24 patients (9 men and 15 women; median age, 41 years) who underwent pulmonary metastasectomy for primary ACC during the study period of 1989 through 2009. Only patients who met the criteria for potentially curative surgery, defined as the presumed feasibility of resecting all visualized tumorous lesions, were included. RESULTS: No perioperative deaths occurred in 56 pulmonary metastasectomies done on the patients in the study. The overall cumulative rate of 5-year survival, calculated from the time of first pulmonary surgery, was 24.5%, and the median survival was 50.2 months. Age younger than 41 years at the time of first pulmonary metastasectomy and repeated pulmonary metastasectomy were associated with longer survival in a univariate analysis. In accord with this, we observed a median survival of 31.9 months in patients 41 years of age or older as compared with a median survival of 59.3 months in younger patients (p = 0.004). In patients with repeated pulmonary metastasectomies, median survival after the first resection was significantly longer, at 59.3 months than in patients who had only one pulmonary resection, whose median survival was 31.9 months (p = 0.001). CONCLUSIONS: We conclude that surgical resection of pulmonary metastases for ACC should be regarded as safe, with the potential for producing long-term survival in a highly selected group of patients. Younger patients may benefit more than older ones from such resection, and the recurrence of pulmonary metastases should not preclude repeated surgical resections of these lesions.

Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ.

OBJECTIVE: To examine whether tumor-selective infiltration, activation, and cytotoxic activity of tumor infiltrating T lymphocytes (TIL) can be demonstrated in situ in colorectal cancer samples. SUMMARY BACKGROUND DATA: Recent studies indicated a correlation between the presence of TIL and an improved prognosis in colorectal cancer. However, tumor-selective activation and cytotoxic activity of CD8 TIL in situ in colorectal cancer patients have not yet been examined. METHODS: Tumor samples from 49 patients and corresponding normal mucosa samples from 23 patients with colorectal cancer (UICC stages II-IV) were examined for TIL. Two-color fluorescence immunohistochemistry and multicolor flowcytometric (FACS) analysis were used for quantification of CD8 T cells and measurement of their activation status (CD69-expression) and cytotoxic activity (CD107a-expression) in situ. Presence of tumor antigen-reactive T cells in tumor, blood, and bone marrow was evaluated by IFN-gamma Elispot analysis. RESULTS: While absolute numbers of CD8 T cells were similar, CD4 T helper cells were significantly increased in tumor tissue compared with normal mucosa. There was a significantly higher proportion of activated and cytotoxically active CD8 TIL in colorectal cancer compared with normal mucosa. Increased activation, cytotoxic activity, and functional reactivity of TIL were correlated with the presence of functional tumor antigen-reactive T cells in the blood and bone marrow. The proportion of activated TIL decreased significantly with higher tumor stage. CONCLUSIONS: Tumor-selective activation and cytotoxic activity of CD8 TIL and tumor-selective migration of CD4 T helper cells were demonstrated in colorectal cancer for the first time. Our data support the immunogenicity of colorectal cancer and suggest clinical significance of tumor-specific immune responses.