Lung cancer and the debrisoquine metabolic phenotype.

In a case-control study, we tested the hypothesis that the genetically determined ability to metabolize debrisoquine is related to risk of lung cancer. Overall, individuals who were extensive metabolizers of debrisoquine were at significantly greater risk of lung cancer than those who were poor or intermediate metabolizers (odds ratio = 6.1; 95% confidence interval = 2.2-17.1). In this study, case patients had lung cancer, and control subjects had either chronic obstructive pulmonary disease or cancers other than lung cancer. Results were adjusted for age, race, asbestos exposure, and smoking. Both black and white individuals who were extensive metabolizers of debrisoquine were at significantly increased risk after similar adjustment (for blacks, odds ratio = 4.5, 95% confidence interval = 1.1-18.1; for whites, odds ratio = 10.2, 95% confidence interval = 2.0-51.4). Significantly increased risk of lung cancer was also present for individuals who were extensive metabolizers when subjects with chronic obstructive pulmonary disease or other cancers were considered separately. These data confirm that the ability to metabolize debrisoquine is a major determinant of susceptibility to lung cancer. Evaluation of the marker in other case-control settings, further exploration of racial differences, and the prospective evaluation of this marker in subgroups at high risk of lung cancer are areas worthy of further study.

IGFBP-3 gene expression and estrogen receptor status in human breast carcinoma.

Insulin-like growth factors (IGF) I and II are potent mitogens for breast carcinoma proliferation. IGF-mediated proliferative activity can be markedly enhanced by the presence of specific IGF-binding proteins (IGFBPs). IGFBP-3 has been shown to enhance IGF-mediated growth in a number of systems. Studies have demonstrated IGFBP-3 secretion only in estrogen receptor (ER)-negative breast carcinoma cell lines while IGFBP-3 could not be detected in media conditioned by ER-positive cell lines. We investigated whether a relationship exists between ER status and IGFBP-3 mRNA expression in human breast carcinoma biopsy specimens. We have detected IGFBP-3 mRNA in breast carcinoma tissue obtained from patients utilizing in situ hybridization. Quantitation of IGFBP-3 mRNA levels was performed utilizing image cytometry. There was a significantly higher expression of IGFBP-3 mRNA in ER-negative breast carcinoma specimens when compared to the ER-positive specimens. Whether this higher expression of IGFBP-3 mRNA and presumed secretion of IGFBP-3 by ER-negative tumors play a role in the rapid proliferation and poor prognosis of these tumors remains to be determined.

Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial.

PURPOSE: To determine the response rate of cisplatin plus doxorubicin plus cyclophosphamide (PAC) in patients with limited-stage unresectable thymoma. In addition, this study was undertaken to determine the toxicity, progression-free survival, and overall survival of combined-modality therapy with PAC plus radiation therapy. PATIENTS AND METHODS: Patients with a histologic diagnosis of limited-stage unresectable thymoma or thymic carcinoma were eligible. Further requirements included a Karnofsky Performance Score of > 60, no prior radiation to the chest, and adequate bone marrow, hepatic, and renal function. No patient had undergone chemotherapy previously. Patients received two to four cycles (repeated every 3 weeks) of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) followed by a total dosage of 54 Gy to the primary tumor and regional lymph nodes for patients with a stable, partial, or complete response to chemotherapy. RESULTS: From November 1983 through January 1995, 26 patients were entered onto the trial. Three patients were ineligible on the basis of pathologic review (lung cancer, germ cell cancer, lymphoma). Toxicity, primarily hematologic, was mild, with only one early death due to a perforated abdominal viscus. Among the 23 assessable patients, there were five complete and 11 partial responses to chemotherapy (overall response rate, 69.6%). The median time to treatment failure was 93.2 months (range, 3 to 99.2+ months), and the median survival time was 93 months (range, 1 to 110 months). The 5-year survival rate is 52.5%. CONCLUSIONS: PAC combination chemotherapy produces response rates in the management of patients with limited thymoma. Combined-modality therapy is feasible and associated with prolonged progressive-free survival. The benefit of combined-modality therapy over radiation therapy alone is suggested for patients with unresectable thymoma.

Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group.

PURPOSE: The purpose of this study was to evaluate the impact of cisplatin, doxorubicin, and cyclophosphamide (PAC) in patients with advanced thymoma with respect to response rate, duration of remission, and overall survival. PATIENTS AND METHODS: Assessable patients with thymoma (n = 29) or thymic carcinoma (n = 1) with metastatic or locally progressive recurrent disease following radiotherapy were treated with intravenous cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) with normal saline hydration. Courses were repeated every 3 weeks for a maximum of eight cycles of therapy. RESULTS: Toxicity, which was primarily hematologic, was mild, with only one patient developing a fever associated with neutropenia. Three complete responses (CRs) and 12 partial responses (PRs) were observed (CR+PR rate, 50%; 95% confidence interval, 31.3% to 68.7%). Ten patients had stable disease. The median duration of response was 11.8 months (range, 0.9 to 70.5+), the time to treatment failure 18.4 months (range, 0.8 to 91.9+), and median survival time 37.7 months (range, 2 to 91.9+). CONCLUSION: This trial demonstrates that objective response rates and prolonged survival can be achieved in patients with advanced thymoma.

The clinical significance of variant-morphology small-cell carcinoma of the lung.

Past attempts to subclassify small-cell lung cancer (SCCL) histology (oat cell, fusiform, polygonal, intermediate, etc) have not been useful because of interrater variability and a lack of clinical significance. A review of outcome in a previous series suggested that a different histologic subtype, small-cell/large-cell (SC/LC) conferred an inferior response and survival analogous to the relative chemotherapy and radiation resistance seen in the variant-morphology (SC/LC) cultured cell lines. To evaluate the clinical impact of SC/LC we applied the proposed International Association for the study of Lung Cancer (IASLC) histology subclassification that incorporates the SC/LC category for patients with extensive-disease SCCL entering Eastern Cooperative Oncology Group (ECOG) protocol 1582. All cases were reviewed for eligibility by one pathologist, and all possible SC/LC (variant) plus 10% of all cases were reviewed together with a second pathologist; 577 of the 628 patients who entered were eligible, of whom 550 had histologic material submitted for review and are considered for this analysis. Initial review disclosed 24 cases with SC/LC (4.4%) and 526 with "classic" histology. The second review showed 100% agreement for classic form, but only 11 SC/LC cases with concordance between the reviewing pathologists. Eight of 24 (33%) cases from first review and three of 11 (27%) with concordance on second review achieved complete response (CR) compared with 101 of 526 (19%) for "classic" SCCL (P = .11 and .45, respectively, for the first and second review groups).(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group.

The present randomized, prospective study was designed to assess whether alternating induction cyclophosphamide, doxorubicin, vincristine-altretamine (hexamethylmelamine), etoposide, and methotrexate (CAV-HEM) chemotherapy is better than standard chemotherapy (CAV) in improving response, survival, and remission time in 577 evaluable patients having extensive-disease small-cell lung cancer (SCLC). In addition, the study was designed to assess the impact of maintenance chemotherapy following a complete response (CR) on the time to progression and survival. The response rates (CR plus partial response [PR]) for CAV-HEM and CAV were 64% and 61%, respectively, but 23% of the patients on CAV-HEM achieved a CR compared with 16% for CAV alone (P = .03). Among complete responders, the continuation of therapy significantly increased the remission time for patients on CAV, while maintenance therapy for patients on CAV-HEM had no significant impact on remission time. However, the increased remission had little effect on survival. Patients on CAV maintenance therapy survived marginally longer than those patients on no maintenance therapy, whereas patients who received CAV-HEM and no maintenance therapy survived longer than those on maintenance therapy. CAV-HEM was associated with significantly higher severity of complications (ie, mainly myelosuppression) than CAV (P = .01). Maintenance chemotherapy was associated with significantly more complications than no maintenance therapy. Patients on CAV-HEM lived significantly longer than those on CAV alone (45.9 weeks v 42.7 weeks; P = .002). Ten percent of patients treated on CAV-HEM survived at least 2 years, compared with 4% on CAV alone. In our study involving patients with extensive-disease SCLC, the alternating induction chemotherapy significantly increased the CR rates and had a small impact on long-term survival compared with the results achieved with standard induction chemotherapy. Moreover, when the alternating induction chemotherapy was used, long-term maintenance chemotherapy was not needed.

Endocrine-related biochemistry in the spectrum of human lung carcinoma.

The association of hormonal syndrome and APUD (amine precursor uptake, decarboxylase) features with small cell carcinoma of the lung (SCC) has suggested that SCC has a separate cell origin from other major forms of lung cancer. Recently, however, both SCC and non-SCC lung cancers have been found to contain small polypeptide hormones and APUD enzymes. The present study quantitates, in 50 samples of human lung cancer tissue, relationships among the 4 major types of lung cancer and endocrine-related properties. Among 4 parameters measured (dopa decarboxylase, histaminase, beta-endorphin, and calcitonin), no single marker clearly separated SCC from non-SCC lung cancer. The high activity of dopa decarboxylase (the "D" in "APUD") best separated SCC from non-SCC, but significant overlap existed even for this critical APUD property. In fact, 2 adenocarcinomas had among the highest concentrations of dopa decarboxylase, histaminase, and calcitonin of any tumor tissue studied. The simultaneous appearance of high levels of 2 or more markers favored SCC. This was quantitated by deriving an index unit based upon the product of the values for the 4 markers in each lesion. This index separated all SCC from all non-SCC lung carcinomas, with the exception of the above 2 adenocarcinomas. Endocrine-related properties thus occur throughout the spectrum of human lung cancer. Biochemical differences between the major histopathological types are quantitative rather than qualitative and probably reflect the fact that the major forms of lung cancer represent a continuum of differentiation within a common cell lineage which includes both SCC and non-SCC lung tumors.

Expression of the retinoic Acid nuclear receptors (rars) and retinoid x-receptor (rxr) genes in estrogen-receptor positive and negative breast-cancer.

Retinoid inhibition of breast carcinoma growth correlates with the estrogen receptor (ER) positivity and elevated retinoic acid nuclear receptor (RARalpha) mRNA levels. We therefore examined retinoid nuclear receptor mRNA levels in patient breast carcinoma biopsy specimens to determine if such a correlation exists between ER positivity and RARalpha mRNA levels. We have now shown that RARalpha mRNA levels are significantly higher in ER positive samples. RARgamma mRNA is expressed at relatively high levels in a majority of the tumor samples independent of the ER-status while RARbeta mRNA was expressed at low levels in only one tumor sample. We also found high RXRalpha mRNA levels in all of the tumor samples examined while RXRgamma mRNA could not be detected. Our study demonstrates that RARalpha mRNA levels are either low or absent in ER-negative patient samples and that RARalpha levels may serve as a potential marker to determine patient responsiveness to RA therapy.

Diffuse interstitial pneumonitis and fibrosis in sarcoidosis.

Interstitial pneumonitis in sarcoidosis is rare. When present, it confined to areas of active granuloma formation. We report finding widespread interstitial pneumonitis and fibrosis in a patient with sarcoidosis. Due to the focal sampling of pulmonary tissue by transbronchial biopsy, a finding of interstitial pneumonitis does not exclude a diagnosis of sarcoidosis.

Inflammatory changes related to active tuberculosis: confusion with oat cell carcinoma of the lung on cytology specimens.

One case of small cell lung carcinoma diagnosed on cytology specimens could not be confirmed histologically. We feel this likely represents cytopathologic changes induced in response to the patient's active tuberculosis. To avoid aggressive systemic therapy in such cases, patients with localized lesions should have further diagnostic procedures to confirm the cytologic diagnosis histologically.

Acquired toxoplasmic lymphadenitis with demonstration of the cyst form.

Acquired toxoplasmosis usually is diagnosed serologically. Specific histologic criteria allow for the recognition of this disease in lymph node sections. However, Toxoplasma cysts are rarely seen in nodes. The lymph node from a 15-year-old male with asymptomatic lymphadenopathy was found to have typical histologic features of toxoplasmic lymphadenitis. Toxoplasma cysts were identified and specific serology was confirmatory.

Elevated expression of retinoic acid receptor-alpha (RAR alpha) in estrogen-receptor-positive breast carcinomas as detected by immunohistochemistry.

Retinoids modulate gene activity, cell growth and differentiation by binding to a series of nuclear receptors, i.e., retinoic acid receptors (RARs) or retinoid X receptors. Retinoic acid (RA) inhibition of estrogen receptor (ER)-positive breast carcinoma seems to be mediated through RAR alpha. Estrogens upregulate RAR alpha in ER-positive breast carcinoma cell lines. In this study we examined RAR alpha expression in the ER-positive MCF7 and ER-negative MDA-MB-231 human breast carcinoma cell lines as well as in 10 ER-negative and 9 ER-positive infiltrating ductal breast carcinoma specimens using immunohistochemistry and quantitation by image cytometry. MCF7 cells expressed twofold higher levels of RAR alpha protein than MDA-MB-231 cells. RAR alpha expression, as detected by immunostaining and quantitated by image cytometry, was upregulated in these cells by estradiol. ER-positive breast carcinoma specimens also exhibited approximately two-fold higher RAR alpha levels than their ER-negative counterparts. Thus, RAR alpha expression is significantly elevated in ER-positive breast tumors as assessed by detection and quantitation using immunohistochemical staining and image cytometry, respectively. Whether the decrease in RAR alpha protein levels and loss of RA-mediated growth inhibition in ER-negative tumor plays a role in the increased metastatic potential of ER-negative tumors remains to be determined.

Endobronchial fibrous histiocytoma.

Fibrous histiocytomas are uncommon pulmonary tumors. They generally involve only the lung parenchyma. Endobronchial involvement is extremely rare. Usually, surgical resection of the mass is required for definitive diagnosis and therapy. We report a case of benign atypical fibrous histiocytoma visualized during fiberoptic bronchoscopy and review the clinical findings and pathologic features of this tumor.

Bilateral granular cell tumors of the posterior mediastinum.

Granular cell tumors are uncommon and generally benign lesions that are commonly accepted to be of Schwann cell origin. These tumors occur most frequently in the skin and oral cavity and are generally asymptomatic. However, when signs and symptoms occur, they are relative to the organ or site involved. The histological features are distinct. Surgical resection is curative in almost all cases, with only rare local recurrences. We report a case of symptomatic bilateral granular cell tumors arising in the posterior mediastinum.

The role of thoracoscopy in the diagnosis of interstitial lung disease.

A study was undertaken to evaluate the safety and efficacy of thoracoscopic lung biopsy for interstitial lung disease. The relation between operative findings, pathologic findings, and preoperative computed tomographic scan findings was examined. Twenty-six patients, 10 male and 16 female, underwent thoracoscopic lung resection to diagnose interstitial lung disease. Sixteen patients were outpatients for an elective procedure; 10 were inpatients including 2 who were ventilator dependent. The mean length of operation was 54 minutes and the mean length of chest tube duration, 1.3 days. There were no deaths. Staphylococcal pneumonia developed in 1 patient postoperatively. One patient with systemic pulmonary hypertension was ventilator dependent for 48 hours. A double-lumen endotracheal tube was used in all but 2 patients. Twelve-millimeter trocar ports were used to allow easy interchange of staplers and endoscopic instruments. Biopsy of at least two lobes was performed in each patient with resection of a piece of grossly abnormal lung. A single chest tube was left routinely. The pathologic diagnosis was usual interstitial pneumonitis in 7 patients. Four patients had interstitial fibrosis and 4, granulomas. Three patients had diffuse alveolar damage and 3, Wegener's granulomatosis. Two patients had bronchiolitis obliterans with organizing pneumonia. One patient each had lymphangioleiomyomatosis, eosinophilic granuloma, and cytomegalovirus. Sixteen patients underwent preoperative computed tomographic scanning. The scans were assessed by 2 radiologists who were blinded to the surgical results. Computed tomography accurately predicted the site of disease in most instances. Four patients had at least one lobe with no evidence of disease on computed tomography but with interstitial lung disease found thoracoscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

EST 2582 phase II trial of cisplatin in metastatic or recurrent thymoma.

In 1982 there were four reports of cisplatin-induced remissions of invasive thymoma. These observations led the Eastern Cooperative Oncology Group (ECOG) to conduct a Phase II trial of cisplatin (50 mg/m2 intravenously every 3 weeks). During a 4-year period 24 patients were entered on this trial; 3 were excluded because review of histologic material failed to confirm the presence of thymoma. The characteristics of the remaining 21 patients were as follows: median age, 51; males/females, 11/10; ECOG performance status, 0-1/2-3, 16/5; previous treatment with chemotherapy, 3; previous surgery, 20; previous radiation, 15; weight loss, < 5%/ > or = 5%: 17/4. One patient was eliminated from response analysis because of failure to return for follow-up tumor measurements. The following responses were observed in the remaining 20 patients. Partial remission, 2 (10%); stable disease, 8 (40%); and progression, 10 (50%). The median survival was 76 weeks, and the 2-year survival rate was 39%. Four patients experienced severe nausea and vomiting, but life-threatening and lethal toxicities were not observed. Cisplatin given at this dose was relatively ineffective in producing tumor regression in recurrent or metastatic thymoma.

Multiple granular cel tumors of the gallbladder and biliary tree. Report of a case.

Granular cell tumors are benign lesions that usually appear in the skin, oral activity, and mucous membrane. Occasionally, they will appear in visceral organs, and cause signs and symptoms similar to those of other organ-related diseases. We studied a patient with granular cell tumors of the common bile duct whose clinical appearance mimicked that of cholecystitis with cholelithiasis. Recognition of granular cell tumors on frozen section will allow surgical resection with probable cure.

Rapid growth of pseudoangiomatous hyperplasia of mammary stroma in axillary gynecomastia in an immunosuppressed patient.

Pseudoangiomatous hyperplasia of mammary stroma is a rare, benign mesenchymal proliferation that sometimes mimics angiosarcoma. To our knowledge, it has not been reported in men. We report the first case of this unusual entity in a man. This case was most unusual in that it occurred in a clinical setting of immunosuppression, in axillary gynecomastia, and was growing rapidly.

Nodular pulmonary amyloidosis: diagnosis by fine-needle aspiration cytology and a review of the literature.

Solitary nodular pulmonary amyloid tumor is an uncommon benign lesion which is seldom diagnosed prior to surgical extirpation. We present a case of unsuspected nodular pulmonary amyloid tumor diagnosed by fine needle aspiration cytology. A 52-yr-old-black woman, presented with a 3-cm right middle lobe mass. Percutaneous fine-needle aspiration cytology (FNA) of the mass revealed waxy amorphous material that demonstrated apple green birefringence on Congo Red Stain. Thoracotomy for diagnosis may be avoided by using FNA to diagnose these unusual lesions.

Aspiration cytology of heterotopic ossification. A case report.

Heterotopic ossification (myositis ossificans) is usually a posttraumatic reactive process involving new bone formation. This nonneoplastic process can be clinically and radiologically confused with osteosarcoma. A case of heterotopic ossification is reported in which cytologic material was obtained from a partially calcified thigh mass from a 17-year-old, athletic male. Aspiration cytology revealed numerous osteoclastic giant cells containing multiple plump nuclei. These cells were admixed in a benign-appearing stromal background composed of mature fibroblasts and were typified by elongated spindle cells. A small incisional biopsy showed new bone formation, osteoclasts, osteoblasts and fibroblasts consistent with maturing heterotopic ossification. Heterotopic ossification may be distinguished cytologically from osteosarcoma by the presence of numerous uniform benign stromal cells composed of mature fibroblasts and osteoclastic giant cells. The differential diagnosis may be more difficult in the early stages of this reactive and proliferative process. Adequate sampling of suspected heterotopic ossification by aspiration cytology may avoid surgery in a selected group of patients.