CT texture analysis can help differentiate between malignant and benign lymph nodes in the mediastinum in patients suspected for lung cancer.

BACKGROUND: In patients with non-small-cell lung carcinoma NSCLC the lymph node staging in the mediastinum is important due to impact on management and prognosis. Computed tomography texture analysis (CTTA) is a postprocessing technique that can evaluate the heterogeneity of marked regions in images. PURPOSE: To evaluate if CTTA can differentiate between malignant and benign lymph nodes in a cohort of patients with suspected lung cancer. MATERIAL AND METHODS: With tissue sampling as reference standard, 46 lymph nodes from 29 patients were analyzed using CTTA. For each lymph node, CTTA was performed using a research software "TexRAD" by drawing a region of interest (ROI) on all available axial contrast-enhanced computed tomography (CT) slices covering the entire volume of the lymph node. Lymph node CTTA comprised image filtration-histogram analysis undertakes two stages: the first step comprised an application of a Laplacian of Gaussian filter to highlight fine to coarse textures within the ROI, followed by a quantification of textures via histogram analysis using mean gray-level intensity from the entire volume of the lymph nodes. RESULTS: CTTA demonstrated a statistically significant difference between the malignant and the benign lymph nodes (P = 0.001), and by binary logistic regression we obtained a sensitivity of 53% and specificity of 97% in the test population. The area under the receiver operating curve was 83.4% and reproducibility was excellent. CONCLUSION: CTTA may be helpful in differentiating between malignant and benign lymph nodes in the mediastinum in patients suspected for lung cancer, with a low intra-observer variance.

Outcome of Incidental Pulmonary Nodules in a Real-World Setting.

OBJECTIVES: Early diagnosis of lung cancer is imperative to improve survival. Incidental pulmonary nodules (IPN) may represent early stages of lung cancer and appropriate follow-up and management of these nodules is important, but also very resource demanding. We aim to describe the results of the CT-based follow-up on a cohort of patients with IPN in terms of detected malignancies, the proportion undergoing invasive procedures, and the subsequent outcome. MATERIALS AND METHODS: Retrospective cohort study of patients in a CT IPN follow-up program who underwent a needle biopsy of the lung from 2018 to 2021 at Aarhus University Hospital. RESULTS: A total of 4181 patients with IPN were followed with CT control scans. Out of these 249 (6%) were diagnosed with lung cancer of which 224 (90%) were diagnosed as a result of the IPN follow-up. Seventy-five percent of the patients were diagnosed in stages I to II and curable treatment was possible in 77.9% of the patients. In the CT IPN follow-up program 449 patients underwent a CT guided needle biopsy. Out of these 190 patients underwent biopsy without the detection of malignancy, corresponding to 4.5% of the entire IPN population. CONCLUSION: The cumulated incidence of lung cancer in our population in the IPN follow-up program was 6%. The probability of malignancy when undergoing an invasive procedure on an IPN was 55.7% of which lung cancer was vastly predominant. The majority of lung cancers were diagnosed in an early and potentially curable stage.

Potential impact of texture analysis in contrast enhanced CT in non-small cell lung cancer as a marker of survival: A retrospective feasibility study.

The objective of this feasibility study was to assess computed tomography (CT) texture analysis (CTTA) of pulmonary lesions as a predictor of overall survival in patients with suspected lung cancer on contrast-enhanced computed tomography (CECT). In a retrospective pilot study, 94 patients (52 men and 42 women; mean age, 67.2 ±â€…10.8 yrs) from 1 center with non-small cell lung cancer (NSCLC) underwent CTTA on the primary lesion by 2 individual readers. Both simple and multivariate Cox regression analyses correlating textural parameters with overall survival were performed. Statistically significant parameters were selected, and optimal cutoff values were determined. Kaplan-Meier plots based on these results were produced. Simple Cox regression analysis showed that normalized uniformity had a hazard ratio (HR) of 16.059 (3.861-66.788, P < .001), and skewness had an HR of 1.914 (1.330-2.754, P < .001). The optimal cutoff values for both parameters were 0.8602 and 0.1554, respectively. Normalized uniformity, clinical stage, and skewness were found to be prognostic factors for overall survival in multivariate analysis. Tumor heterogeneity, assessed by normalized uniformity and skewness on CECT may be a prognostic factor for overall survival.

High resolution spiral CT for determining the malignant potential of solitary pulmonary nodules: refining and testing the test.

BACKGROUND: A solitary pulmonary nodule (SPN) may represent early stage lung cancer. Lung cancer is a devastating disease with an overall 5-year mortality rate of approximately 84% but with early detection and surgery as low as 47%. Currently a contrast-enhanced multiple-row detector CT (MDCT) scan is the first examination when evaluating patients with suspected lung cancer. PURPOSE: To apply an additional high resolution CT (HRCT) to SPNs to test whether certain morphological characteristics are associated with malignancy, to assess the diagnostic accuracy of HRCT in the characterization of SPNs, and to address the reproducibility of all measures. MATERIAL AND METHOD: Two hundred and thirteen participants with SPNs were included in a follow-up study. Blinded HRCT images were assessed with regard to margin risk categories (MRCs), calcification patterns and certain other characteristics and overall malignancy potential ratings (MPRs) were given. Morphological characteristics were tested against reference standard and ROC methodology was applied to assess diagnostic accuracy. Reproducibility was measured with Kappa statistics and 95% confidence intervals were computed for all results. Histopathology (90%) and CT follow-up (10%) were used as reference standard. RESULTS: MRCs (P < 0.001), calcification patterns (P = 0.003), and pleural retraction (P < 0.001) were all statistically significantly associated to malignancy. Reproducibility was moderate to substantial. Sensitivity, specificity, and overall diagnostic accuracy of HRCT were 98%, 23% and 87%, respectively. Reproducibility was substantial. CONCLUSION: Statistically significant associations between SPN MRCs, calcification patterns, pleural retraction and malignancy were found. HRCT yielded a very high sensitivity and a somewhat lower specificity for malignancy. Reproducibility was high.

Prognostic value of DCE-CT-derived blood volume and flow compared to core biopsy microvessel density in patients with metastatic renal cell carcinoma.

BACKGROUND: Angiogenesis is prominent in metastatic renal cell carcinoma (mRCC). We compared two angiogenesis assessment methods: dynamic contrast-enhanced computed tomography (DCE-CT)-derived blood volume (BV) and blood flow (BF) and core biopsy microvessel density (MVD). METHODS: As planned in DaRenCa Study-1 study, DCE-CT and core biopsy were performed from the same tumour/metastasis at baseline. MVD was assessed by CD34 immunostaining in tumour (CD34-indexT) or tumour including necrosis (CD34-indexTN). BV and BF were assessed using the DCE-CT software. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier analysis. Spearman coefficient (rho) tested the correlation between MVD and BV, BF, or CT density (HU). RESULTS: At baseline, 25 patients had analysable scans and tissue. BVdeconv, BVPatlak, and BFdeconv > median were associated with favourable OS (43.2 versus 14.6 months, p = 0.002; 31.6 versus 20.2 months, p = 0.015; and 31.6 versus 24.5 months, p = 0.019). CD34-indexT and CD34-indexTN did not correlate with age (p = 0.543), sex (p = 0.225), treatment (p = 0.848), International mRCC Database Consortium category (p = 0.152), synchronous versus metachronous metastatic disease (p = 0.378), or tumour volume (p = 0.848). CD34-indexT or CD34-indexTN > median was not associated with PFS (p = 0.441 and p = 0.854, respectively) or OS (p = 0.987 and p =0.528, respectively). CD34-indexT or CD34-indexTN was not correlated with BV, BF, or HU (rho 0.20-0.26). CONCLUSIONS: Differently from MVD, DCE-CT-derived BV and BF had prognostic impact and may better reflect angiogenesis in mRCC. TRIAL REGISTRATION: NCT01274273.

Use of patient outcome endpoints to identify the best functional CT imaging parameters in metastatic renal cell carcinoma patients.

OBJECTIVE: To use the patient outcome endpoints overall survival and progression-free survival to evaluate functional parameters derived from dynamic contrast-enhanced CT. METHODS: 69 patients with metastatic renal cell carcinoma had dynamic contrast-enhanced CT scans at baseline and after 5 and 10 weeks of treatment. Blood volume, blood flow and standardized perfusion values were calculated using deconvolution (BVdeconv, BFdeconv and SPVdeconv), blood flow and standardized perfusion values using maximum slope (BFmax and SPVmax) and blood volume and permeability surface area product using the Patlak model (BVpatlak and PS). Histogram data for each were extracted and associated to patient outcomes. Correlations and agreements were also assessed. RESULTS: The strongest associations were observed between patient outcome and medians and modes for BVdeconv, BVpatlak and BFdeconv at baseline and during the early ontreatment period (p < 0.05 for all). For the relative changes in median and mode between baseline and weeks 5 and 10, PS seemed to have opposite associations dependent on treatment. Interobserver correlations were excellent (r ≥ 0.9, p < 0.001) with good agreement for BFdeconv, BFmax, SPVdeconv and SPVmax and moderate to good (0.5 < r < 0.7, p < 0.001) for BVdeconv and BVpatlak. Medians had a better reproducibility than modes. CONCLUSION: Patient outcome was used to identify the best functional imaging parameters in patients with metastatic renal cell carcinoma. Taking patient outcome and reproducibility into account, BVdeconv, BVpatlak and BFdeconv provide the most clinically meaningful information, whereas PS seems to be treatment dependent. Standardization of acquisition protocols and post-processing software is necessary for future clinical utilization. Advances in knowledge: Taking patient outcome and reproducibility into account, BVdeconv, BVpatlak and BFdeconv provide the most clinically meaningful information. PS seems to be treatment dependent.

Dynamic Contrast-Enhanced Computed Tomography-Derived Blood Volume and Blood Flow Correlate With Patient Outcome in Metastatic Renal Cell Carcinoma.

OBJECTIVES: The aim was to explore the potential for using dynamic contrast-enhanced computed tomography as a noninvasive functional imaging biomarker before and during the early treatment of metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Dynamic contrast-enhanced computed tomography scans were performed at baseline and after 5 and 10 weeks' treatment in 69 prospectively included mRCC patients receiving treatment with interferon alpha and interleukin 2 (n = 26); interferon alpha, interleukin 2, and bevacizumab (n = 24); sunitinib (n = 7); pazopanib (n = 5); or temsirolimus (n = 7). Using a prototype software program (Advanced Perfusion and Permeability Application, Philips Healthcare, Best, the Netherlands), blood volume (BV), blood flow (BF), and permeability surface area product (PS) were calculated for each tumor at baseline, week 5, and week 10. These parameters as well as relative changes between baseline and weeks 5 and 10 were tested for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. RESULTS: Using the 25th percentile as the cutoff, baseline BV for all patients independent of subsequent treatment was statistically significantly associated with PFS (10.8 vs 5.3 months, P = 0.007) and OS (35.2 vs 13.3 months, P = 0.001), and baseline BF was significantly associated with OS (31.7 vs 14.6 months, P = 0.024) with high values for both parameters being associated with significantly longer PFS and OS. Baseline PS was not associated with PFS or OS.In patients treated with angiogenesis inhibitors (bevacizumab, sunitinib, pazopanib, or temsirolimus), the relative change in BV from baseline to week 5 using 25th percentile as the cutoff was associated with PFS (5.6 vs 24.8 months, P = 0.001) and OS (19.1 months vs not reached, P = 0.008) and from baseline to week 10 with PFS (8.1 vs 16.4 months, P = 0.014) and OS (15.5 months vs not reached, P = 0.002). The relative change in BF from baseline to week 5 using medians as the cutoff was associated with PFS (5.5 vs 14.3 months, P = 0.018) and OS (14.6 vs 31.7 months, P = 0.027). The relative change in BF from baseline to week 10 using 25th percentile as the cutoff was associated with PFS (8.3 vs 46.9 months, P = 0.011) and OS (19.1 vs 53.0 months, P = 0.006). For both parameters, the largest reductions during early treatment were associated with increased PFS and OS.In patients receiving immunotherapy only (interferon alpha and interleukin 2), relative changes in PS between baseline and weeks 5 and 10 were significantly associated with PFS with larger increases associated with longer PFS. In patients receiving angiogenesis inhibitors, the relative changes in PS between baseline and week 10 were significantly associated with PFS and OS with larger reductions associated with favorable outcomes. CONCLUSIONS: In patients with mRCC treated with angiogenesis inhibitors, the largest reductions in BV and BF between baseline and weeks 5 and 10 were associated with favorable outcomes. At baseline, the lowest BV and BF were associated with the poorest outcomes regardless of the subsequent treatment. Early reductions in PS were associated with favorable outcomes for those treated with angiogenesis inhibitors and with poor outcomes for those treated with immunotherapies.

Can visual assessment of blood flow patterns by dynamic contrast-enhanced computed tomography distinguish between malignant and benign lung tumors?

BACKGROUND: Dynamic contrast-enhanced computed tomography (DCE-CT) is a tool, which, in theory, can quantify the blood flow and blood volume of tissues. In structured qualitative analysis, parametric color maps yield a visual impression of the blood flow and blood volume within the tissue being studied, allowing for quick identification of the areas with the highest or lowest blood flow and blood volume. PURPOSE: To examine whether DCE-CT could be used to distinguish between malignant and benign lung tumors in patients with suspected lung cancer. MATERIAL AND METHODS: Fifty-nine patients with suspected lung cancer and a lung tumor on their chest radiograph were included for DCE-CT. The tumors were categorized using structured qualitative analysis of tumor blood flow patterns. Histopathology was used as reference standard. RESULTS: Using structured qualitative analysis of tumor blood flow patterns, it was possible to distinguish between malignant and benign lung tumors (Fisher-Freeman-Halton exact test, P = 0.022). The inter-reader agreement of this method of analysis was slight to moderate (kappa = 0.30; 95% confidence interval [CI] = 0.13-0.46). CONCLUSION: DCE-CT in suspected lung cancer using structured qualitative analysis of tumor blood flow patterns is accurate as well as somewhat reproducible. However, there are significant limitations to DCE-CT.

Intralymphatic immunotherapy induces allergen specific plasmablasts and increases tolerance to skin prick testing in a pilot study.

BACKGROUND: Allergen Immunotherapy is a promising treatment of allergy. Seven patients with rhinoconjunctivitis to grass allergen were treated with intralymphatic immunotherapy (ILIT) to explore whether this treatment could be performed. Effect of treatment was assessed as change in symptom medication score, response in skin prick test and nasal allergen provocation. ILIT deposits allergen in an inguinal lymph node to elicit a strong immune stimulus. This allowed us to monitor appearance of allergen specific plasmablasts 7 days after allergen injection. FINDINGS: In an open trial of seven patients with a history of symptomatic allergic rhinoconjunctivitis due to grass pollen, three injections of allergen into inguinal lymph nodes were performed with monthly intervals. Allergen injections induced grass allergen specific plasmablasts expressing other isotypes than IgE after 7 days, induced a trend toward improvement in symptom and medication score and rhinoconjunctivitis-related quality of life during the grass pollen season 2013 and significantly raised the threshold in nasal allergen challenge and titrated skin prick testing. Mild side-effects were recorded after 3 of the 21 of injections (14 %). CONCLUSIONS: This pilot study shows that ILIT may induce allergen specific plasmablasts, and confirms an effect on provocation of mast cells in skin and nasal mucosa during the ensuing winter.

Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: no in vivo effect of Fas ligand tumor counterattack.

PURPOSE: It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)-based immunotherapy in metastatic renal cell carcinoma. EXPERIMENTAL DESIGN: Tumor core needle biopsies were obtained before IL-2-based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expressing CD4, CD8, CD56, and CD57 were analyzed by immunohistochemistry. RESULTS: At baseline, negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies, whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment, tumor FasL expression did not change from baseline levels. Moreover, tumor FasL expression was not correlated with objective response or survival whereas the absolute number of CD4(+), CD8(+), CD56(+), and CD57(+) cells per mm(2) tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01, P = 0.008, P = 0.015, and P < 0.001, respectively). During the first course of immunotherapy, the absolute number of CD4(+), CD8(+), and CD57(+) cells per mm(2) tumor tissue was significantly higher in responding patients compared with nonresponding patients (P = 0.034, P < 0.001, and P < 0.001, respectively). However, no correlation was observed between the number of intratumoral lymphocytes and tumor FasL expression level. CONCLUSION: These observations do not support the hypothesis that FasL tumor "counterattack" has an effect on the clinical outcome in metastatic renal cell carcinoma during IL-2-based immunotherapy.

Malignant ascites in patients with terminal cancer is effectively treated with permanent peritoneal catheter.

BACKGROUND: Malignant ascites is a pathological condition caused by intra- or extra-abdominal disseminated cancer. The object of treatment is palliation. In search of an effective and minimally invasive palliative treatment of malignant ascites placement of a permanent intra peritoneal catheter has been suggested. PURPOSE: To evaluate our experiences with treatment of malignant ascites by implantation of a permanent PleurX catheter. MATERIAL AND METHODS: A retrospective study was conducted, comprising 20 consecutive patients with terminal cancer, who had a permanent PleurX catheter implanted because of malignant ascites in the period from February to November 2014. Using the patients' medical records, we retrieved data on patients and procedures. RESULTS: The technical success rate was 100%. Catheter patency was 95.2%, one catheter was removed due to dislocation. Ten patients (50.0%) experienced minor adverse events. No procedural difficulties were reported and there was no need for additional treatment of malignant ascites after catheter implantation. Median residual survival after catheter implantation was 27 days. CONCLUSION: Implantation of a permanent PleurX catheter is a minimally invasive and effective procedure with only minor adverse events and a high rate of catheter patency in patients with malignant ascites caused by terminal cancer disease.

Dynamic contrast-enhanced computed tomography as a potential biomarker in patients with metastatic renal cell carcinoma: preliminary results from the Danish Renal Cancer Group Study-1.

OBJECTIVES: The aim of this study was to explore the impact of dynamic contrast-enhanced (DCE) computer tomography (CT) as a biomarker in metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Twelve patients with favorable or intermediate Memorial Sloan Kettering Cancer Center risk group and clear cell mRCC participating in an ongoing prospective randomized phase II trial comprising interleukin-2-based immunotherapy and bevacizumab were included in this preliminary analysis. All patients had a follow-up time of at least 2 years. Interpretation of DCE-CT (max slope method) was performed blinded to treatment group. The DCE-CT scans were performed at baseline, at weeks 5 and 10, and thereafter every third month. Blood flow (BF; mL/min/100 mL), peak enhancement (Hounsfield units), time to peak (seconds), and blood volume (BV; mL/100 g) were calculated. Parameters for DCE-CT were correlated with sum of diameters (defined by Response Evaluation Criteria in Solid Tumors 1.1), progression-free survival (PFS), and overall survival (OS) using Wilcoxon, Man-Whitney, Kaplan-Meier, and log rank statistics, as appropriate. RESULTS: Blood flow at baseline ranged from 4.9 to 148.1 mL/min/100 mL (median, 62.2; 25th percentile, 25.8; 75th percentile, 110.0). Patients with high baseline BF (using quartiles as cutoffs) had significantly longer OS (not reached vs 5.2 months, P = 0.011) and longer PFS (not reached vs 3.9 months, P = 0.026). Blood volume at baseline ranged from 8.8 to 74.1 mL/100 g tissue (median, 21.5), and at week 5, from 4.9 to 34.7 mL/100 g (median, 17.2). Relative changes in BV between baseline and week 5 ranged from -64% to +68% (median, -16%; 25th percentile, -41%; 75th percentile, +2%) and were significantly associated with OS using quartiles as cutoffs (5.2 months vs not reached, P = 0.038) and PFS using the median as cutoff (5.3 months vs not reached, P = 0.009), with larger reductions associated with longer survival. Using medians as cutoffs, relative changes in both BF and BV between baseline and week 10 were significantly associated with OS (for both, 8.6 months vs not reached, P = 0.031). CONCLUSIONS: Dynamic contrast-enhanced CT is a potential biomarker in patients with mRCC. High baseline BF and reductions in BF and BV during early treatment are associated with improved outcome. Large-scale studies are required.

Mediastinal staging in Non-Small-Cell Lung Carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography.

BACKGROUND: After the diagnosis Non-Small-Cell Lung Carcinoma (NSCLC) has been established, consideration must turn toward the stage of disease, because this will impact directly on management and prognosis. Staging is used to predict survival and to guide the patient toward the most appropriate treatment regimen or clinical trial. Distinguishing malignant involvement of the mediastinal lymph nodes (N2 or N3) from the hilar lymph nodes, or no lymph nodes (N0 or N1) is critical, because malignant involvement of N2 or N3 lymph nodes usually indicates non-surgically resectable disease. The purpose of this study was to examine and compare CT versus integrated F18-FDG PET/low dose CT (FDG PET/CT) for mediastinal staging in NSCLC, and the desire was to safely distinguish between malignant and benign lesions without the need for invasive procedures. All results were controlled for reproducibility. METHODS: 114 participants with NSCLC were included in a prospective cohort study. Blinded CT and FDG PET/CT images were reviewed. The participants' mediastinums were staged based on lymph node sizes (CT), or on FDG uptake (FDG PET/CT). Reference standard was tissue sampling. RESULTS: We found that there was no measureable difference between CT and FDG PET/CT mediastinal staging results; overall two-thirds of the participants in the study were correctly staged, and almost one-third of the participants were falsely staged. CONCLUSION: Neither CT nor FDG PET/CT could obviate the need for further invasive staging prior to thoracotomy in patients with NSCLC; for that purpose, the results of both modalities were too meagre. Therefore, these patients still depend on invasive staging methods. In our study, invasive staging was accomplished by mediastinoscopy. However, today this is increasingly replaced by EBUS or EUS.

Characterization of pulmonary lesions in patients with suspected lung cancer: computed tomography versus [¹8F] fluorodeoxyglucose-positron emission tomography/computed tomography.

Pulmonary nodules are of high clinical importance, given they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A solitary pulmonary nodule is a single, small (<-30 mm in diameter) opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of pulmonary nodules remains unclear. However, the question of malignancy of any given nodule remains the same. A standard contrast-enhanced computed tomography (CT) scan is often the first examination, followed by a number of other examinations. The purpose of this study was to examine the clinical feasibility of CT versus integrated [18F]fluorodeoxyglucose-positron emission tomography (PET)/low-dose CT scan in patients with suspected lung cancer and pulmonary lesions on CT. All results were controlled for reproducibility. We found that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point where further diagnostic imaging examination could be considered futile. We also found that the overall diagnostic accuracy, as well as the classification probabilities and predictive values of the two modalities were not significantly different; the reproducibility of these results was substantial.

Complete pathologic response in lung tumors in two patients with metastatic non-small cell lung cancer treated with erlotinib.

INTRODUCTION: Patients with non-small cell lung cancer with a sensitizing mutation in the epidermal growth factor receptor (EGFR) are likely to respond to treatment with an EGFR inhibitor. In some patients, residual tumor tissue can be visualized for several years without any signs of progression. METHODS: Two patients with pathologically verified adenocarcinoma of the lung and multiple bone metastases were monitored after start of treatment with erlotinib by examining clinical parameters and imaging of lung tumors and bone metastases. Pretreatment biopsies and blood samples were examined for the presence of EGFR mutations, and lobectomy was performed according to standard procedures after 10 months of treatment in one patient and 30 months in the other. RESULTS: Both patients responded to treatment with erlotinib and displayed a mutated EGFR. At the time of surgery, tumor was still visible in the lungs of both patients, but cancer cells could not be identified in the resected lung tumor tissue. In one patient, blood samples were available and the EGFR mutation was detected in the circulating DNA in the pretreatment blood sample but was no longer detectable 4 weeks after start of treatment and could not be detected in any of the following 12 blood samples. CONCLUSIONS: Treatment with erlotinib may induce complete response in patients with metastatic non-small cell lung cancer. It remains to be shown whether treatment with erlotinib can be discontinued in such patients. The disappearance of EGFR mutations in the DNA of the blood sample early in treatment might be used as an indicator of response to erlotinib.

Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma.

With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon alpha (IFN-alpha) alone (n = 23) or in combination with histamine dihydrochloride (n = 26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3+, CD4+, CD8+ and CD57+ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low zeta expression, whereas blood lymphocytes showed almost normal levels of zeta expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, zeta-chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients.