Clonality Testing in Veterinary Medicine: A Review With Diagnostic Guidelines.

The accurate distinction of reactive and neoplastic lymphoid proliferations can present challenges. Given the different prognoses and treatment strategies, a correct diagnosis is crucial. Molecular clonality assays assess rearranged lymphocyte antigen receptor gene diversity and can help differentiate reactive from neoplastic lymphoid proliferations. Molecular clonality assays are commonly used to assess atypical, mixed, or mature lymphoid proliferations; small tissue fragments that lack architecture; and fluid samples. In addition, clonality testing can be utilized to track neoplastic clones over time or across anatomic sites. Molecular clonality assays are not stand-alone tests but useful adjuncts that follow clinical, morphologic, and immunophenotypic assessment. Even though clonality testing provides valuable information in a variety of situations, the complexities and pitfalls of this method, as well as its dependency on the experience of the interpreter, are often understated. In addition, a lack of standardized terminology, laboratory practices, and interpretational guidelines hinders the reproducibility of clonality testing across laboratories in veterinary medicine. The objectives of this review are twofold. First, the review is intended to familiarize the diagnostic pathologist or interested clinician with the concepts, potential pitfalls, and limitations of clonality testing. Second, the review strives to provide a basis for future harmonization of clonality testing in veterinary medicine by providing diagnostic guidelines.

Hepatosplenic and hepatocytotropic T-cell lymphoma: two distinct types of T-cell lymphoma in dogs.

The clinical, clinicopathologic, and pathological findings of 9 dogs with T-cell lymphoma that involved the liver in the absence of peripheral lymphadenopathy were assessed. Seven dogs had hepatosplenic T-cell lymphoma (HS-TCL). Dogs with HS-TCL presented with hepato- and/or splenomegaly, regenerative anemia, thrombocytopenia, and hypoproteinemia. The clinical course was rapidly progressive with all dogs but 1 dead within 24 days of initial presentation. Neoplastic lymphocytes were centered on hepatic and splenic sinusoids and had a CD3+ (5/7), TCRαß- (5/5), TCRγδ+ (3/5), CD11d+ (6/7), granzyme B+ (5/7) immunophenotype. Bone marrow and lungs were consistently but variably involved. These findings closely resemble the human disease and support the classification of HS-TCL as a distinct World Health Organization entity in dogs. The remaining 2 dogs markedly differed in the pattern of hepatic involvement by neoplastic lymphocytes, which were not confined to hepatic sinusoids but invaded hepatic cords. In addition, neoplastic cells had a CD11d- immunophenotype, and clinicopathologic data indicated marked cholestasis and mild to absent anemia. Based on the distinct tropism of neoplastic lymphocytes for hepatocytes, the name hepatocytotropic T-cell lymphoma (HC-TCL) is proposed. Given the histomorphologic, clinicopathologic, and immunophenotypic differences, HC-TCL likely represents a separate biological entity rather than a histomorphologic variant of HS-TCL.

Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral functioning.

The long-term effects of developmental alcohol and stress exposure are well documented in both humans and non-human animal models. Damage to the brain and attendant life-long impairments in cognition and increased risk for psychiatric disorders are debilitating consequences of developmental exposure to alcohol and/or psychological stress. Here we discuss evidence for a role of epigenetic mechanisms in mediating these consequences. While we highlight some of the common ways in which stress or alcohol impact the epigenome, we point out that little is understood of the epigenome's response to experiencing both stress and alcohol exposure, though stress is a contributing factor as to why women drink during pregnancy. Advancing our understanding of this relationship is of critical concern not just for the health and well-being of individuals directly exposed to these teratogens, but for generations to come.

A comprehensive test system to identify suitable antibodies against p53 for immunohistochemical analysis of canine tissues.

The tumour suppressor p53 is commonly detected in tissues of companion animals by means of antibodies raised against the human protein. The following three-step procedure was devised to test the suitability of such antibodies for immunohistochemistry on canine tissues. (1) Western blot and immunohistochemical analyses on bacterially expressed recombinant canine protein to assess human-to-canine cross-reactivity. (2) Immunohistochemistry of cultured, UVB-irradiated canine keratinocytes to evaluate suitability for detection of endogenous p53. (3) Immunohistochemistry on tissue arrays to further substantiate suitability of the antibodies on a panel of normal and neoplastic human and canine tissues. Five of six antibodies cross-reacted with recombinant canine p53. Three of these (PAb122, PAb240, CM-1) also immunolabelled stabilized wild type p53 in cell cultures and elicited a consistent, characteristic labelling pattern in a subset of tumours. However, two alternative batches of polyclonal antibody CM-1 failed to detect p53 in cell cultures, while showing a characteristic labelling pattern of a completely different subset of tumours and unspecific labelling of normal tissues. The test system described is well suited to the selection of antibodies for immunohistochemical p53 detection. The results emphasize the need to include appropriate controls, especially for polyclonal antibodies.

Recurrent deletions of specific chromosomal sites in 1p, 3p, 6q, and 9p in human malignant mesothelioma.

Detailed cytogenetic analyses were carried out on primary tumor specimens and cell lines from 23 patients with pleural malignant mesothelioma (MM). Clonal abnormalities were identified in 20 of 23 MM. In 3 cases, karyotypic data were compiled from harvests of both short-term cultures (1-3 days), and primary cultures grown on murine feeder layers for several weeks. The karyotypes obtained with these 2 different culture methods were very similar, although polyploid versions of abnormal clones were found only in the long-term cultures. In addition, while short-term cultures from 9 tumor biopsies usually exhibited near-diploid clones, cell lines derived from 11 tumors tended to have higher ploidies. Each of the cytogenetically abnormal MM displayed multiple clonal alterations. The 2 most frequent changes were chromosomal losses of specific regions in 1p (17 cases) and 9p (16 cases). The shortest regions of overlap of these losses were at 1p21-p22 and 9p21-p22, respectively. Other common abnormalities included losses of 3p21 (13 cases) and 6q15-q21 (9 cases), and numerical losses of chromosomes 14, 16, 18, and 22 (each observed in 10-13 tumors). In many of the MM examined, most or all of these recurrent changes occurred in combination, suggesting the involvement of a pathogenetic cascade in this cancer. The pattern of recurrent chromosomal losses suggests that these regions represent the locations of tumor suppressor genes whose loss/inactivation may have a pivotal role in MM tumorigenesis.

Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy.

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.

Report of phase II trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 Gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky IIIA non-small cell lung cancer.

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.

Management of adenocarcinoma of the esophagus with chemoradiation alone or chemoradiation followed by esophagectomy: results of sequential nonrandomized phase II studies.

PURPOSE: The incidence of adenocarcinoma of the esophagus is increasing, but the optimal treatment for this disease is unknown. We evaluated the efficacy of chemoradiation and chemoradiation followed by esophagectomy as treatment for adenocarcinoma of the esophagus in sequential prospective nonrandomized phase II studies. METHODS AND MATERIALS: Between May 1981 and June 1992, all previously untreated patients (N = 35) with potentially resectable adenocarcinoma of the esophagus (clinical Stage I or II) were treated with curative intent in sequential prospective Phase II studies. From May 1981 to August 1987, 11 patients (median age 66) were treated with concurrent chemotherapy [mitomycin C, and 5-fluorouracil (5-FU)] and radiotherapy to a median dose of 60 Gy (CRT group). From September 1987 to June 1992, 24 patients (median age 65) were treated with the same regimen of chemoradiation followed by planned esophagectomy (CRT+PE group). Of these, 12 patients (median age 62) actually underwent esophagectomy (CRT+E subgroup). RESULTS: The median overall survival was 19 months for the CRT group and 15 months for the CRT+PE group. For the CRT+E subgroup, the median overall survival was 33 months. The 3-year actuarial overall survival for the CRT and the CRT+PE groups were 36 and 28% (p = 0.949). The subset of patients treated with chemoradiation followed by esophagectomy had a 3-year actuarial overall survival of 33% (p = 0.274). The 3-year actuarial freedom from local failure rates were similar: 62% in the CRT group vs. 58% in the CRT+PE group. Of the 12 patients who underwent esophagectomy (CRT+E group), 9 (75%) were free of local failure. Four of 12 (33%) patients had no pathologic evidence of malignancy in their surgical specimen. Six of 11 patients (55%) in the CRT group were free of local failure at the time of analysis. Two of five patients in this group who had local recurrence at 2 and 10 months underwent surgical salvage with subsequent survivals of 20 and 100 months, respectively. Treatment-related mortality was 0 out of 11 in the CRT group and 2 out of 24 in the CRT+PE group. Dysphagia relief was similar in the CRT group vs. the CRT+E subgroup; however, a greater percentage of patients treated with chemoradiation alone had normal long-term swallowing function when compared to those patients also undergoing esophagectomy (100% vs. 73%). CONCLUSION: High-dose chemoradiation alone appears to provide similar survival and relief of dysphagia compared with high-dose chemoradiation followed by esophagectomy for patients with potentially resectable esophageal adenocarcinoma. Local failure may be higher in patients undergoing chemoradiation compared to chemoradiation followed by esophagectomy, but surgical salvage is possible, thus providing similar overall local control. However, because of the small number of patients in each group, these treatment modalities need to be further evaluated in a prospective randomized Phase III study.

Pulmonary immunocytoma with massive crystal storing histiocytosis: a case report with review of literature.

An unusual immunocytoma (lymphoplasmacytoid lymphoma) composed predominantly of sheets of globoid and spindle-shaped crystal-storing histiocytes was detected incidentally in the right lung of a 72-year-old woman. Scattered lymphoplasmacytic aggregates within the tumor had monoclonality with anti-kappa immunoglobulin (Ig) M antibodies. The crystals were outlined positively by the same antibodies. They stained an intense blue with phosphotungstic acid-hematoxylin (PTAH) and were found during electron microscopy to be membrane bound and also within type I pneumocytes and the extracellular space. Excessive production of kappa IgM by neoplastic low-grade lymphoplasmacytoid cells of B-cell origin in an altered intra- or extracellular milieu may lead to crystallization and phagocytosis by reactive histiocytes. Review of the literature revealed seven more cases: four in the head and neck, and one each in the skin, the lymph node, and the lung. IgM was the most frequently crystallizing immunoglobulin (four of seven) and all had kappa light chains. The lesion needs to be differentiated from neoplastic and nonneoplastic histiocytic and lymphoplasmacytic disorders. The difference with bronchial mucosa-associated lymphoid tissue lymphoma and marginal zone lymphoma is, perhaps, semantic.

HER-2/neu: a differentiation marker in adenocarcinoma of the esophagus.

Adenocarcinoma of the esophagus is an aggressive malignancy which is increasing in frequency. The HER-2/neu oncogene product is a putative differentiation marker which exhibits decreased expression in colon carcinoma, while there is overexpression in breast and ovarian cancers. We analyzed the relationship of cell differentiation to HER-2/neu expression in esophageal adenocarcinoma using immunohistochemistry on formalin-fixed, paraffin-embedded material from 14 patients whose tissue contained normal, dysplastic, and malignant features. HER-2/neu expression was detected in 1 of 14 biopsy specimens and 2 of 9 resection specimens. The oncoprotein staining was greatest in normal tissue, less in dysplastic tissue, and not detected in malignant tissue. Our findings, similar to what is seen in the colon, suggest that the HER-2/neu oncogene product is a differentiation marker which is lost in esophageal adenocarcinoma.

Current and future therapy for malignant pleural effusion.

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.

Intrathoracic organ injury associated with photodynamic therapy.

Photodynamic therapy has been proposed as a new modality for the local treatment of neoplasms limited to the pleural surface. Clinical use of photodynamic therapy will involve exposure of large surface areas of normal intrathoracic organs to tumoricidal doses of photodynamic therapy. This study details the pathologic changes that occur within the lung, heart, trachea, and diaphragm of Sprague-Dawley rats after administration of tumoricidal photodynamic therapy. Animals were injected with the photosensitizer Photofrin-II (Quadralogic Technologies, Vancouver, B.C., Canada), 10 mg/kg intraperitoneally, 24 hours before surface illumination of a portion of the target organ with gold vapor laser light (628 nm) (124 joules/cm2). Control animals were treated with light alone. After endotracheal intubation and mechanical ventilation, the lung and heart were exposed via left thoracotomy. The trachea was dissected in the neck, and the diaphragm was visualized via celiotomy. One site was treated per animal. Animals were killed at 24 hours, 48 hours, 72 hours, 1 week, 1 months, and 6 months after therapy. Histologic injury was numerically assessed by a single observer blinded to treatment and time of organ harvest. The Wilcoxon matched-pair signed-rank test was used to determine the statistical significance of differences between treated and control groups. Twenty-four hours after treatment the lung, heart, and trachea of rats subjected to photodynamic therapy demonstrated parenchymal injury (p less than 0.05). The diaphragm showed delayed injury 72 hours after therapy (p less than 0.05). Microscopic pulmonary changes included alveolar and endothelial disruption, intraalveolar hemorrhage, and fibrin deposition. Coagulation necrosis of myocardial fibers extending through the epicardium to involve up to 50% of myocardial thickness was observed. The diaphragm showed mesothelial hyperplasia with necrosis of superficial skeletal muscle. No similar gross or microscopic changes were present in the organs of control animals, or more than 48 hours after treatment in the trachea of animals that received photodynamic therapy. Photodynamic therapy induces a spectrum of tissue-specific injury, which may affect its usefulness in subsequent clinical trials.

The influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer.

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.

Bilobectomy for bronchogenic carcinoma.

During a 12-year period, bilobectomy was performed on 166 patients for the treatment of primary lung carcinoma: 108 patients (65%) underwent right upper and middle lobectomy, while 58 patients (35%) underwent right middle and lower lobectomy. Indications for bilobectomy were tumor extending across a fissure (45%), absent fissure (21%), endobronchial tumor (14%), extrinsic tumor or nodal invasion of bronchus intermedius (10%), and vascular invasion (5%). Thirty-one patients (19%) suffered 41 perioperative complications, and 7 patients (4.2%) died. Upper and middle lobectomies were not associated with a significantly different morbidity (p greater than 0.10) or mortality (p greater than 0.10) when compared with middle and lower lobectomy. The postoperative chest roentgenograms of all patients demonstrated ipsilateral volume loss, and 31 patients were found to have asymptomatic hydropneumothoraces, which cleared during the follow-up period. Late complications occurred in 4 patients (2%) and included two empyemas, one bronchopleural fistula, and one superficial wound infection. These results indicate that bilobectomy is associated with morbidity and mortality that lie between those currently reported for lobectomy and pneumonectomy.

Schwannoma of the brachial plexus mimicking an apical lung tumor.

Primary tumors of the brachial plexus are unusual. We describe a patient with a large schwannoma of the lower trunk of the brachial plexus that had the radiologic appearance of an apical lung mass. Use of a posterior subscapular approach as well as intraoperative nerve action potential recording permitted resection with spared function.

Evaluation of noninvasive tests for the preoperative staging of carcinoma of the esophagus: a prospective study.

A prospective study was undertaken to define the usefulness of conventional full-lung linear tomography, radionuclide liver plus spleen and bone scans, and thoracic and abdominal computed tomography for the preoperative staging of carcinoma of the esophagus. Thirty-three patients with carcinoma of the esophagus were studied. The computed tomographic (CT) scan of the thorax and upper abdomen was the single most accurate noninvasive study. With computed tomography, the relationship of the tumor to the tracheobronchial tree was the feature most useful in predicting local resectability. In all patients with the finding of tracheobronchial compression by the tumor, the tumor could not be resected completely. The predictive value of this CT finding in patients with locally unresectable tumor was high (0.83), indicating its usefulness in assessing unresectability. The CT finding of visible separation between tumor mass and tracheobronchial tree was present in 10 of 14 patients with locally resectable tumor (predictive value, 0.63). However, tumor abutting the tracheobronchial tree without compression was a poor predictor of unresectability (predictive value, 0.36). The radionuclide bone scan was the only other noninvasive study to demonstrate a metastasis not evident by CT scan. The combination of chest and abdominal CT scan, bone scan, and bronchoscopy before operation will accurately stage the majority of patients with esophageal cancer but no noninvasive test is of sufficient reliability to exclude patients from operative resection if otherwise indicated.

Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group.

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.

Postoperative complications after combined neoadjuvant treatment of lung cancer.

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.

DNA content in correlation with postsurgical stage in non-small cell lung cancer.

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.

Clinical relevance of chromosome abnormalities in non-small cell lung cancer.

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.