Undifferentiated Carcinoma Of Lung Research Articles

Contrast-Enhanced Ultrasound in Distinguishing between Malignant and Benign Peripheral Pulmonary Consolidations: The Debated Utility of the Contrast Enhancement Arrival Time

Background. Limited studies and observations conducted on a too small number of patients prevent determining the actual clinical utility of pulmonary contrast-enhanced ultrasound (CEUS). The aim of the present study was to examine the efficacy of contrast enhancement (CE) arrival time (AT) and other dynamic CEUS findings for differentiating between malignant and benign peripheral lung lesions. Methods. 317 inpatients and outpatients (215 men, 102 women; mean age: 52 years) with peripheral pulmonary lesions were included in the study and underwent pulmonary CEUS. Patients were examined in a sitting position after receiving an intravenous injection of 4.8 mL of sulfur hexafluoride microbubbles stabilized by a phospholipid shell as ultrasound contrast agent (SonoVue-Bracco; Milan, Italy). Each lesion was observed for at least 5 min in real-time and the following temporal characteristics of enhancement were detected: the arrival time (AT) of microbubbles in the target lesion; the enhancement pattern; the wash-out time (WOT) of microbubbles. Results were then compared in light of the definitive diagnosis of community acquired pneumonia (CAP) or malignancies, which was not known at the time of CEUS examination. All malignant cases were diagnosed by histological results, while pneumonia was diagnosed on the basis of clinical and radiological follow-up, laboratory findings and, in some cases, histology. Results. CE AT has not been shown to differ between benign and malignant peripheral pulmonary lesions. The overall diagnostic accuracy and sensibility of a CE AT cut-off value < 10 s in discriminating benign lesions were low (diagnostic accuracy: 47.6%; sensibility: 5.3%). Poor results were also obtained in the sub-analysis of small (mean diameter < 3 cm) and large (mean diameter > 3 cm) lesions. No differences were recorded in the type of CE pattern showed between benign and malignant peripheral pulmonary lesions. In benign lesions we observed a higher frequency of delayed CE wash-out time (WOT) > 300 s. Anyhow, a CE WOT cut-off value > 300 s showed low diagnostic accuracy (53.6%) and sensibility (16.5%) in discriminating between pneumonias and malignancies. Similar results were also obtained in the sub-analysis by lesion size. Squamous cell carcinomas showed a more delayed CE AT compared to other histopathology subtypes. However, such a difference was statistically significant with undifferentiated lung carcinomas. Conclusions. Due to an overlap of CEUS timings and patterns, dynamic CEUS parameters cannot effectively differentiate between benign and malignant peripheral pulmonary lesions. Chest CT remains the gold standard for lesion characterization and the eventual identification of other pneumonic non-subpleural localizations. Furthermore, in the case of malignancy, a chest CT is always needed for staging purposes.

Myocarditis as a rare, yet serious adverse event associated with immune checkpoint inhibitors in patients with non-small cell lung cancer: Case series from a large community-based cancer center.

e21047 Background: Patients (pts) with lung cancer and other cancers treated with immune checkpoint inhibitors (ICI) may experience immune related adverse events (irAE). These can present with variable severity and with single- or multi-organ involvement including pneumonitis, colitis, hepatitis, and myocarditis/pericarditis. The incidence of myocarditis has been reported between 0.06% and 2.4% and is associated with a high mortality (25% to 50%). This retrospective review of real-world data (RWD) investigates myocarditis as a high-grade adverse event in pts with lung cancer treated with ICIs. Methods: Pts were identified and characterized using RWD in the Syapse Learning Health Network platform from 2010 to 2020 at Advocate Aurora Health Care. Eligible pts included: ≥18 years old; histologically confirmed NSCLC; and myocarditis diagnosis by ICD codes. Additional chart review was performed to confirm timing of ICI treatment and myocarditis. All pts identification and review were performed after IRB review. Results: 12,686 pts with non-small cell lung cancer were eligible for review. The median age at diagnosis was 70; 54% were female; 86% were White and 12% were Black; 1,975 (15.6%) were treated with an ICI and of those 4 cases (0.2%) of myocarditis were identified. All 4 pts were White females, ages 46, 59, 65, and 74 years. Pathology included lung adenocarcinoma (3) and an undifferentiated lung carcinoma (1). All pts had metastatic disease, and none had a prior history of cardiac disease. ICIs were pembrolizumab (2), durvalumab (1), and nivolumab (1). Median time from initial dose of ICI to diagnosis of myocarditis was 62 days [range: 42-185]. All 4 pts presented with chest pain and elevated troponin T [median 0.07 ng/ml (range: 0.06-0.08)]. All pts had echocardiography at the time of diagnosis, and 2 pts had cardiac MRI that confirmed myocarditis. 3 pts were treated with a prednisone taper. 1 pt died of recurrent congestive heart failure and ventricular tachycardia despite rescue attempt with high dose corticosteroids. 2 pts had additional concomitant irAEs of hypothyroidism/colitis, and thyroiditis/pneumonitis, respectively. Conclusions: Many irAEs are reversible. This RWD analysis confirms that clinically evident myocarditis is a rare but serious adverse event of ICI therapy. Early consideration, diagnosis, and intervention may help prevent poor outcomes. Termination of ICI therapy along with initiation of corticosteroids constitute the current standard of management. Further research is warranted to better identify high risk groups, surveillance measures, and improved management of ICI associated myocarditis.

King Boletus mushroom‐derived bioactive protein hydrolysate: characterisation, antioxidant, ACE inhibitory and cytotoxic activities

SummaryThe enzymatic‐bromelain King Boletus mushroom protein hydrolysate (eb‐KBM) was determined in terms of the biological properties (antioxidant, antihypertensive and cytotoxic activities) and compared with unhydrolysed or water‐soluble King Boletus mushroom extract (ws‐KBM). The eb‐KBM showed high antioxidant activities, as assessed by ABTS (70.9%), DPPH (60.9%) assays and hydroxyl radicals (66.0%) scavenging method. Angiotensin‐I converting enzyme (ACE) inhibitory activity of eb‐KBM was 21.1% at 1 mg protein mL−1. Anticancer activity‐relevant cytotoxicity of eb‐KBM in ChaGo‐K1 (undifferentiated lung carcinoma) and HEP‐G2 (hepatocarcinoma) cells was higher than that of ws‐KBM, with lower IC50 values (6.43 and 6.35 µg mL−1, respectively). The great biological activities of eb‐KBM were related to its amino acid composition, with high contents of hydrophobic amino acids and aromatic amino acids. These results indicate that King Boletus mushroom protein hydrolysate or bioactive peptide could be used as natural antioxidative, ACE inhibitory and anticancer activities in the nutraceutical and pharmaceutical industries.

Correlation analysis of expression and prognosis of TTF-1 and CD44v6 in undifferentiated lung carcinoma.

The correlation between expression and prognosis of thyroid transcription factor-1 (TTF-1) and CD44v6 in undifferentiated lung carcinoma was investigated. There were 116 cases with large cell undifferentiated carcinoma in group A, 120 cases with small cell undifferentiated carcinoma in group B and 80 normal individuals from the same period in group C. The expression levels of TTF-1 and CD44v6 in the serum of group A, B and C and the cancer tissues and adjacent tissues of group A, B and C were detected using enzyme-linked immunosorbent assay (ELISA), and the levels in each group were compared. Pearsons test was used to analyze the correlation between TTF-1 and CD44v6 expression in serum of group A and group B and cancer tissues. Patients were divided into the survival group and the deceased group according to their 5-year survival. Multivariate logistic regression was applied to analyze the risk factors of mortality, and receiver operating characteristic curve (ROC) was used to analyze the diagnostic value of TTF-1 and CD44v6. The best cut-off values of TTF-1 and CD44v6 were divided into the high and low expression groups to observe the 5-year mortality of patients and the Kaplan-Meier (K-M) survival curve was drawn. Multivariate logistic regression was used to analyze the risk factors of mortality. The expression of CD44v6 in the serum of group A and group B was higher than that in group C, and that of group B was higher than that in group A (P<0.05). The expression of TTF-1 in serum of group A and group B was higher than that of group C, and the expression of TTF-1 in group A was higher than that in group B (P<0.05). The expression of TTF-1 and CD44v6 in group A and group B were significantly higher than those in adjacent tissues (P<0.05). The expression of TTF-1 in group A was higher than that in group B (P<0.05), and that of CD44v6 was lower than that in group B (P<0.05). The 5-year survival of patients showed that 209 patients died and 27 survived at 5 years; the survival rate was 11.44%. The course of disease, TNM stage, TTF-1 and CD44v6 were independent mortality factors for undifferentiated lung cancer.

Large-cell carcinoma of the lung: a diagnostic category redefined by immunohistochemistry and genomics.

The current classification system defines large-cell carcinoma (LCC) morphologically as an undifferentiated lung carcinoma lacking features of adenocarcinoma (ADC), squamous cell, or small-cell carcinoma. As a result, LCC has evolved into a clinicopathologically heterogeneous entity. In the current era of histology-driven predictive molecular testing and oncologic management, ambiguous diagnostic categories frustrate attempts to provide more personalized cancer care, thus the pathology community has engaged in a concerted effort to revise the criteria for LCC. Most cases of LCC are immunophenotypically similar to ADC or squamous cell carcinoma. LCC lacking squamous and neuroendocrine features is clinically and genomically indistinguishable from solid ADC. Even cases of LCC lacking immunophenotypic differentiation may contain genomic alterations characteristic of other forms of lung carcinoma. Applying ancillary techniques, most cases of LCC can be reclassified into more informative categories that may guide molecular testing for predictive biomarkers and enable selection of more appropriate therapies.

Upregulation of MMP-2 by HMGA1 Promotes Transformation in Undifferentiated, Large-Cell Lung Cancer

Although lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we show that HMGA1 is an important oncogene that drives transformation in undifferentiated, large-cell carcinoma. First, we show that the HMGA1 gene is overexpressed in lung cancer cell lines and primary human lung tumors. Forced overexpression of HMGA1 induces a transformed phenotype with anchorage-independent cell growth in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA1 expression blocks anchorage-independent cell growth in the H1299 metastatic, undifferentiated, large-cell human lung carcinoma cells. We also show that the matrix metalloproteinase-2 (MMP-2) gene is a downstream target upregulated by HMGA1 in large-cell carcinoma cells. In chromatin immunoprecipitation experiments, HMGA1 binds directly to the MMP-2 promoter in vivo in large-cell lung cancer cells, but not in squamous cell carcinoma cells. In large-cell carcinoma cell lines, there is a significant, positive correlation between HMGA1 and MMP-2 mRNA. Moreover, interfering with MMP-2 expression blocks anchorage-independent cell growth in H1299 large-cell carcinoma cells, indicating that the HMGA1-MMP-2 pathway is required for this transformation phenotype in these cells. Blocking MMP-2 expression also inhibits migration and invasion in the H1299 large-cell carcinoma cells. Our findings suggest an important role for MMP-2 in transformation mediated by HMGA1 in large-cell, undifferentiated lung carcinoma and support the development of strategies to target this pathway in selected tumors.

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno- and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as ‘non-small-cell lung carcinoma’, desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno- and large-cell types.

Clinicopathologic characteristics of metastatic carcinomas to spleen

To study the clinicopathologic characteristics of metastatic carcinomas to the spleen. Sixteen cases of metastatic carcinoma to the spleen were retrieved from archival clinical, surgical pathology and autopsy records. The demographic data (including sex and age of patients), clinical symptoms, primary sites, tumor histologic types, gross appearance of spleen and growth patterns within the spleen were analyzed. Among the 16 patients studied, 12 were males and 4 were females. The male predilection was obvious. The age ranged from 48 to 90 years, the median age 66.5 years. Major clinical symptoms included discomfort in the left upper quadrant, pain, emaciation and loss of appetite. Splenomegaly was noted in some patients and computerized tomography could show space-occupying lesions in the spleen. In general, lung was the most common primary site for splenic metastasis and accounted for 43.8% of all cases (7/16). In male patients, primary lung tumor was found in 50.0% cases (6/12). On the other hand, primary ovarian tumor was commonly seen in females (2/4). Histologically, undifferentiated carcinoma of lung was frequently encountered (25.0%, 4/16), including 3 cases of small cell undifferentiated carcinoma and 1 case of large cell undifferentiated carcinoma. Other histologic tumor types included bronchioloalveolar carcinoma (2 cases), colonic adenocarcinoma (2 cases), ovarian serous papillary adenocarcinoma (2 cases), and prostatic adenocarcinoma (2 cases). The commonest histologic tumor type found in male patients was pulmonary undifferentiated carcinoma. The growth patterns of metastatic carcinoma in spleen included nodular, diffuse and multinodular. Most cases presented as a single splenic nodule. Sometimes, tumors with high metastatic potential (5/16) showed diffuse and multinodular growth patterns. Examples of these tumors included small cell undifferentiated carcinoma (3 cases), pulmonary adenocarcinoma (1 case) and prostatic adenocarcinoma (1 case). Metastatic carcinoma to the spleen is rare. Understanding of the clinicopathologic characteristics is helpful in guiding clinical management and pathologic diagnosis.

Alveolar macrophage function is altered in patients with lung cancer.

The alveolar macrophage (AM) is believed to be of central importance in the immune response against infection and tumour. We examined patients with lung cancer in order to evaluate the immuno-stimulatory potential of AM in lung cancer. Bronchoalveolar lavage fluid samples were obtained from patients with adenocarcinoma, squamous cell carcinoma, large cell undifferentiated lung carcinoma, small cell carcinoma and control subjects. AM were isolated and phagocytic function, flow cytometry and cytokine analysis were assessed. AM from patients with small and squamous cell carcinoma had impaired uptake in vitro of 40 nm fluorescent polystyrene beads. AM from patients with small, squamous and large cell undifferentiated carcinoma showed impaired uptake of 1000 nm fluorescent polystyrene beads. Secreted levels of TNF-alpha and IL-1 from AM of patients with small, squamous, and large cell undifferentiated carcinoma were decreased compared to controls. Secreted AM IL-6 levels were decreased in small and large cell undifferentiated carcinoma. AM from adenocarcinoma patients showed similar levels of IL-10, IL-6, IL-1 and TNF-alpha compared to controls. Phenotypic analysis demonstrated that patients with small cell carcinoma were the only group that showed a decrease in MHC class II surface expression. Surface expression of ICAM-1 and CD83 was decreased on AM from patients with large, squamous and small cell carcinoma compared to controls but not adenocarcinoma. Mannose receptor levels were only decreased on AM from patients with squamous and small cell carcinoma but not adenocarcinoma and large cell undifferentiated carcinoma. We conclude that there are type-specific alterations in uptake ability, cytokine secretion and phenotype of AM from lung cancer patients, which may result in an inability to stimulate anti-tumour immunity. The observed differences between lung cancer subgroups may explain previously reported inconsistencies in descriptions of AM characteristics in lung cancer.

Urticaria and Large Cell Undifferentiated Carcinoma of Lung

Urticaria and Large Cell Undifferentiated Carcinoma of Lung

Clinical research of selective bronchial artery infusion and chemotherapy of lung cancer

To study the effect of selective bronchial artery infusion (BAI) and chemotherapy in the treatment of patients with intermediate and advanced lung cancer. Forty-five cases of advanced lung cancer were treated by BAI, which were compared with 40 cases of advanced lung cancer treated by systemic chemotherapy. The response rate of BAI (33/44, 75.0%) was better than that of systemic chemotherapy (20/40, 50.0%)( P < 0.05). The side-effect of BAI was lower than that of systemic chemotherapy ( P < 0.05), but one case occured paraplegia after BAI. The response rate of small cell undifferentiated lung cancer, squamous cell carcinoma and adenocarcinoma was 94.5% (17/18), 66.6% (14/21) and 40.0% (2/5) respectively in the BAI group. Significant difference of the response rate was found in squamous cell carcinoma and adenocarcinoma between the two groups ( P < 0.05). BAI has better response rate and less toxicity than systemic chemotherapy in intermediate and advanced lung cancer, especially in patients with squamous cell carcinoma. Small cell undifferentiated lung carcinoma should be treated by systemic chemotherapy firstly and then BAI. Adenocarcinoma should be treated by BAI firstly and then other therapy.

Paclitaxel-induced apoptosis in non–small cell lung cancer cell lines is associated with increased caspase-3 activity

Objective: Our objective was to determine whether paclitaxel-induced apoptosis in human lung cancer cells is Fas dependent. Methods: Human lung cancer cell lines were evaluated for morphologic evidence of apoptosis, DNA fragmentation (TUNEL positivity), and caspase-3 activation after paclitaxel treatment. Human lung adenocarcinoma, squamous cell carcinoma, undifferentiated lung carcinoma, and bronchoalveolar carcinoma cell lines were each cultured in 10 μmol/L paclitaxel. Results: After 24 hours of culture in paclitaxel, a 22% to 69% increase in the number of apoptotic cells was evident by means of methylene blue-azure A-eosin staining with characteristic blebbing and nuclear condensation. TUNEL assay also confirmed an increase of 19.9% to 73.0% of cells with nuclear fragmentation. Caspase-3 activity, assayed by Z-DEVD cleavage, increased from 20% to 215% ( P < .05). ZB4, an antagonistic anti-Fas antibody, did not block paclitaxel induction of caspase-3 activity (155.8 vs 165.8 U, not significant). Apoptotic morphologic changes were inhibited in cells cultured in the presence of paclitaxel and Ac-DEVD-CHO, a caspase-3 inhibitor. Conclusions: Paclitaxel induces apoptosis in lung cancer cell lines, as assessed by a consistent increase in caspase-3 activity, DNA laddering, and characteristic morphologic changes. Paclitaxel-induced apoptosis in human lung cancer cells is associated with caspase-3 activation but is not Fas dependent. (J Thorac Cardiovasc Surg 2000;119:795-803)

Control of proteinase expression by phorbol-ester- and Fos-dependent pathways in human non-small-cell lung-cancer cells.

Activation of protein kinase C- (PKC) and Fos/Jun-dependent signal transduction pathways are thought to be major effects of oncogene action in different tumor systems including human non-small-cell lung carcinoma (NSCLC). We have previously shown that the phorbol ester analogue phorbol-myristate-acetate (PMA), which is a potent activator of PKC, can induce squamous-type cellular differentiation and the expression of proteinases, such as plasminogen activators and pro-cathepsin L, in several NSCLC cell lines. To investigate the PMA-dependent effect on proteinase secretion in more detail, we have now analysed the role of a downstream transmitter of PKC activity in this process, namely Fos, which is part of the AP-1 transcription factor in the nucleus. We transfected a cell line derived from an undifferentiated squamous-cell lung carcinoma with different chimeric fos-estrogen receptor constructs (fos-ER) which makes selective activation of this transcription factor possible. The resulting clones were treated either with PMA as activator of PKC, or with diethylstilbestrol (DES), an estrogen analogue binding to and thereby activating preformed Fos-ER molecules. We show that cells treated with either substance undergo similar phenotypic changes (change from cuboidal to spindle-cell type) and decrease their doubling rates and cloning efficiencies. This is paralleled by the induction of several proteinase genes such as t-PA, urokinase, and pro-cathepsins B and L. Contrary to activated PKC, Fos in this system seems to be unable to initiate terminal squamous-cell differentiation, as assessed by the production of cornified envelopes. It is, however, efficient in the stimulation of neutral or lysosomal proteinase secretion as determined by Western-blot analysis and zymography. This Fos-ER expressing system thus seems to be a valuable tool in the molecular dissection of pathways that lead to the activation and secretion of proteinases in NSCLC cells.

Granulocyte Colony-Stimulating Factor-Producing Large Cell Undifferentiated Carcinoma of the Lung.

We report a case of granulocyte colony-stimulating factor (G-CSF) producing lung cancer. A 38-year-old Japanese woman had a large cell undifferentiated carcinoma of the left lung with severe granulocytosis without any evidence of infection. A specimen was taken from a metastatic cervical lymph node and a tumor cell line was established. The culture supernatant of the line as well as patient's serum exhibited a high level of G-CSF by sandwich enzyme immunoassay. Immunohistochemical analysis demonstrated that tumor cells from transplanted nude mice were stained granularly in the cytoplasma by anti-human G-CSF monoclonal antibody, 4A6.

Secondary screening system for preclinical testing of human lung cancer therapies.

The National Cancer Institute has instituted a primary screening system for testing new agents against cultured cancer cell lines. The purpose of this study was to determine the feasibility of using a nude rat orthotopic (organ-specific) human lung cancer model system as an in vivo secondary screen for general evaluation of new anticancer agents and therapies active against lung cancer. To make this determination, we tested whether this system allows measurement of uptake and tumoricidal activity of anticancer therapies. Tumor-bearing lungs from 53 Rowett nude rats with orthotopically implanted human large-cell undifferentiated lung carcinoma (NCI-H460) were perfused ex vivo for 1 hour with or without each of two anticancer modalities. Lungs were perfused with blood-free perfusate alone (untreated control), perfusate with 100 micrograms/mL doxorubicin (treated positive control), or perfusate with lymphokine-activated killer cells plus human recombinant interleukin-2 (LAK/rIL-2). Weight gain during perfusion was the criterion used to quantitate lung injury. Treatment efficacy was measured by clonogenic assay after enzymatic disaggregation of the perfused tumors. Doxorubicin levels in the tumor and in the uninvolved lung were measured by high-performance liquid chromatography. Both treatment groups showed only slight increases in lung weight compared with that in the untreated control group, suggesting good lung tolerance of the procedure. Lung and tumor levels of doxorubicin were 320 +/- 21 ng/mg of tissue and 32 +/- 5 ng/mg of tissue (means +/- SE), respectively. Clonogenic assay demonstrated a fivefold to 10-fold reduction in the surviving fraction of tumor cells with doxorubicin but no change with LAK/rIL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastrin-releasing peptide gene expression in small cell and large cell undifferentiated lung carcinomas

Gastrin-releasing peptide (GRP; mammalian bombesin) is present in the neuroendocrine cells of human fetal lung and in small cell lung carcinomas (SCLCs), where it may act as a growth factor. Considering the potential importance of GRP as a tumor marker, we have conducted a retrospective immunohistochemical analysis of 176 lung tumors for markers of GRP gene expression, as well as several other markers of neuroendocrine cell differentiation: chromogranin A, neuron-specific enolase, and calcitonin. The majority of carcinoids contained mature GRP, in contrast to only a minority of SCLCs and large cell lung carcinomas (LCLCs). However, a majority of SCLCs and LCLCs contained proGRP immunoreactivity. In situ hybridization did not add any information beyond what was obtained using proGRP antisera. In spite of sharing these neuroendocrine cell markers, SCLCs are associated with a graver prognosis than LCLCs. No prognostic significance was associated with immunostaining for GRP or several other markers of neuroendocrine cell differentiation.

Characterization of a full-length cDNA which codes for the human spermidine/spermine N 1-acetyltransferase

Spermidine/spermine N 1-acetyltransferase is the rate-limiting enzyme in the catabolism of cellular polyamines. Using a combination of cDNA library screening and anchored PCR methodologies, a full length cDNA designated AP3 F7 corresponding to the human SSAT was cloned using RNA from the human large cell undifferentiated lung carcinoma line NCI H157. The resulting cDNA clone is 1,060 base pairs with a 513 base open reading frame coding for a 171 amino acid protein, with a predicted subunit molecular weight of 20,023. The 5′ non-coding region of AP3 F7 is 165 bases and the 3′ untranslated region is 382 bases with a polyadenylation site 20 bases 5′ to the poly(A) tail. This full length cDNA should be an aid in the study of the regulation of spermidine/spermine N 1-acetyltransferase expression and the significance of the acetyltransferase in polyamine metabolism.

Differential induction of spermidine/spermine N 1-acetyltransferase in human lung cancer cells by the bis(ethyl)polyamine analogues : Casero RA Jr, Celano P, Ervin SJ, Porter CW, Bergeron RJ, Libby PR. The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231. Cancer Res 1989;49:3829-33

We have investigated the induction of an important polyamine metabolic enzyme, spermidine/spermine N1-acetyltransferase, in two human lung cancer cell lines which respond differently to treatment with the bis(ethyl)polyamine analogues. The human small cell lung carcinoma line NCI H82 has previously been shown to be minimally affected by treatment with these analogues, whereas the large cell undifferentiated lung carcinoma line, NCI H157, responds in a rapid cytotoxic manner (R.A. Casero, Jr., S. J. Ervin, P. Celano, S. B. Baylin, and R. J. Bergeron, Cancer Res., 49:639-643, 1989). The mechanisms underlying the differential response are unknown. In the responsive NCI H157 cells, the bis(ethyl)polyamines were found to induce spermidine/spermine N1-acetyltransferase in a time- and dose-dependent manner to maximum levels greater than 1700-fold over baseline. By contrast, the unresponsive NCI H82 cells exhibit minimal induction of spermidine/spermine N1-acetyltransferase to less than 7-fold increase after bis(ethyl)polyamine treatment, regardless of time or concentration examined. The results of the current study suggest that the differential induction of this key enzyme, which is rate limiting in the back conversion pathway of polyamine metabolism, may play a role in determining cell specific to the bis(ethyl)polyamine analogues.

Unusual Primary Lung Neoplasms: Spindle Cell and Undifferentiated Lung Carcinomas Expressing only Vimentin

Two unusual primary carcinomas of the lung are described. One occurred in a 31-year-old man and was composed of large, undifferentiated, ovoid to polygonal cells. The other occurred in a 72-year-old man, was composed of spindle-shaped cells, and was initially diagnosed as a localized fibrous mesothelioma. The neoplastic cells of these tumors expressed only vimentin intermediate filaments and showed no other immunohistochemical features of epithelial neoplasms, although they exhibited a metastatic pattern characteristic of lung carcinomas. These two malignant neoplasms further expand the spectrum of unusual lung neoplasms, and suggest that there are pulmonary carcinomas that contain only vimentin intermediate filaments.

Uptake of Tc-99m MDP by Adrenal Metastases from Undifferentiated Large-Cell Carcinoma of the Lung

A case is presented in which Tc-99m MDP bone imaging demonstrated uptake in bilateral adrenal metastases from an undifferentiated large-cell lung carcinoma