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For detecting field carcinogenesis non-invasively, early technical development and case-control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically "fingerprinted", using paired EBC, upper and lower airway donor sample sets. A clinic-based case-control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case-control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1-2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e-04)); former smokers 2.5% (p = 3.6e-05); early stage 1.2% (p = 9.0e-03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment., (© 2023. The Author(s).)

Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

We evaluated the importance of tumor cell selection for generating gene signatures in non-small cell lung cancer. Tumor and nontumor tissue from macroscopically dissected (Macro) surgical specimens (31 pairs from 32 subjects) was homogenized, extracted, amplified, and hybridized to microarrays. Adjacent scout sections were histologically mapped; sets of approximately 1000 tumor cells and nontumor cells (alveolar or bronchial) were procured by laser capture microdissection (LCM). Within histological strata, LCM and Macro specimens exhibited approximately 67% to 80% nonoverlap in differentially expressed (DE) genes. In a representative subset, LCM uniquely identified 300 DE genes in tumor versus nontumor specimens, largely attributable to cell selection; 382 DE genes were common to Macro, Macro with preamplification, and LCM platforms. RT-qPCR validation in a 33-gene subset was confirmatory (ρ = 0.789 to 0.964, P = 0.0013 to 0.0028). Pathway analysis of LCM data suggested alterations in known cancer pathways (cell growth, death, movement, cycle, and signaling components), among others (eg, immune, inflammatory). A unique nine-gene LCM signature had higher tumor-nontumor discriminatory accuracy (100%) than the corresponding Macro signature (87%). Comparison with Cancer Genome Atlas data sets (based on homogenized Macro tissue) revealed both substantial overlap and important differences from LCM specimen results. Thus, cell selection via LCM enhances expression profiling precision, and confirms both known and under-appreciated lung cancer genes and pathways.

Many studies have shown that microRNA expression in cancer may be regulated by epigenetic events. Recently, we found that in lung cancer miR-212 was strongly down-regulated. However, mechanisms involved in the regulation of miR-212 expression are unknown. Therefore, we addressed this point by investigating the molecular mechanisms of miR-212 silencing in lung cancer. We identified histone modifications rather than DNA hypermethylation as epigenetic events that regulate miR-212 levels in NSCLC. Moreover, we found that miR-212 silencing in vivo is closely associated with the severity of the disease.

Taxol may contribute to intrinsic chemoresistance by activating the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in human lung tumors heterotransplanted into nude mice. Unlike xenograft models that are derived from cells with multiple genetic alterations due to prolonged passage, heterotransplanted tumor models are more clinically relevant. Combined treatment with both drugs resulted in inhibition of tumor growth in all models and tumor regressions in three of four models tested, supporting our previous observation that Taxol's efficacy is potentiated by MEK inhibition. Concurrent administration was superior to intermittent dosing. Pharmacodynamic assessments of tumors indicated that suppression of MEK was associated with induction of S473 phosphorylated Akt and reduced proliferation in the combination groups relative to single agents, in addition to suppression of fibroblast growth factor-mediated angiogenesis and reduced expression of vascular endothelial growth factor. These findings are significant and indicate that this combination may have broad therapeutic applications in a diverse range of lung tumors with different intrinsic chemosensitivities.

This study evaluates the influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer (NSCLC). The Eastern Cooperative Oncology Group conducted a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC. A laboratory correlative study assessed the prevalence and prognostic significance of p53 and K-ras mutations. Patients were randomized to receive either radiotherapy (RT) alone or four cycles of cisplatin and VP-16 administered concurrently with radiotherapy (CRT). Median survival was 35 months for the 285 men and 41 months for the 203 women enrolled in the study (P = 0.12). The relative risk (RR) of death for men vs women was 1.19 (95% confidence interval [CI], 0.95-1.49). Median survival of the 147 men and 95 women randomized to the RT arm was 39 months each (P = 0.35). Median survival of the 138 men and 108 women randomized to the CRT arm was 30 and 42 months, respectively (P = 0.18). Disease recurrence patterns were similar between the genders. Univariate and multivariate analyses demonstrated improved survival for women with tumors of non-squamous histology (P < 0.01). The distribution of p53 and K-ras mutations was similar between the genders and had no influence on survival. Gender does not influence survival following adjuvant RT or CRT administered to patients with completely resected stages II and IIIa NSCLC. However, women with non-squamous histology have increased survival when compared to men., (Copyright 2002 Elsevier Science Ireland Ltd.)

Non-small-cell lung cancer (NSCLC) has one of the highest death rates among the various forms of cancer. In attempts to improve on this unsatisfactory outcome, different radiation schedules and chemo-therapy agents have been examined in phase II or III studies. These have led to modest improvements in local control and survival, but combined therapies are associated with substantial hematologic toxicity. In this phase II study, 80 consecutive stage IIIA or IIIB NSCLC patients were treated with concomitant chemotherapy and twice-a-day irradiation in a total dose of 60 Gy in 1.5 Gy fractions. Patients scheduled for surgery received 45 Gy only. Paclitaxel (30 mg/m 2 ) on days 1-4 and cisplatin (100 mg/m 2 ) on day 5 were administered in the first and fourth weeks of treatment. Granulocyte colony stimulating factor (30 ng/m 2 ) was given on days 10-15. The local control, the 1- and 2-year survival rates and the occurrence of acute hematologic toxicity in the non-surgically treated patients were examined. Fifty-two patients were treated without and 28 with surgery. Among the non-surgically treated cases, 43 were evaluable for response and 47 for acute toxicity during a median follow-up of 22 months. The rate of local control was 65% (28/43), and the 1- and 2-year survival rates proved to be 68% and 48%, respectively, with a median survival of 28 months. Severe acute grade 3-4 toxicities included grade 4 leukopenia in 6 cases (13%), grade 3 leukopenia in 4 cases (9%), grade 3 esophagitis in 3 cases (6%) and grade 3 anemia in 3 cases (6%). Our results and the relevant data from the literature support the application of twice-a-day irradiation with concomitant chemotherapy in stage IIIA and IIIB NSCLC. Local control and survival were improved relative to once-a-day irradiation with sequential or concomitant chemotherapy.

Purpose: To determine the prognostic and predictive significance of p53 and K-ras mutations in patients with completely resected non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients were randomized preoperatively to receive adjuvant postoperative radiotherapy (Arm A) or radiotherapy plus concurrent chemotherapy (Arm B). p53 protein expression was studied by immunohistochemistry (IHC) and p53 mutations in exons 5 to 8 were evaluated by single-strand conformational analysis. K-ras mutations in codons 12, 13, and 61 were determined using engineered restriction fragment length polymorphisms., Results: Four hundred eighty-eight patients were entered onto E3590; 197 tumors were assessable for analysis. Neither presence nor absence of p53 mutations, p53 protein expression, or K-ras mutations correlated with survival or progression-free survival. There was a trend toward improved survival for patients with wildtype K-ras (median, 42 months) compared with survival of patients with mutant K-ras who were randomized to chemotherapy plus radiotherapy (median, 25 months; P = .09). Multivariate analysis revealed only age and tumor stage to be significant prognostic factors, although there was a trend bordering on statistical significance for K-ras (P = .066). Analysis of survival difference by p53 by single-stranded conformational polymorphism and IHC, interaction of p53 and K-ras, interaction of p53 and treatment arm, nodal station, extent of surgery, weight loss, and histology did not reach statistical significance., Conclusion: p53 mutations and protein overexpression are not significant prognostic or predictive factors in resected stage II or IIIA NSCLC. K-ras mutations may be a weak prognostic marker. p53 or K-ras should not be routinely used in the clinical management of these patients.

Background: We conducted a randomized trial to determine whether combination chemotherapy plus thoracic radiotherapy is superior to thoracic radiotherapy alone in prolonging survival and preventing local recurrence in patients with completely resected stage II or IIIa non-small-cell lung cancer., Methods: After surgical staging and resection of the tumor (usually by lobectomy or pneumonectomy), the patients were randomly assigned to receive either four 28-day cycles of cisplatin (60 mg per square meter of body-surface area intravenously on day 1) and etoposide (120 mg per square meter intravenously on days 1, 2, and 3) administered concurrently with radiotherapy (a total of 50.4 Gy, given in 28 daily fractions) or radiotherapy alone (a total of 50.4 Gy, given in 28 daily fractions)., Results: Of the 488 patients who were enrolled in the study, 242 were assigned to receive radiotherapy alone and 246 were assigned to receive chemotherapy and radiotherapy. The median duration of follow-up was 44 months. Treatment-associated mortality was 1.2 percent in the group given radiotherapy alone and 1.6 percent in the group given chemotherapy and radiotherapy. The median survival was 39 months in the group given radiotherapy and 38 months in the group given chemotherapy and radiotherapy (P= 0.56 by the log-rank test). The relative likelihood of survival among patients assigned to receive chemotherapy and radiotherapy, as compared with those assigned to receive radiotherapy alone, was 0.93 (95 percent confidence interval, 0.74 to 1.18). Intrathoracic disease recurred within the radiation field in 30 of 234 patients (13 percent) in the group given radiotherapy and in 28 of 236 patients (12 percent) in the group given chemotherapy and radiotherapy (P=0.84); data on recurrence were not available for 18 patients., Conclusions: As compared with radiotherapy alone, adjuvant radiotherapy and chemotherapy with cisplatin and etoposide does not decrease the risk of intrathoracic recurrence or prolong survival in patients with completely resected stage II or IIIa non-small-cell lung cancer.

Background: Mediastinal lymph node dissection (MLND) is an integral part of surgery for non-small cell lung cancer (NSCLC). To compare the impact of systematic sampling (SS) and complete MLND on the identification of mediastinal lymph node metastases and patient survival, the Eastern Cooperative Oncology Group (ECOG) stratified patients by type of MLND before participation in ECOG 3590 (a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC)., Methods: Eligibility requirements for study entry included a thorough investigation of the mediastinal lymph nodes with either SS or complete MLND. The former was defined as removal of at least one lymph node at levels 4, 7, and 10 during a right thoracotomy and at levels 5 and/or 6 and 7 during a left thoracotomy, while the latter required complete removal of all lymph nodes at those levels., Results: Three hundred seventy-three eligible patients were accrued to the study. Among the 187 patients who underwent SS, N1 disease was identified in 40% and N2 disease in 60%. This was not significantly different than the 41% of N1 disease and 59% of N2 disease found among the 186 patients who underwent complete MLND. Among the 222 patients with N2 metastases, multiple levels of N2 disease were documented in 30% of patients who underwent complete MLND and in 12% of patients who had SS (p = 0.001). Median survival was 57.5 months for those patients who had undergone complete MLND and 29.2 months for those patients who had SS (p = 0.004). However, the survival advantage was limited to patients with right lung tumors (66.4 months vs 24.5 months, p<0.001)., Conclusions: In this nonrandomized comparison, SS was as efficacious as complete MLND in staging patients with NSCLC. However, complete MLND identified significantly more levels of N2 disease. Furthermore, complete MLND was associated with improved survival with right NSCLC when compared with SS.

The relationship between clonal chromosome alterations and various clinical parameters was evaluated in 70 patients with non-small cell lung cancer (NSCLC) for whom detailed karyotypic assessment was possible. Included in the analysis are karyotypes of 63 previously published cases and seven new NSCLCs. Clinical features investigated were diagnosis, tumor stage and grade, gender, smoking history measured in pack years, and survival. Certain chromosome abnormalities were significantly associated with histologic subtype, tumor grade, stage, and prognosis. Rearrangements involving chromosome arms 2p and 3q were more common in squamous cell carcinoma (SCC) than in adenocarcinoma (ADC). Loss of 3p was observed more often in SCC. Gain of 7p was more frequent in ADC. Rearrangement of 17p was associated with a lower tumor grade. Rearrangement of Xp and loss of chromosome 12 or 22 were each associated with higher tumor stage. Rearrangement of 3p or 6q was correlated with a better survival outlook. In contrast, loss of chromosomes 4 or 22 portended a poor prognosis. Finally, an increased number of marker chromosomes was observed in patients having a higher number of pack years. These data indicate that chromosome abnormalities can have clinical and pathologic significance in NSCLC.

Purpose: Patients with locally advanced, initially unresectable non-small cell lung cancer (NSCLC) have a median survival time of 9 to 11 months, a 2-year survival rate of 13%, and a long-term survival rate of 5% to 7% when treated with radical thoracic radiation alone. Because of the preclinical radiosensitizing capabilities of 5-fluorouracil and cisplatin and the therapeutic synergy of etoposide and cisplatin, we combined these agents with full-dose radical thoracic radiation to determine the feasibility and efficacy of this approach in locally advanced NSCLC., Methods: Patients with clinical stage IIIb and bulky IIIa NSCLC and ECOG performance status 0 or 1 received 5-fluorouracil infusion (640-800 mg/m2/d CVI days 1-5, 29-34), cisplatin (20 mg/m2/d, days 1-5, 29-34), etoposide (50 mg/m2, days 1, 3, 5, 29, 31, 33) and concurrent thoracic radiation (60 Gy/2 Gy/d/30 Fx). Patients with adequate cytoreduction proceeded to surgical resection., Results: From March 1987 to July 1990, 41 patients were enrolled on study; 40 are evaluable. The objective response rate was 90%. Thirteen patients (39%), five with clinical stage IIIb disease and eight with IIIa disease, underwent thoracotomy and resection; three proved to have pathological complete remissions. Ten of 77 chemotherapy courses were complicated by neutropenic fever. Grade 3 or 4 esophagitis occurred in 21 patients (52%). Cardiac ischemia or infarction occurred in two patients (5%). There were seven deaths in the first 6 months in the absence of disease progression. Two-year survival was 38%, 3-year survival 25%, and 4- to 5-year survival 18%. Six patients (15%) remain alive at the median follow-up time of 66 months (range, 64-84)., Conclusions: Despite substantial early morbidity and mortality, concurrent, aggressive chemoradiation produced a long-term survival rate in locally advanced NSCLC comparable to other combined modality approaches. However toxicity, particularly esophagitis and postoperative complications, preclude the use of this regimen in phase III studies. Combined modality approaches for locally advanced, initially unresectable NSCLC have become standard; research must simultaneously focus on ways to enhance efficacy and reduce toxicity.

Present methods of predicting nodal progression preoperatively in patients with non-small cell lung cancer (NSCLC) are inadequate. Our hypothesis was that p53 expression in primary NSCLC would predict disease progression, making it a useful marker of adverse outcome. From 1987 to 1992, sixty-eight consecutive NSCLC patients underwent potentially curative lung resection and mediastinal lymph node dissection by one surgeon. Primary tumours were analysed using the p53 monoclonal antibody 1801. p53 overexpression was found in 53% of tumours. p53 expression did not correlate with age, gender, histology or stage. A trend toward a higher incidence of p53 expression was seen in tumours with nodal spread (P = 0.06), and p53 expression correlated significantly (P = 0.03) with improved disease-free survival in patients with squamous cell carcinoma (SCC). p53 was the fourth most important independent predictor of survival, behind histology, gender and nodal disease. As a weak independent predictor of survival, the correlation of p53 expression with survival in patients with SCC must be evaluated with caution. If borne out in a larger patient population, p53 expression may be a marker of nodal disease progression in patients with NSCLC.

Background: The role of resection in Stage IIIA (N2) non-small cell lung cancer (NSCLC) remains controversial despite reported survival rates of 25-40%. This study was undertaken to identify factors associated with a high risk of treatment failure after resection of clinically occult Stage IIIA (N2) NSCLC: Such prognostic factors may identify high risk patients as candidates for future clinical trials of multimodality lung cancer treatment and be important stratification factors in such trials., Methods: The clinical and pathological records of 32 patients with clinical NO pathologic N2 NSCLC who underwent lobectomy (n = 17), pneumonectomy (n = 12), or bilobectomy (n = 3) and complete mediastinal lymph node dissection at Fox Chase Cancer Center from 1987 to 1991 were reviewed. A multivariate analysis of clinical and pathologic variables was performed., Results: Median follow-up was 15 months (range 5-55). Fifty-nine percent have recurred and 44% have died. Median disease free and overall survival were 16 and 19 months, respectively. Two year disease free and overall survival were 24% and 43%, respectively. No patient with more than one level of mediastinal lymph node metastases survived two years free of disease. Univariate and multivariate analysis revealed a longer disease free survival for those receiving adjuvant radiation therapy (19 vs 5 months) but no increase in overall survival., Conclusions: This experience with clinically occult Stage IIIA (N2) NSCLC suggests that multiple levels of mediastinal lymph node metastases predict treatment failure in patients following resection and that adjuvant mediastinal radiation improves disease free but not overall survival.

A detailed cytogenetic analysis of 63 non-small cell lung carcinomas (NSCLCs) was carried out for identification of recurrent chromosomal alterations. Most specimens displayed very complex karyotypes with multiple numerical and structural changes (median number, 31). Losses of chromosomes 9 (65% of cases) and 13 (71%) were the most frequent numerical changes. Loss of the Y was often observed in tumors from males. Gain of chromosome 7 was also frequent (41%). Chromosome arms 1p, 1q, 3p, 3q, 6q, 7q, 8q, 9p, 11q, 17p, and 19q were particularly prone to rearrangement. The chromosome arm most often contributing to losses was 9p (79%). Other arms that were frequently lost included 3p, 6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, 22q, and the short arm of each acrocentric chromosome. The percentage of cases with loss of 3p was significantly higher in squamous cell carcinomas (94%) than in adenocarcinomas (60%). There was also a statistically significant increase in the proportion of cases with gains of 1q, 7p, and 11q in adenocarcinomas compared to squamous cell carcinomas. Several recurrent isochromosomes and unbalanced exchanges were found. Among these was i(5p), which was observed in nine tumors, eight of which displayed adenomatous features. An i(8q) was identified in six cases, including five adenocarcinomas. Double minutes and/or homogeneously staining regions were seen in seven specimens. These data indicate that numerous chromosome alterations contribute to the pathogenesis of NSCLC and that, amid this widespread genomic disarray, recurrent abnormalities exist that could have biological and clinical implications.

Background: Many human tumor cells display alterations in blood group antigen expression, and the loss of antigen A expression by non-small cell lung cancer (NSCLC) in blood group A patients has recently been associated with decreased survival., Methods: To confirm this finding, we performed a retrospective study of 62 NSCLC patients undergoing potentially curative resection between August 1987 and December 1991 who were blood group A and had paraffin-embedded primary lung cancer tissue suitable for immunohistological analysis of antigen A expression. Twenty-seven patients expressed antigen A in their tumors, whereas 35 had loss of antigen expression. Disease-free survival (DFS) curves were calculated for stage I (n = 26) and IIIA (n = 25) patients., Results: The two groups of patients with or without antigen A expression did not have significantly different DFS. A proportional hazards regression analysis identified no significant difference in the DFS of stage I patients with or without antigen A, but stage IIIA patients who had preservation of antigen A had significantly shorter DFS than did those who lost antigen A (p = 0.0002)., Conclusions: The loss of expression of antigen A by primary tumor cells was not a significant adverse prognostic factor in DFS in our series, and we would recommend further studies to define clearly the clinical importance of antigen A expression in pulmonary carcinoma.

Purpose: To assess the response rate, median and long-term survival of patients (pts) with locally advanced, initially inoperable non-small cell lung cancer (NSCLC) treated on a phase II study of radical thoracic radiotherapy (TRT) and concurrent radiosensitizing chemotherapy., Methods and Materials: From 3/87 to 7/90, 41 previously untreated patients at Fox Chase Cancer Center with locally advanced non-small cell lung cancer, 24 with bulky clinical Stage IIIA, and 17 with IIIB disease, received concurrent thoracic radiotherapy (60 Gy/2.0 Gy/d in 6 weeks) and 2 cycles of infusional 5FU (640-800 mg/m2/24 hrs x 5 d); cisplatin (20 mg/m2 qd x 5); and etoposide (50 mg/m2 d 1, 2, 5) administered days 1 and 28 of TRT., Results: Forty of 41 were evaluable. Response rate was 90%, with radiographic CR in 20%. Thirteen pts (33%) underwent thoracotomy and complete resection with clinical downstaging in 10, including three pathologic CR's. Overall median survival was 14 months and 2-year survival was 38% with no difference between CS IIIA and IIIB pts (p = 0.2224). At median potential follow-up of 42 months, 8/40 pts. (20%) are alive and progression-free, including 4 of 13 resected pts. The chief toxicity was esophagitis, occurring in 32 pts. (80%), Grade 3-4 in 21 (52%), with 13 (33%) requiring hospitalization and 7 (18%) needing TPN. Grade 3-4 granulocytopenia was noted in 20 pts. (50%) with ten episodes of fever mandating intravenous antibiotics. Cardiac ischemia was documented in 2 (5%). Of 13 thoracotomy pts, six underwent lobectomy without perioperative mortality; 3 of 7 pneumonectomy pts died post-operatively, two from broncopleural fistula, and one from ARDS., Conclusion: This aggressive regimen produced a 2-year survival (38%) comparable to the best arm of cancer and leukemia groups B study 8433, which administered radical thoracic radiotherapy after protoadjuvant vinblastine and cisplatin in similar and earlier stage non-small cell lung cancer patients. Toxicity, particularly esophagitis, was severe, but of short duration. An unacceptably high complication rate was seen following pneumonectomy, but not lobectomy.

Preoperative chemotherapy and radiation administered separately or in combination have been used in the treatment of locally advanced non-small cell lung cancer. To assess the postoperative morbidity and mortality associated with aggressive neoadjuvant therapy, we reviewed the records of 13 patients who underwent resection of locally advanced non-small cell lung cancer after two monthly cycles of infusional 5-fluorouracil, 640 to 800 mg/m2 (days 1 through 5); cisplatin, 20 mg/m2 (days 1 through 5); etoposide, 50 mg/m2 (days 1, 3, and 5); and concomitant radical thoracic irradiation (6,000 cGy) administered in 200-cGy daily fractions. Six patients underwent lobectomy with no mortality, whereas 7 pneumonectomies were associated with three deaths (43%). Culture-negative, diffuse pulmonary infiltrates developed 3 to 6 days after operation in 5 of 7 pneumonectomy patients and in 1 of 6 lobectomy patients. Two patients who had undergone pneumonectomy died of progressive adult respiratory distress syndrome. A third death resulted from a bronchopleural fistula that developed 30 days after pneumonectomy. Morbidity and mortality were not associated with preoperative pulmonary function test results, nutritional status, or intraoperative inspired oxygen fraction (p > 0.05 by chi 2 test). Only pneumonectomy correlated with increased morbidity and mortality (p < 0.05 by chi 2 test). We conclude that lobectomy may be performed safely after this combination of aggressive chemotherapy and high-dose radiation, but pneumonectomy is associated with unacceptable morbidity and mortality.

Primary tumors from 39 patients with non-small cell lung carcinoma (NSCLC) were examined for cytogenetic abnormalities by conventional short-term harvest (1-39 days) of primary cultures of minced solid-tumor tissues and by harvest of monolayer cultures of tumor tissue (6 days to 5 months) on murine fibroblast feeder layers. A successful karyotype was obtained with both methods in nine of 39 cases. Among the remaining 30 cases, a successful karyotype was obtained in eight cases by the conventional method only and in three cases by the feeder cell method only. The success rates were 44% for the conventional method, and 31% for the feeder cell method, and the combined success rate was 51% for one or the other method. The feeder culture method, in which harvests were usually performed at later times than with the conventional method, generally produced metaphases with superior banding, which allowed clearer definition of cytogenetic abnormalities. In addition, cell lines were established in eight of these cases by the feeder cell method. Karyotypes from the longer-term harvests typically were very similar to those from short-term conventional cultures. Minor numerical differences and/or a few additional structural abnormalities were noted in seven of the nine cases analyzed by both methods. Overall, however, even in karyotypes from 5-month cultures, the prominent recurrent changes and modal chromosome numbers observed in short-term cultures were still present. The results indicate that long-term culture with fibroblast feeder cells is a valid means of obtaining cells from solid lung tumors for cytogenetic and molecular analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Several options are available for treatment of malignant pleural effusions in patients with non-small-cell lung cancer. Repeat thoracentesis may be appropriate for the patient with limited survival and a slowly recurrent effusion. Pleurodesis with a sclerosing agent administered via a chest tube is the most widely used therapy, though controversy exists as to which drug produces the best results. Pleuroperitoneal shunting remains an option for those patients whose lung is trapped by tumor. Video-assisted thoracoscopy is likely to change the treatment patterns of malignant pleural effusion. Thoracoscopic pleurectomy can be performed with minimal morbidity. Alternatively, sclerosing agents such as talc can be easily and uniformly introduced into the thoracic cavity under thoracoscopic control. Future therapy is likely to entail a diagnostic thoracentesis followed by a definitive thoracoscopic procedure.

The relationship between DNA content, TNM stage, tumor size, grade, histology, and disease-free survival was assessed in a retrospective study of patients with non-small cell lung cancer who had undergone resection and complete mediastinal lymph node dissection. Flow cytometric analysis was performed on paraffin-embedded tissue of 90 consecutive patients. The patients were analyzed both as a group and by individual stage. Median follow-up was 11 months (range, 1 to 35 months). Aneuploid tumors were not significantly different from diploid tumors with regard to pathologic TNM stage (p = 0.34), size (p = 0.5), grade (p = 0.5), or histology (p = 0.34). Disease-free survival of patients with aneuploid tumors was not significantly different than that of patients whose tumors had normal DNA content (p = 0.69). DNA content did not correlate with established prognostic factors in patients with non-small cell lung cancer who underwent resection and complete mediastinal lymph node dissection.

The outcome of thirty-seven patients with a post-resection locoregional recurrence of non-small cell lung cancer treated with radiation therapy alone between 1979 and 1989 was compared to that of 759 patients with unresected non-small cell lung cancer also treated with standard radiation during the same period. Each patient's locoregional recurrence was staged using the current American Joint Committee on Cancer staging system. Comparison of pretreatment characteristics between the two groups, including age, sex, extent of weight loss, performance status, stage, and histologic subtype revealed fewer patients with greater than 5% weight loss (35 vs. 47%, p = 0.04) and more cases with squamous histology (54 vs. 28%, p = 0.01) among the patients with locoregional recurrences than those with newly diagnosed lesions. Over 80% of both groups had clinical stage III lesions. The median radiation doses were 56 and 59 Gy for recurrent and newly diagnosed cases (p = NS). For the patients with locoregional recurrences, the median time from resection to recurrence was 13 months (range: 3-118 months), and the recurrences were predominantly nodal in 25 cases, chest wall/pleural in four and at the bronchial stump in eight. When measured from the date of documented recurrence, the median survival time and 2-year actuarial survival rate of the patients with recurrent lesions were 12 months and 22%, as compared to 12 months and 26% for the newly diagnosed patients (p = NS). Freedom from documented locoregional tumor progression at 2 years was 30% for both groups. Patients with bronchial stump lesions had superior survival to those with nodal or chest wall recurrences, with a median survival time of 36 versus 9 months. A therapeutic approach to selected patients with post-resection locoregional recurrence of non-small cell lung cancer equally aggressive to that for newly diagnosed lung cancer patients is justified by these results, especially for patients with bronchial stump recurrences.

Cytogenetic analysis was performed on 16 primary tumors, 2 effusions, and 3 cell lines from 21 patients with non-small cell lung cancer (NSCLC). In 20 patients specimens were obtained prior to initiating cytotoxic therapy. Extensive clonal chromosome alterations were found in all cases. The most frequent numerical changes were polysomy 7 and polysomy 20 (each seen in 12 specimens). In addition, tumor cells from another six cases exhibited partial trisomy 7, with the shortest region of overlap (SRO) at 7p11-p13. Rearrangements of chromosomes 1, 3, 6, 8, 11, 15, 17, and 19 were each observed in nine or more tumors. Breakpoints were clustered at several chromosomal sites, including 1p13, 3p13, 15p11-q11, 17p11, and 19q13. Recurrent loss involving 1p, 3p, 6q, 11p, 15p, 17p, and 19q were each seen in at least eight cases. The SRO of 3p losses was at band 3p21. Double minute chromosomes were found in three tumors. Overall, our findings indicate that even though karyotypes in newly diagnosed NSCLC are very complex, recurrent cytogenetic changes can be identified. The high incidence of loss of 17p (14 of 21 specimens) appears to be compatible with reports implicating the TP53 gene (at band 17p13) as a frequent site for genetic alteration in lung cancer. Moreover, the recurrence of loss of 3p (12 cases) and 11p (10 cases) is also consistent with recent molecular evidence. The existence of other "hot spots" for cytogenetic change, particularly those involving specific regions on chromosomes 7, 15, and 19, warrants further molecular investigation of these sites in NSCLC.

Extramucosal microscopic residual disease (MRD) at the bronchial resection margin was identified in 45 (1.6%) of 2,890 patients who underwent resection of primary non-small cell lung cancer between 1975 and 1985. In 9 of these patients, residual tumor was confined to submucosal lymphatics, whereas in the other 36, MRD was found in peribronchial soft tissue. All patients underwent complete mediastinal lymphadenectomy. Three patients had stage I disease, 3 had stage II, 33 had stage IIIa, 4 had stage IIIb, and 2 had stage IV. Recurrent disease developed in 34 (81%) of the evaluable patients; the recurrence was local in 11 (32%). Median time from operation to diagnosis of local recurrence was 8 months. Sixty percent of the recurrences in the N0 group were local, and only 23% of those in the N2 group were local. Extramucosal MRD is most frequently associated with advanced-stage disease. Postoperative therapy had no effect on the development of recurrent disease. We found no difference in survival between patients whose initial site of recurrence was local as opposed to distant. Median survival after the identification of either local or distant recurrence was 5 months. The finding of extramucosal MRD identifies a subset of patients with a poorer prognosis compared with those with clear resection margins.