Operable Non-small Cell Lung Carcinoma Research Articles

The advanced lung cancer inflammation index (ALI) predicted the postoperative survival rate of patients with non-small cell lung cancer and the construction of a nomogram model

ObjectiveTo investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with operable non-small-cell lung carcinoma (NSCLC). By constructing the nomogram model, it can provide a reference for clinical work.MethodsA total of 899 patients with non-small cell lung cancer who underwent surgery in our hospital between January 2017 and June 2021 were retrospectively included. ALI was calculated by body mass index (BMI) × serum albumin/neutrophil to lymphocyte ratio (NLR). The optimal truncation value of ALI was obtained using the receiver operating characteristic (ROC) curve and divided into two groups. Survival analysis was represented by the Kaplan-Meier curve. The predictors of Overall survival (OS) were evaluated by the Cox proportional risk model using single factor and stepwise regression multifactor analysis. Based on the results of multi-factor Cox proportional risk regression analysis, a nomogram model was established using the R survival package. The bootstrap method (repeated sampling 1 000 times) was used for internal verification of the nomogram model. The concordance index (C-index) was used to represent the prediction performance of the nomogram model, and the calibration graph method was used to visually represent its prediction conformity. The application value of the model was evaluated by decision curve analysis (DCA).ResultsThe optimal cut-off value of ALI was 70.06, and the low ALI group (ALI < 70.06) showed a poor survival prognosis. In multivariate analyses, tumor location, pathological stage, neuroaggression, and ALI were independently associated with operable NSCLC-specific survival. The C index of OS predicted by the nomogram model was 0.928 (95% CI: 0.904–0.952). The bootstrap self-sampling method (B = 1000) was used for internal validation of the prediction model, and the calibration curve showed good agreement between the prediction and observation results of 1-year, 2-year, and 3-year OS. The ROC curves for 1-year, 2-year, and 3-year survival were plotted according to independent factors, and the AUC was 0.952 (95% CI: 0.925–0.979), 0.951 (95% CI: 0.916–0.985), and 0.939 (95% CI: 0.913–0.965), respectively. DCA shows that this model has good clinical application value.ConclusionALI can be used as a reliable indicator to evaluate the prognosis of patients with operable NSCLC, and through the construction of a nomogram model, it can facilitate better individualized treatment and prognosis assessment.

Objective improvement in dexterity for trainees undergoing a video-assisted thoracoscopic surgery simulation program, a prospective single center study.

Video-assisted thoracoscopic surgery (VATS) is the recommended approach for the management of early-stage operable non-small cell lung carcinoma as well as for other pathologies of the thoracic cavity. Although VATS approaches have been largely adopted in Europe and North America, teaching the technique to novice thoracic surgery trainees remains challenging and non-standardized. Our objective was to assess the impact of a VATS simulation training program on the dexterity of thoracic surgery residents in a prospective single institution study. We developed a 6-month VATS simulation training program on two different dry-lab simulators (Johnson & Johnson Ethicon Stupnik® lobectomy model; CK Surgical Simulation® Crabtree perfused lobectomy model) and assessed the skills of first year thoracic surgery residents (study group, n=7) before and after this program using three standardized exercises on the Surgical Science Simball® Box (peg placement on a board, rope insertion in loops, precision circle cutting). The results were compared to those of last-year medical students who performed the same Simball® Box exercises at a 6-month interval without undergoing a training program (control group, n=5). For each participant, the travel distances of instruments, operation time and absences of periods of extreme motion were assessed for each exercise by the use of the computer-based evaluation of the Simball® Box. After the 6-month VATS training program, all residents revealed a significant increase of their performance status with respect to instrument travel distances operation times and absence of periods of extreme motion in all three exercises performed. The performance of the control group was not different from the study group prior to the training program and remained unchanged 6 months later, for all exercises and parameters assessed. Our results suggest that the implementation of a VATS simulation training program objectively increases the dexterity of thoracic surgery residents and could be an interesting training tool for their surgical education.

FOXP3 infiltrating lymphocyte density and PD-L1 expression in operable non-small cell lung carcinoma

Purpose/Aim: Regulatory FOXP3+ T-cells control the cytotoxic activity of effector cells and may have an essential role in the development of immune tolerance in cancer patients. Programed death ligand 1 PD-L1, expressed on cancer cell membranes also blocks the cytotoxic activity of PD1+ cytotoxic lymphocytes. Materials and Methods: We assessed the immunohistochemical detection of these immune-tolerance related markers in a series of 98 non-small cell lung carcinomas (NSCLC) treated with surgery. The Tumor Infiltration Lymphocyte TIL density (mean number per x400 optical field) and the percentage of FOXP3+ TILs were assessed. Results: PD-L1 expression was directly linked with the TIL density (p = 0.01) and with the extent of infiltration with FOXP3+ TILs, named as the FIL-score (p = 0.01). FIL-score was significantly higher in stage I disease (p = 0.04). IL6 expression was linked with high TIL-score. A low TIL-score, characterizing immune deficient tumors defined a significantly poorer prognosis subgroup of patients (p = 0.03). Stratification of these tumors according to the FIL-score showed that FOXP3 expression by TILs correlated with an even a poorer prognosis in univariate (p = 0.007; median survival 14 vs. 44 months, respectively) and in multivariate analysis (p = 0.01, hazard ratio 4.3). Conclusion: Tumor stroma infiltration by FOXP3+ Tregs is an early event in the progression of NSCLC. Low lymphocytic infiltration defines poor prognosis, which becomes worse when the small numbers of infiltrating lymphocytes characterizing these tumors contain FOXP3 + Tregs. Furthermore, the direct association of FOXP3+ Treg infiltration density with PD-L1 expression by cancer cells implies a co-ordinated immune-suppressive activity in NSCLC.

Multi-institutional analysis of stereotactic body radiation therapy for operable early-stage non-small cell lung carcinoma

PurposeAlthough stereotactic body radiation therapy (SBRT) is the standard of care for inoperable early-stage non-small cell lung carcinoma (NSCLC), its role for medically operable patients remains controversial. To address this knowledge gap, we conducted a multi-institutional study to assess post-SBRT disease control and survival outcomes in medically operable patients. MethodsWe conducted a retrospective cohort study including patients with biopsy-proven cT1-2N0M0 NSCLC treated with definitive SBRT (2006–2015). Per patient charts, inoperability referred to documentation of poor surgical candidacy with a given rationale for lack of resection. Charts of operable patients contained documentation of patients refusing surgery or choosing SBRT, without a documented rationale for inoperability. Subjects were excluded in cases of ambiguity regarding the aforementioned definitions and/or lack of clearly documented operability status. Endpoints included local failure (LF) and regional-distant failure, both evaluated with Fine and Gray competing risks regression; Kaplan-Meier methodology analyzed overall survival (OS) and progression-free survival (PFS). ResultsOf 952 patients, 408 (42.9%) were operable, and 544 (57.1%) were inoperable. Median follow-up was 22 months. Two-year LF was 9.7% in operable patients and 8.2% in inoperable patients (p = 0.36). There was no statistical difference in regional-distant failure (p = 0.55) between cohorts. Operable patients experienced statistically higher OS (p = 0.04), but not PFS (p = 0.11). Respective 1-, 2-, and 3-year OS in operable patients were 85.4%, 66.2%, and 51.2%. ConclusionsAlthough patients with operable NSCLC experience higher OS than their inoperable counterparts, disease-related outcomes are similar. These results may better inform shared decision-making between medically operable patients and their multidisciplinary providers.

Preoperative increased systemic immune-inflammation index predicts poor prognosis in patients with operable non-small cell lung cancer

BackgroundA novel systemic immune-inflammation index (SII) has been recently reported to be associated with clinical outcome in several tumors. However, the prognostic value of SII has not been reported in operable non-small cell lung carcinoma (NSCLC). We aimed to investigate its clinical and prognostic value in patients with operable NSCLC underwent curative surgery. MethodsFour hundred ten NSCLC patients staged I-IIIA were included in this retrospective study. The SII was calculated by the formula: neutrophil× platelet/lymphocyte. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for SII. Kaplan-Meier method and Cox proportional regression were used to analyze the prognostic value of SII. ResultsPatients were stratified into high low SII (≤395.4) and SII (>395.4) groups. High SII was significantly associated with advanced T stage and positive lymph node metastasis. Kaplan-Meier survival analysis showed that SII, PLR, NLR and LMR were all associated with OS. Multivariate analysis identified that SII was an independent predictor of OS. Furthermore, SII remained prognostic significance for NSCLC patients stratified by TNM subgroups. ConclusionsPreoperative SII was a powerful prognostic biomarker for predicting outcome in patients with operable NSCLC. Preoperative SII may assist clinicians treatment strategy making and individual treatment choice.

P1.03-016 Video-Thoracoscopic Pulmonary Resection Avoids Delay and Increase Adjuvant Chemotherapy Compliance for Non-Small Cell Lung Carcinoma

Adjuvant chemotherapy compliance and the full dose delivery of agents are believed to be superior after video-thoracoscopic lobectomy (VATS-L) for operable non-small cell lung carcinoma (NSCLC), compared with thoracotomy. The purpose of this study was to determine the role of minimally invasive lobectomy on when to start and the percentage of provided planned regimen. All patients undergoing pulmonary resection for NSCLC between January 2010 and May 2016 were reviewed retrospectively. For comparison, analyzes were performed only on patients receiving sole adjuvant chemotherapy, after the final pathology. Chemotherapy was planned according to Adjuvant Navelbine International Trialist Association (ANITA) trial. The analyzed variables were the duration between the discharged day form surgical unit and the initial chemotherapy day, the planned and the received chemotherapy doses. Total of 74 patients were subsequently underwent adjuvant chemotherapy for NSCLC either after thoracoscopic surgery (n=26) or thoracotomy (n=48). Patients undergoing VATS-L had a shorter median length of hospital stay (4.4 versus 7.3 days; P<0.001), that leads significantly reduced time delay on chemotherapy commencement (29.4 versus 37.0 days; P=0.002). VATS-L group received 83.0% of planned Cisplatin and 81.7% of Navelbine dose. In the thoracotomy group, the compliance to planned doses of Cisplatin and Navelbine was 77.6% and 75.0%, respectively. Both of the drug regime tolerance was significantly (Cisplatin P=0.005; Navelbine P=0.020) increased in the VATS-L group (Table 1). It is known that VATS-L has several advantages over conventional open surgery. Moreover, our data presented that it also allows more accurate and rapid adjuvant chemotherapy in terms of treatment initiation timing and compliance, by enabling quick postoperative recovery.

Adjuvant chemotherapy in stage II non-small cell lung cancer: A population-based analysis utilizing NCDB.

e18511 Background: Many prospective trials show that addition of chemotherapy after operable non-small cell lung carcinoma improves survival. Studies determining the effects of patient characteristics and insurance status on the use of adjuvant chemotherapy are lacking. Our aim was to examine the practice patterns for adjuvant chemotherapy in surgically resectable stage II non-small cell lung carcinoma using the National Cancer Database (NCDB). NCDB is a nationwide oncology outcomes database for ~70% of newly diagnosed cases from more than 1,500 accredited cancer programs in the United States and Puerto Rico. Methods: It is a retrospective study of patients diagnosed with non-small cell lung cancer stage II between the years 2000 and 2011 from the NCDB (n=102617). We focused on the patients who received adjuvant chemotherapy to see if there is any difference based on demographic and insurance characteristics. Chi-square test was used as the test of significance. Results: Between the years 2000 to 2011, th...

Video-Assisted Thoracic Surgery Lobectomy versus Lobectomy by Thoracotomy for Lung Cancer: Pilot Study

Video-assisted thoracic surgery lobectomy (VATS-L) has become accepted as a safe and effective procedure to treat early-stage non-small cell lung carcinoma (NSCLC). However, the advantages of VATS-L compared with lobectomy by thoracotomy (TL) remain controversial. The aim of this study was to compare the outcomes of patients who underwent VATS-L with those who underwent TL. We studied 103 patients who underwent surgery for operable NSCLC between October 2009 and March 2012. All operations were performed by a single surgeon. The inclusion and exclusion criteria for VATS-L and TL were formulated before the study was initiated. Data on age, sex, preoperative comorbidities, intraoperative and postoperative complications, hospital stay, morbidity, mortality, and other characteristics were recorded preoperatively, in real time intraoperatively, and during hospitalization and were statistically compared. Comorbidities were scaled according to the Charlson Comorbidity Index, and propensity scores between the patients who underwent TL and VATS-L were compared. Sixty-three VATS-L operations and 40 TL operations were performed. There were no postoperative complications in 39 patients (61.9%) who underwent VATS-L compared with 25 patients (62.5%) who underwent TL. The patients who underwent TL were significantly younger than the patients who underwent VATS-L (mean ± SD, 64.7 ± 12.6 vs 70.9 ± 8.4; P = 0.003). Hospital stay was not found to be related to the type of surgery (mean ± SD, 8.43 ± 3.15 days vs 8.32 ± 4.13 days; P = 0.888). There were no significant differences when comparing postoperative complications. Our initial data suggest that VATS-L is a safe procedure in patients with resectable IA/IB NSCLC and may be the preferred strategy for treatment of the older patient population.

Prognostic significance of different immunohistochemical S100A2 protein expression patterns in patients with operable nonsmall cell lung carcinoma

S100 proteins are involved in carcinogenesis, metastasis, and survival. S100A2 is a member of the S100 family, and its expression and precise role in patients with non-small cell lung carcinoma (NSCLC) has been debated. Therefore, we examined the immunohistochemical expression patterns of S100A2 in NSCLC in relation to clinicopathological parameters, important molecular biomarkers, and patient outcome. Microarray data for 74 paraffin-embedded specimens from patients with NSCLC were immunostained for S100A2 and p53 proteins. Immunohistochemical staining patterns of S100A2 in the NSCLC tissue samples examined were either nuclear (nS100A2), cytoplasmic (cS100A2), or both. A significant association between nS100A2 positivity and better disease-free interval was observed (hazards ratio 0.47; 95% confidence interval 0.23–0.99; P = 0.047). Similarly, cS100A2 negativity was marginally associated with shorter overall survival (P = 0.07). Patients without lymphatic infiltration and an earlier disease stage had significantly better overall survival and disease-free interval. The S100A2 expression pattern in operable NSCLC varies widely, and this differential expression (nuclear, cytoplasmic or both) seems to correlate with prognosis. Intensity of expression was highest in the early and advanced stages, and equally distributed in the middle stages. This observation may be indicative of a dual role for this protein both during earlier and advanced disease stages, and may also explain the differential immunoexpression of S100A2. Analysis of the disease-free interval showed that nS100A2-negative and p53-positive expression was associated with a statistically significant (P = 0.003) shorter disease-free interval in comparison with nS100A2-positive and p53-negative expression (12 versus 30 months, respectively). Further studies are required to establish whether S100A2 protein may have a substantial role as a prognostic or predictive indicator in this unfavorable group of patients.

Prognostic value of epidermal growth factor receptor expression in operable non-small cell lung carcinoma

&#x0D; &#x0D; &#x0D; Background and aim: Increased expression of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC), supporting the tumor growth by a possible endocrine mechanism, affects patient survival negatively. We designed a study to test EGFR expression by immunohisto- chemistry (IHC) in resected stage I–II NSCLC and to correlate its overexpression with survival.&#x0D; Methods: EGFR expression was evaluated in 98 consecutive NSCLC patients after complete resection (53 squamous cell carcinomas, 40 adenocarcinomas, 5 large cell carcinomas: stage I, 57 (58%) and stage II, 41 (42%). IHC was used to examine the expression of EGFR in resected lung tumor sam- ples obtained from these patients, who had no pre- or post- operative chemotherapy or radiotherapy. Univariate and multivariate analyses were performed for factors influencing patient survival.&#x0D; Results: EGFR was expressed in 51 (52%) of 98 NSCLC sam- ples. More squamous tumors (61%) were EGFR-positive than adenocarcinomas (38%) (p = 0.038). There was a statistically significant correlation between EGFR expression and stage (p = 0.04). No difference was found between EGFR positive and negative tumors in the 5-year overall survival (57% vs. 73%, p = 0.13).&#x0D; Conclusion: The level of EGFR expression in tumors was not a successful predictor of survival in resected NSCLC.&#x0D; &#x0D; &#x0D;

Prognostic value of epidermal growth factor receptor expression in operable non-small cell lung carcinoma

Background and aimIncreased expression of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC), supporting the tumor growth by a possible endocrine mechanism, affects patient survival negatively. We designed a study to test EGFR expression by immunohistochemistry (IHC) in resected stage I-II NSCLC and to correlate its overexpression with survival.MethodsEGFR expression was evaluated in 98 consecutive NSCLC patients after complete resection (53 squamous cell carcinomas, 40 adenocarcinomas, 5 large cell carcinomas: stage I, 57 (58%) and stage II, 41 (42%). IHC was used to examine the expression of EGFR in resected lung tumor samples obtained from these patients, who had no pre- or post-operative chemotherapy or radiotherapy. Univariate and multivariate analyses were performed for factors influencing patient survival.ResultsEGFR was expressed in 51 (52%) of 98 NSCLC samples. More squamous tumors (61%) were EGFR-positive than adenocarcinomas (38%) (p = 0.038). There was a statistically significant correlation between EGFR expression and stage (p = 0.04). No difference was found between EGFR positive and negative tumors in the 5-year overall survival (57% vs. 73%, p = 0.13).ConclusionThe level of EGFR expression in tumors was not a successful predictor of survival in resected NSCLC.

1185 PUBLICATION Relationship between expression of xiap protein in operable non-small cell lung carcinomas and apoptosis index and postoperative prognosis

1185 PUBLICATION Relationship between expression of xiap protein in operable non-small cell lung carcinomas and apoptosis index and postoperative prognosis

Relationship between Expression of XIAP Protein in Operable Non-small Cell Lung Carcinomas and Apoptosis Index and Postoperative Prognosis

Background : Dysregulation of apoptosis plays an important role in carcinogenesis, tumor progression, and resistance to chemotherapy. X-linked inhibitor of apoptosis (XIAP) is considered to be the most potent caspase inhibitor of all known IAP (inhibitor of apoptosis) family members. This study was designed to assess the pattern of expression and the prognostic value of XIAP in radically resected non-small cell lung carcinoma (NSCLC) patients. Method : The expression of XIAP and its relationship with clinicopathologic parameters (patient age, TNM stage, TNM-pT, TNM-pN, histologic type, VEGF expression, microvessel density, PCNA index) and overall survival were analysed with formalin-fixed, paraffin-embedded blocks from eighty cases of NSCLC. In addition, the apoptotic index (AI) was also assessed. Results : In a regard to histologic type, squamous cell carcinoma (SCC) showed XIAP expression in 91.3%(42/46) and adenocarcinoma (AC) in 61.8%(21/34). The difference was significant(p=0.001). There was no correlation between XIAP expression and other parameters. In the group of AC, XIAP expression showed the signifcant correlation with older age group and VEGF expression(p=0.028, p=0.014, respectively). The AI in the group with or without XIAP expression were and , respectively(p=0.001). Both groups just aforementioned showed no significant difference in median survival time (42.5 months, 29.8 months, respectively). Conclusion : This study suggests that the XIAP expression in NSCLCs could have relation to inhibition of apoptosis, and show differential expression according to histologic type. However, its prognostic role during the progression of NSCLC needs to be further defined.

Differential expression of hypoxia inducible factor-1 alpha and tumor cell proliferation between squamous cell carcinomas and adenocarcinomas among operable non-small cell lung carcinomas.

This study aimed to evaluate whether the elevated level of hypoxia-inducible factor-1alpha (HIF-1alpha) correlated with histologic types, angiogenesis, tumor cell proliferation, and clinical parameters in common non-small cell lung carcinomas (NSCLCs). We performed immunohistochemical stains using paraffin-embedded tissue blocks from 84 cases of operable NSCLC [No. of squamous cell carcinoma (SCC), 45; No. of adenocarcinoma (AC), 39]. HIF-1alpha expression was related with histologic types (66.7% in SCCs vs 20.5% in ACs, p<0.001), but not with lymph node status, tumor stage, vascular endothelial growth factor expression, microvessel density (MVD), and proliferating cell nuclear antigen (PCNA) index (p>0.05, respectively). As for the histologic types, MVD and PCNA index were significantly higher in SCCs than in ACs (p=0.009 and p=0.016, respectively). Among HIF-1alpha positive carcinomas, MVD was significantly higher in HIF-1alpha positive SCCs than in HIF-1alpha positive ACs (p=0.023). The overall survival curves were not associated with HIF-1alpha expression or any other histologic parameters (p>0.05). These findings suggest that HIF-1alpha expression in NSCLCs may play a differential role according to histologic types, but its prognostic significance is indeterminate.

Immune function, telomerase, and angiogenesis in patients with primary, operable nonsmall cell lung carcinoma: tumor size and lymph node status remain the most important prognostic features.

Lung carcinoma usually is advanced at the time of presentation and frequently shows metastatic spread. In recent times, prognostic factors such as c-erbB-2 in patients with breast carcinoma have provided useful information and beneficial therapeutic targets. The objective of this study was to evaluate angiogenesis, immune function, and telomerase expression in patients with nonsmall cell lung carcinoma (NSCLC) to determine their prognostic significance. Immunohistochemistry was used to evaluate the expression of human telomerase reverse transcriptase (hTERT; n = 115 patients), interleukin-2r (IL-2r; n = 40 patients), microvessel density (MVD; n = 81 patients), and vascular endothelial growth factor (VEGF; n = 61 patients). Three-year survival follow-up information was available for most patients, and a comprehensive review of clinicopathologic features was carried out. Fifty percent of tumors showed nuclear staining for hTERT, 55% of tumors showed some degree of lymphocyte IL-2r expression, 33% of tumors were recorded with an MVD that was higher than average, and VEGF staining was detected in 85% of tumors. None of the parameters measured had an impact on survival. hTERT expression was correlated with lymph node status. Lymph node status and tumor size were identified as independent prognostic factors. This study failed to identify a marker of prognosis for patients with NSCLC other than tumor size and lymph node status in this population. Telomerase expression was associated with metastases, raising the possibility that this enzyme is involved in the metastatic process. Tumor cell VEGF expression was identified frequently: This growth factor may have potential as a target for antiangiogenic therapy. Lung carcinoma typically is the result of large numbers of mutations. Further understanding of the biologic implications of these mutations will lead to the development of effective prognostic markers and treatments for patients with NSCLC.

DNA aneuploidy, S-phase fraction and nuclear p53 positivity in non-small cell lung carcinoma

Objectives: Surgical resection currently offers the best option for managing non-small cell lung carcinoma (NSCLC) but its efficiency is limited by subsequent tumor recurrence. We evaluated whether flow cytometric study and the p53 gene staining pattern may be useful in this respect. Design and Methods: We took biopsy samples of 40 patients with operable NSCLC to study the frequency of aneuploidy, proliferative activity, and alterations in the p53 tumor suppressor gene and compared them with clinicopathological parameters such as age, gender, smoking, histological type, tumor size, and degree of differentiation. To study DNA content, the nuclei were analyzed by flow cytometry using a FACS flow cytometer (Becton-Dickinson) equipped with an argon ion laser, with a propidium iodide excitation of 488 nm. We used the immunohistochemical technique for p53 analysis in samples of paraffin-embedded tissue corresponding to the same patients from whom fresh tissue was taken. Results: Nuclear p53 staining was detected in 66.7% of the samples; 69.4% of the cases revealed aneuploid DNA histograms and 59% presented with an S phase fraction of more than 12%. Comparison with clinicopathological parameters showed that p53 protein was associated significantly with histological classification (p= 0.04), gender ( p = 0.01), and smoking ( p= 0.04). Conclusions: Immunodetection of p53 overexpression and DNA ploidy in the bronchial epithelium may be a useful tool in any future multifactorial analysis in such tumors for identifying previous lesions that may progress to malignancy.

Prognostic value of angiogenesis in operable non-small cell lung cancer: Giatromanolaki A, Koukourakis M, O'Byrne K et al. Department of Cellular Science, John Radcliffe Hospital, Oxford OX3 9DU. J Pathol 1996;179:80–88

Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2-N0,1) operable non-small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7-12), medium (5-6), and low (2-4). There was a significant correlation between eye appraisal and Chalkley counting (P < 0.0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis (P = 0.05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis (P < 0.0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor (P = 0.0004), followed by N-stage (P = 0.001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor (P = 0.007). Kaplan-Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment.

PROGNOSTIC VALUE OF ANGIOGENESIS IN OPERABLE NON-SMALL CELL LUNG CANCER

Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2-N0,1) operable non-small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7-12), medium (5-6), and low (2-4). There was a significant correlation between eye appraisal and Chalkley counting (P < 0.0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis (P = 0.05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis (P < 0.0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor (P = 0.0004), followed by N-stage (P = 0.001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor (P = 0.007). Kaplan-Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment.

Detection of occult bone marrow micrometastases in patients with operable lung carcinoma.

A large proportion of patients with operable lung carcinoma (no evidence of systemic spread of tumor) develop metastatic disease after primary therapy. More sensitive and specific methods are needed to identify patients at highest risk for recurrence who may benefit most from adjuvant therapy, while sparing those patients who do not require such treatment. Using epithelial-specific monoclonal antibodies, the authors have developed an immunocytochemical assay capable of detecting as few as 2 lung cancer cells in 1 million bone marrow cells. The assay was used to test the bone marrow (from resected ribs) of 43 patients with primary non-small cell lung carcinoma who showed no clinical or pathologic evidence of systemic disease. Occult bone marrow micrometastases (BMMs) were detected in 40% of patients (17/43) with non-small cell lung cancer, including 29% (5/17) of patients with stage I or II disease and 46% of whom (12/26) had stage III disease. The median follow-up was 13.6 months. Patients with occult BMMs had significantly shorter times to disease recurrence compared with patients without BMMs (7.3 vs. > 35.1 months, p = 0.0009). Furthermore, for patients with stage I or II disease, the presence of occult BMMs was significantly associated with a higher rate of recurrence (p = 0.0004). The detection of occult BMMs identifies patients with operable non-small cell lung carcinoma who are at significantly increased risk for recurrence, independent of tumor stage, and may be useful in evaluating patients for adjuvant treatment protocols.

Expression of major histocompatibility class I and class II antigens and intercellular adhesion molecule-1 on operable non-small cell lung carcinomas: Frequency and prognostic significance

Major histocompatibility complex (MHC) antigens and adhesion molecules, such as the intercellular adhesion molecule-1 (ICAM-1), appear to play an important role in the immunological recognition and destruction of tumour cells. We, therefore, examined the expression patterns of these proteins on primary tumours of 91 patients with operable non-small cell lung cancer (NSCLC). Applying immunohistochemistry with monoclonal antibody (MAb) W6/32 against a common framework determinant of HLA class I antigens revealed a deficient expression in 33.0% of the cases analysed, while neo-expression of either HLA class II antigens (MAb TAL.1B5) or ICAM-1 (MAb PA3.58-14) was observed in 26.4 or 29.7% of tumours, respectively. Analysis of consecutive tumour specimens indicated that HLA antigens and ICAM-1 were frequently coexpressed. With regard to clinicopathological risk factors, we could demonstrate a preferential expression of those markers in patients with locally restricted and well-differentiated tumours or no lymph node metastases, which was more pronounced in adenocarcinomas than in squamous cell carcinomas. In contrast, the presence versus the absence of HLA antigens and ICAM-1 was not correlated with the rate of tumour recurrence or overall survival in patients with NSCLC. In conclusion, the co-ordinated expression of immunologically relevant cell surface molecules on primary NSCLC is a frequent event that correlates with distinct parameters of favourable prognosis. However, we have no evidence that the immune response facilitated by these molecules can effectively influence the clinical course of the disease.