Alfredo Cesario

Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas.

We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing αVβ3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and αVβ3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0–60%) expressed LH39, while αVβ3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5–90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed.

Pulmonary metastases: can accurate radiological evaluation avoid thoracotomic approach?

OBJECTIVESnTo evaluate the effectiveness of radiological assessment (high-resolution CT (HRCT), helical CT (HCT) scan) of lung metastases and to verify if a complete manual exploration by thoracotomy is necessary.nnnMATERIALS AND METHODSnFrom 1/96 to 1/00, 166 consecutive patients presenting with lung metastases were treated. Preoperative CT scan (HRCT in 78 patients, group A; HCT in 88 patients, group B) to assess the number, size and location of the lesions (slice thickness 5 mm; reconstruction interval 3-5 mm) was always performed. All patients underwent axillary thoracotomy (staged when lesions were bilateral); accurate palpation of the lung parenchyma was always performed to identify any undetected lesion. Non-metastatic lesions were excluded.nnnRESULTSnWe performed 356 wedge resections in 161 patients (113 monolateral, 70.2%; 48 bilateral, 29.8%) and five lobectomies. In group A, primary neoplasm was epithelial in 44 patients, sarcoma in 26 and germ cell in eight, and in group B, epithelial in 61 patients, sarcoma in 20 and germ cell in seven. Three hundred and sixty-one histologically proven metastases were resected (188 in group A and 173 in group B). HRCT correctly identified 142/188 lesions (sensitivity 75%); HCT revealed 142/173 metastases (sensitivity 82.1%). Sensitivity for lesions less than 6 mm in maximum diameter was 48% (30/58 false negative) in group A and 61.5% (20/52 false negative) in group B.nnnCONCLUSIONSnThe sensitivity of HCT exceeds that of HRCT. However, complete manual exploration by thoracotomy remains the procedure of choice for patients undergoing pulmonary metastasectomy, because of limitation in preoperative radiological assessment of lung lesions smaller than 6 mm.

Non-small cell lung cancer with single brain metastasis: the role of surgical treatment

OBJECTIVEnThe prognosis of non-small cell lung cancer (NSCLC) with brain metastasis is very poor, with median survival rate below 6 months, even if treated with palliative radio and/or chemotherapy. To assess the effectiveness of surgical treatment for this kind of patients we reviewed our experience.nnnMETHODSnFrom January 1989 to October 1999, 30 patients (26 males and four females; mean age: 58.7 years) with NSCLC and single brain metastasis underwent surgical treatment of both primary lung cancer and secondary cerebral lesion. Patients (pts) were divided into two major groups. In group 1 (G1) 20 pts (18 males and two females) presented a synchronous brain metastasis. In group 2 (G2) 10 pts (eight males and two females) presented a metachronous brain metastasis during the follow-up period (range 3-24 months since the primary tumor). Patients selected in G1 had T1-2, N0-1 clinical staging, good performance status (ECOG:0--1; Karnofsky index > 70%), age < 75 years. Craniotomy has always been the first approach. In G2 also patients with locally advanced tumors (T3 and/or N2) were included. Whole brain radiotherapy and/or chemotherapy was the post-operative choice treatment.nnnRESULTSnHistologic findings have shown: adenocarcinoma in 17 cases (12 in G1; five in G2), squamous cell carcinoma in 10 cases (six in G1; four in G2), large cell carcinoma in 2 (one in G1; one in G2) and large cell neuroendocrine carcinoma in one (G1). Survival analysis (Kaplan--Meier method) has shown an overall value of 80% at 1 year (95% in G1; 50% in G2), 41% at 2 years (47% in G1; 30% in G2) and 17% at 3 years (14% in G1; 20% in G2). Overall median survival is 23 months (23 in G1; 11 in G2); mean survival 27.8 months (30.3 months in G1; 22.8 months in G2). According to univariate analysis prognosis is definitively better in N0 tumors compared to N1-2 tumors and in adenocarcinoma cases compared to other histotypes (P < 0.05).nnnCONCLUSIONSnWe can conclude that combined surgical therapy is, nowadays, the choice treatment for this kind of patients, even though restricted to selected cases. The knowledge of prognostic factors may optimize indications for surgery.

Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases

Background:Anti-angiogenic therapy with bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) predominantly targets immature blood vessels. Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases. However, it is not known whether bevacizumab is effective against brain metastases or whether metastases are representative of their primary in terms of VEGF expression, hypoxia, proliferation and vascular phenotype. The aim of this study was to evaluate these factors in a series of matched primary NSCLCs and brain metastases.Methods and Results:Immunohistochemistry showed strong correlation of carbonic anhydrase 9 expression (a marker of hypoxia) in primary and secondary cancers (P=0.0002). However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers. The mean proportion of mature vessels was 63.2% higher in the brain metastases than the primary tumours (P=0.004). Moreover, the vascular pattern of the primary tumour was not representative of the metastasis.Conclusions:Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy. These findings may have implications for clinical trials and biomarker studies evaluating anti-angiogenic agents in brain metastases.

Arginase 2 is expressed by human lung cancer, but it neither induces immune suppression, nor affects disease progression

In human prostate cancer, Arginase 2 (ARG2) and nitric oxide synthase (NOS) are concomitantly expressed by tumor cells, and induce tumor immune escape via peroxynitrite‐dependent Tyrosine nitrosylation. Since there were no data regarding this immune suppressive mechanism in other tumor types, and an evaluation of its clinical relevance in human tumors had still to be provided, we have investigated presence and clinical relevance of ARG2 and NOS expression in lung cancer. No evidence of NOS expression was found, no significant NOS enzymatic activity was detected. Instead, ARG2 protein was expressed by tumor cells. In a cohort of 120 patients, the amount of ARG2‐positive tumor cells was significantly higher in small cell lung cancers (SCLC) than in non‐small cell lung cancers (NSCLC). Large cell undifferentiated carcinomas had twice ARG2 than the other NSCLC subtypes. ARG2 expression was increased in Grade 3 tumors, as compared to Grades 1 and 2. However, no relationship was found with tumor size and stage, and with patient survival. Indeed, the enzyme was active, since the Arginine catabolite Ornithine was produced, but Arginine depletion was not attained. In addition, nitrotyrosine was not found in tumor tissue. Accordingly, when tumor cells isolated from lung cancer were incubated with activated autologous T cells, no inhibition of proliferation was detected. Our results indicate that ARG2 is expressed in lung cancer, but it does not induce tumor immune escape and does not affect disease progression, most probably due to the lack of concomitant NOS expression.

Unsuspected primary pulmonary meningioma.

Primary pulmonary meningioma is an uncommon, usually benign, soft tissue tumour which has rarely been reported. We report an additional case of primary pulmonary meningioma occurring in an asymptomatic 56-year-old man whose diagnosis was only established after resection. The features of this lesion together with a review of the previous literature are described.

Radiotherapy versus follow-up in the treatment of pathological stage Ia and Ib non-small cell lung cancer. Early stopped analysis of a randomized controlled study

OBJECTIVEnThis is an analysis of a randomized controlled clinical trial planned to evaluate the effects of adjuvant radiotherapy (AR) on the local recurrence rate in patients with non-small cell lung cancer (NSCLC) with pathological stage (pStage) Ia (pT1N0) and Ib (pT2N0). The effects of AR on the long-term survival have also been marginally evaluated.nnnMATERIALS AND METHODSnThis clinical trial was planned with the hypothesis that AR on pStage Ia and Ib, R0 NSCLCs was effective on local recurrence rate. From July 1989 through March 1997, 104 patients with NSCLC who presented with pStage Ia and Ib have been observed and treated and entered the study. Male/female ratio was 91:13; the mean age was 62 years (range 41-75 years). All patients underwent major pulmonary resection and homolateral standard hilar and mediastinal lymph node dissection. pStage was T1N0 in 29 and T2N0 in 75 cases. Patients have been randomized by chance into two groups (G1 and G2). G1 received radiotherapy, G2 did not receive any adjuvant treatment. Fifty-two patients entered G1 and 52 entered G2.nnnRESULTSnPost-operative mortality was nil. Seven patients have been excluded from the study (four in G1 and three in G2), due to incomplete follow-up data. We do not report any radiotherapy-related complication or deterioration of lung function. The treatment effect on the local recurrence rate demonstrated a clearly significant protective effect of the AR. No statistically significant difference was found from the comparison of the 5-year survival rate of the treated (83%) versus untreated (70%) patients. No detrimental effect of the radiotherapy has been assessed.nnnCONCLUSIONSnAR in the treatment of pStage Ia and Ib NSCLC has been well tolerated and had a significant relative effect on the local recurrence rate but did not significantly modify overall survival even if a positive trend in the group of treated patients is reported.

Incidental surgical findings of a phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with unresectable non-small cell lung cancer

OBJECTIVEnto report the surgical facts of unresectable patients with locally advanced non-small cell lung cancer (NSCLC) treated in a phase I trial with concurrent weekly gemcitabine and radiotherapy who achieved a clinical downstaging so as to re-enter resectability.nnnMATERIALS AND METHODSnfrom 3/99 to 11/00, 30 patients (ten stage IIIa, 16 IIIb and four IV) with histologically proven, unresectable NSCLC, were enrolled in this phase I trial. Gemcitabine was given weekly for 5 consecutive weeks as a 30-min intravenous infusion, at least 4 h before radiotherapy. Starting dose: 100 mg/m(2). Maximum tolerated dose (MTD): 350 mg/m(2). Radiotherapy total dose: 50.4 Gy (1.8 Gy/day) on primitive tumour and involved lymph nodes.nnnRESULTSn27 out of 30 patients (90%) were evaluable for clinical restaging (three patients who decided to continue their treatment elsewhere have been excluded). A major clinical response (partial+complete response) was observed in 17 out of 27 cases (62.9%). Clinical complete response rate was 3.7% (1/27) while partial response rate was 59.2% (16/27). Nine patients (33.4%) showed a clinical stable disease and one a disease progression (3.7%). Fourteen patients re-entered resectability and were operated upon: seven lobectomies; four bilobectomies; two pneumonectomies and one explorative thoracotomy. Mean operation duration time was 112 min; mean blood loss was 390 cc. Thirty-day morbidity and mortality were nil. Mean post-operative hospital stay was 6.8 days. A slight increase in operational technical difficulty was encountered. Definitive histology showed a pathologic downstaging of 71.4% (10/14). In four patients, only microscopic neoplastic remnants were found.nnnCONCLUSIONSncombined treatment with weekly gemcitabine and concurrent radiotherapy is feasible. In patients with advanced NSCLC who achieved a good clinical response and therefore were judged to be resectable, surgery was possible without any increase in thirty-day morbidity and mortality. Satisfactory pathologic results were obtained.

Predicting Walking-Induced Oxygen Desaturations in COPD Patients: A Statistical Model

BACKGROUND: Oxygen desaturation during walking can have important consequence on prognosis of COPD patients. However, a standard 6-min walk test (6MWT), useful in detecting desaturation in COPD patients, can be difficult to execute in some settings of COPD management, as in the community healthcare service. We evaluated a new scoring system for the risk of oxygen desaturation during walking in COPD patients: the walking desaturation score. METHODS: We collected data from symptomatic COPD in-patients admitted for rehabilitation (derivation cohort) and out-patients referred to the local community health service (validation cohort). SpO2 was monitored during 6MWT, and the subjects were classified as walking desaturators or non-desaturators. By a regression analysis model we assigned a weighted score proportional to the measured percentage of explained variance for each variable. Risk estimates were computed as odds ratios. A receiver operating characteristic curve analysis and a Hosmer-Lemeshow goodness-of-fit test were then performed to measure discrimination and calibration of walking desaturation score. RESULTS: Baseline characteristics in the derivation cohort (n = 435, 74% of whom were walking desaturators) and the validation cohort (n = 238, 37% of whom were walking desaturators) were different. Resting arterial oxygen saturation measured from an arterial blood sample, PaO2, and percent-of-predicted FEV1 were the variables that predicted walking desaturation. The proportion of walking desaturators (and odds ratio estimate) gradually increased according to walking desaturation score (range 0–6) and associated categories of desaturation risk (total walking desaturation score: low 0 or 1, high 2–3, very high 4–6) (chi-square P < .001). There was considerable predictive discrimination (area under the curve 0.90, 95% CI 0.86–0.93, P < .001), and calibration (Hosmer-Lemeshow chi-square 1.31, P = .86) values have been shown. CONCLUSIONS: Walking desaturation score accurately predicts and classifies the risk of walking desaturation in COPD patients. ClinicalTrials.gov Number NCT01303913.

Concurrent radio-chemotherapy in N2 non small cell lung cancer : interim analysis

OBJECTIVEnIn recent years many authors have been focused on N2 non-small cell lung cancer patients to determine whether the rate of resectability and long term survival can be improved by a combined preoperative treatment, with significant results. Following these experiences, we planned an induction therapy trial to assess the impact on downstaging, resectability and survival of concurrent radio-chemotherapy on N2 non-small cell lung cancer patients.nnnMETHODSnBetween January 1990 and August 1995, 82 N2 non-small cell lung cancer patients (44 IIIA and 38 IIIB) received preoperative chemo-radiotherapy with a single cycle of Carboplatin (90 mg/m2 per day for days 1-4), concurrent with radiotherapy (daily radiation dose of 180 cGray for a total of 5040). After surgery, all patients received multi-drug chemotherapy with Carboplatin 300 mg/m2 per day on day 1 and VP-16 100 mg/m2 per day on days 1, 2 and 3, for a total of 6 monthly cycles. Patients with unresectable tumors underwent to this multi-drug chemotherapy, directly.nnnRESULTSnTwo patients were excluded from the study. When the remaining 80 patients had a clinical re-staging, 41 (51.3%) showed a major response, 36 (45%) had minimal or none response, and 3 (3.7%) had progression of disease. Forty-one patients were judged to be resectable, 11 staged IIIB, and 30 IIIA; 2 patients of the IIIB group refused surgery. Of the 39 operated cases, 37 were completely resected (resectability rate: 94.8%). We report one perioperative death due to respiratory failure and two major complications. The overall actuarial 5 year survival is 24.5%. Downstaging was observed in 22 patients (56.4%), with three patients (7.7%) having no evidence of tumor in the specimen, 16 (41%) having sterilization of all lymph nodes, and three (7.7%) having sterilization of mediastinal nodes but positive N1 nodes. The 5-year actuarial survival is 53% for patients who had complete resection and 0% for patients with no resection (P = 0.0000).nnnCONCLUSIONSnThe following conclusions are possible: preoperative radiotherapy and chemotherapy with Carboplatin is well tolerated by patients, does not increase postoperative complications and produces an high rate of response. There is an high resection rate for patients who respond to the therapy. Patients with major response who undergo complete surgical resection had statistically significant improved survival compared with patients whose disease was not resected.