Antiangiogenic and antitumor effects of a protein kinase Cβ inhibitor in murine Lewis lung carcinoma and human Calu-6 non-small-cell lung carcinoma xenografts

The relationship between expression and function of the epidermal growth factor (EGF) family of receptors and chemosensitivity remains controversial. We studied the chemosensitivity to various anticancer agents of human cervical squamous carcinoma ME180 cells, and two resistant subclones, ME180/TNF and ME180/Pt, which also differ in their EGF receptor (EGFR) expression. Compared with ME180 cells, EGFR is overexpressed sixfold in ME180/TNF cells and is barely detectable in ME 180/Pt cells. Cell cycle analysis by flow cytometry and BrdU incorporation into DNA showed a correlation between EGFR expression and percentage of cells in S phase and active DNA replication (35% in high EGFR-expressing ME180/TNF cells, 19% in non-EGFR-expressing ME180/Pt cells and 23% in parental, intermediate-level EGFR-expressing ME 180 cells). By MTT assay and compared with parental, intermediate-level EGFR-expressing ME180 cells, high EGFR-expressing ME180/TNF cells had a three- to fourfold increased sensitivity to cisplatin, camptothecin (CPT), and topotecan, and low EGFR-expressing ME180/Pt cells had a five- to ninefold reduced sensitivity to the same agents. In contrast, the degree of cross-resistance with the topoisomerase II inhibitors doxorubicin and etoposide was minimal and the pattern of sensitivity to the anti-microtubulin agents vinblastine and paclitaxel was different, with a two- to fourfold decreased sensitivity in the high EGFR-expressing ME180/TNF cells and only a 1.5-fold decreased sensitivity in the low EGFR-expressing ME180/Pt cells. Neither alterations in intracellular CPT levels nor changes in topoisomerase I expression or activity, measured as ability to form DNA-protein complexes, were found to explain the differences in sensitivity to CPT among the three cell lines. Co-treatment with CP358774, a specific EGFR tyrosine kinase inhibitor, reduced the enhanced sensitivity of high EGFR-expressing ME180/TNF cells to the values observed in intermediate EGFR-expressing ME180 cells, but only reduced modestly the sensitivity of intermediate expressing ME180 cells. As a result, the resistance index of low EGFR-expressing ME180/Pt cells compared with intermediate EGFR-expressing ME180 cells was reduced only from five- to fourfold for cisplatin and from seven- to fourfold for CPT when ME180 cells were exposed to CP358774. CP358774 did not affect the sensitivity to either agent in low EGFR-expressing ME180/Pt cells. These results provide evidence that changes in EGFR expression or function may play a role in determining chemosensitivity to platinum and topoisomerase I poisons in some human tumor systems, and that the EGFR-related changes in chemosensitivity may vary depending on the level of EGFR expression and/or function.     

Down-regulation of IL-6, IL-8, TNF-α and IL-1β by glucosamine in HaCaT cells, but not in the presence of TNF-α

There is considerable evidence that glucosamine exerts an inhibitory effect on inflammatory cytokine expression in cells. Glucosamine has been recommended as a promising anti-inflammatory modulator, which has been applied in clinical trials for attenuation of the inflammatory process. However, it is unknown whether glucosamine reduces the expression of TNF-α-induced inflammatory cytokines in HaCaT cells. The anti-inflammatory effects of curcumin in HaCaT cells have been extensively investigated in several studies. Thus, in this study we investigated the expression of IL-6, IL-8, TNF-α and IL-1β in glucosamine-treated HaCaT cells, and the effects of glucosamine were compared to those of curcumin-treated HaCaT cells. Our data showed that the expression of IL-6, IL-8, TNF-α and IL-1β was decreased by glucosamine treatment in the HaCaT cells. In contrast, the expression of IL-6, IL-8, TNF-α and IL-1β was not attenuated by glucosamine treatment in the TNF-α-treated HaCaT cells. Notably, curcumin induced an increased expression of IL-8 and IL-1β in the HaCaT cells, but not that of IL-6 and TNF-α. On the other hand, curcumin attenuated the expression of IL-6 and IL-8 in the TNF-α-treated HaCaT cells. Our data indicated that glucosamine induced the down-regulation of IL-6, IL-8, TNF-α and IL-1β expression in the HaCaT cells. However, the stimulation of TNF-α abolished the inhibitory effects of glucosamine on the expression of inflammatory cytokines in the HaCaT cells. Thus, even though glucosamine induces the down-regulation of inflammatory cytokines in HaCaT cells, the anti-inflammatory role of glucosamine in TNF-α-mediated inflammatory skin diseases should be investigated.     

β-Cyclodextrin tetradecasulfate/tetrahydrocortisol±minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic lewis lung carcinoma

Tetrahydrocortisol, -cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 M, 24 h) and -cyclodextrin tetradecasulfate (100 M, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 M, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studies. Tetrahydrocortisol and -cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14×5mg/kg, days 4–18) and cyclophosphamide (3×150 mg/kg, days, 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.Abbreviations 14(SO₄)ßCD -cyclodextrin tetradecasulfate - THC tetrahydrocortisol - CDDP cis-diamminedichloroplatinum(II) - 4-HC 4-hydroperoxycyclophosphamide - BCNU N,N-bis(2-chloroethyl)-N-nitrosourea - CAM chick embryo chorioallantoic membrane; IC₅₀, concentration of a drug required to kill 50% of the cells This work was supported by NIH grant P01-CA38493 and a grant from Bristol-Myers-Squibb, Inc., Wallingford, Connecticut     

Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer

Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-α PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-α-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-α PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-α in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-α was superior to sequential delivery of IL-12 followed by TNF-α, but not TNF-α followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-α is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-α results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-α resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-α PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.     

High serum levels of TNF-α and IL-6 predict the clinical outcome of treatment with human recombinant erythropoietin in anaemic cancer patients

BackgroundA number of anaemic cancer patients are not responsive to treatment with recombinant human erythropoietin (rHuEPO). The aim of the present study is to investigate whether serum levels of tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and additional laboratory parameters, together with clinical variables, can predict the clinical outcome of treatment with rHuEPO in anaemic cancer patients.Patients and methodsThirty-five cancer patients and 25 healthy controls were enrolled in this study. Patients were treated with epoetin alfa at the dose of 150 IU/kg s.c. three times a week for 12 weeks. If the haemoglobin (Hb) level failed to improve at least 2 g/dl above baseline by week 6 of treatment, dose was increased to 300 IU/kg s.c. for the remainder of the treatment period. All patients filled out the Brief Fatigue Inventory (BFI), a questionnaire for the self-evaluation of cancer-related fatigue. Serum samples from patients and control groups were frozen at -80°C and TNF-α, IL-1β and IL-6 were later examined by enzyme-linked immunosorbent assay.ResultsFatigued cancer patients had significant higher levels of circulating TNF-α, IL-1β and IL-6 than healthy controls. Responders (Rs) to erythropoietin had significant lower medium levels of TNF-α and IL-6 than nonresponders (NRs). Fatigued patients with a general BFI score ≥6 presented higher medium level of cytokines than nonfatigued patients (general BFI score <6), but each group responded similarly to treatment with rHuEPO.ConclusionsHigh serum levels of TNF-α and IL-6 at the baseline are significantly correlated with a negative response to administration with rHuEPO. Thus, pretreatment evaluation of TNF-α and IL-6 serum levels can help to select those patients who are most likely to benefit from treatment with rHuEPO. On the contrary, Hb level, red blood cell count, lactate dehydrogenase and BFI score do not predict the outcome of treatment with rHuEPO.     

IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo

Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). Tumor antigen-sensitized DLN lymphocytes from BALB/c mice with 10-day 4T1 mammary carcinomas were harvested, activated with B/I, and expanded in culture with either interleukin-2 (IL-2) or IL-7 + IL-15. Cell yields, proliferation, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for antitumor activity against established 4T1 mammary carcinomas after inoculation of tumor cells subcutaneously (s.c.). IL-7/15 resulted in much faster and more prolonged proliferation of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately 5–10-fold greater yields of viable cells. Culture in IL-7/15 yielded higher proportions of CD8⁺ T cells and a higher proportion of cells with a central memory phenotype. T cells grown in IL-2 had higher interferon-gamma (IFN-γ) release responses to tumor antigen than cells grown in IL-7/15. Adoptive transfer of B/I-activated T cells grown in IL-7/15 demonstrated much greater efficacy against 4T1 tumors in vivo. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in AIT of cancer.     

Effect of topical chamomile on immunohistochemical levels of IL-1β and TNF-α in 5-fluorouracil-induced oral mucositis in hamsters

Purpose

The aim of the present study was to evaluate the effect of topical chamomile and corticosteroid treatment on the profile of tissue cytokines (IL-1β and TNF-α) in 5-fluorouracil-induced oral mucositis in hamsters.

Methods

Thirty-six hamsters were randomly separated into three groups (12 animals each): Group I—without treatment (control); Group II—treatment with chamomile (Ad-Muc^®); and Group III—treatment with corticosteroid (betamethasone elixir- Celestone^®). The animals received an intraperitoneal injection of 5-fluorouracil on Days 0 and 2. On Days 3 and 4, the buccal mucosa was scratched and therapy was initiated on Day 5. Three animals from each group were killed on Days 0, 5, 10, and 14 and the buccal mucosa was removed. The streptavidin–biotin complex method was used to delineate the in situ distribution, localization, and semiquantitative analysis of IL-1β and TNF-α. Data from the semiquantitative analysis of immunohistochemical staining were comparatively analyzed using the Kruskal–Wallis test, followed by Dunn’s multiple comparisons test.

Results

The distribution and localization of IL-1β and TNF-α immunolabeling were similar. These proteins exhibited a diffuse pattern distributed throughout the connective tissue. The epithelium and adipose tissue were negative for both proteins. The semiquantitative analysis revealed that immunolabeling of IL-1β and TNF-α increased in all groups with the development of mucositis. On Day 10 (period of peak mucositis), the group treated with chamomile had lower scores for both pro-inflammatory cytokines.

Conclusions

Treatment with topical chamomile reduced the tissue levels of IL-1β and TNF-α, thereby demonstrating anti-inflammatory action in oral mucositis in hamsters.     

Clinicopathological significance of chemotactic factor IL-8, MCP-1 and MIP-1α expressions in gallbladder carcinoma

Objective:Gal bladder carcinoma was one of the malignant tumors in the digestive system, characterized by high recurrence and invasion. Recent research indicates that chemotactic factors such as IL-8, ...     

In vivo antitumor activity by 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone in a solid human carcinoma xenograft model

Previously we have shown that 2,4-dihydroxy-6-methoxy-3,5-dimethylchalcone (DMC), which is isolated from the buds of Cleistocalyx operculatus, significantly inhibits the growth of human liver cancer SMMC-7721 cells and is able to induce apoptosis of SMMC-7721 cells in vitro. Here we report the antitumor effects of DMC in vivo, using a solid human tumor xenograft mouse model using human liver cancer SMMC-7721 cells. The average tumor weights in the control group and in mice injected with 150 mg/kg DMC were 1.42±0.11 g and 0.59±0.12 g, respectively. Flow cytometric analysis of the tumor cell population demonstrated an aneuploid peak (representing 33.60±0.80% of the total in mice injected with 150 mg/kg DMC). To our knowledge, this is the first time that chalcone compounds have been applied to a human tumor xenograft model.     

In vivo antitumor activity by 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone in a solid human carcinoma xenograft model

Previously, we showed that 2,4-dihydroxy-6-methoxy-3,5-dimethylchalcone (DMC), isolated from the buds of Cleistocalyx operculatus, significantly inhibited the growth of human liver cancer SMMC-7721 cells and could induce SMMC-7721 cells apoptosis in vitro. Here, we report the antitumor effects of DMC in vivo, using a solid human tumor xenograft model with a human liver cancer SMMC-7721 cell line. Our results revealed that the average tumor weight in a control group and a 150-mg/kg DMC injection group was 1.42±0.11 g and 0.59±0.12 g, respectively. Flow cytometric analysis of the tumor cell population demonstrated the existence of an aneuploid peak (representing 33.60±0.80% of the total in the 150-mg/kg DMC injection group). To our knowledge, this is the first time that chalcone compounds were applied to a human tumor xenograft model.     

Synergistic efficacy of γ-radiation together with gallium trichloride and/or doxorubicin against Ehrlich carcinoma in female mice

Tumor Biology - Combining chemotherapy with radiotherapy represents a key oncology strategy for a more comprehensive attack toward cancers and improves treatment outcome for various solid tumor...     

Metastatic cells can escape the proapoptotic effects of TNF-α through increased autocrine IL-6/STAT3 signaling

The liver is a common site for cancer metastases in which the entrance of tumor cells has been shown to trigger a rapid inflammatory response. In considering how an inflammatory response may affect metastatic colonization in this setting, we hypothesized that tumor cells may acquire resistance to the proapoptotic and tumoricidal effects of TNF-α, a cytokine that is elevated in a proinflammatory tissue microenvironment. In this study, we investigated molecular mechanisms by which such resistance may emerge using tumor cells in which the overexpression of the type I insulin-like growth factor receptor (IGF-IR) enhanced the inflammatory and metastatic capacities of poorly metastatic cells in the liver. Mechanistic investigations in vitro revealed that IGF-IR overexpression increased cell survival in the presence of high levels of TNF-α, in a manner associated with increased autocrine production of interleukin-6 (IL)-6. In turn, tumor cell-derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis. We found that IL-6 production and cell death resistance were dose dependent with increasing TNF-α levels. In addition, RNA interference-mediated knockdown of either IL-6 or gp130 that established a blockade to autocrine STAT3 induction was sufficient to abolish the prosurvival effect of TNF-α and to inhibit liver metastasis. Taken together, our findings define an IGF-IR-mediated mechanism of cancer cell survival that is critical for metastatic colonization of the liver.     

Could age modify the effect of genetic variants in IL6 and TNF-α genes in multiple myeloma?

Cytokines play a central role in multiple myeloma (MM) pathogenesis thus genetic variations within cytokines coding genes could influence MM susceptibility and therapy outcome. We investigated the impact of 8 SNPs in these genes in 202 MM cases and 235 controls also evaluating their impact on therapy outcome in a subset of 91 patients. Despite the overall negative findings, we found a significant age-modified effect of IL6 and TNF-α SNPs, on MM risk and therapy outcome, respectively. Therefore, this observation suggests that genetic variation in inflammation-related genes could be an important mediator of the complex interplay between ageing and cancer.     

Association of -308 TNF-α promoter polymorphism with clinical aggressiveness in patients with head and neck squamous cell carcinoma

Genetic polymorphisms in the promoter region of the tumour necrosis factor-α (TNF-α) gene are involved in the regulation of the expression levels of its cytokine. Besides, these polymorphisms have been associated with the clinical behaviour of cancer. We investigated the −308 promoter region polymorphisms of the TNF-α gene and its association with the clinicopathological factors of a head and neck squamous cell carcinoma (HNSCC) sample. Furthermore, we analysed the impact of all the variables on the overall survival of patients. A sample of HNSCC (n = 89) was evaluated. Clinicopathological factors and overall survival data were gathered. The TNF-α gene was analysed by using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Data analyses were performed by using bivariate and multivariate statistical tests. Significance was set at p < 0.05. HNSCC subjects carrying the A allele (GA/AA) exhibited associations with poor performance status (OR = 2.82, p = 0.039), lesions located on posterior areas (OR = 4.02, p = 0.002), and large-size tumours (OR = 2.91, p = 0.015). Subjects carrying only AA genotype exhibited association with poor performance status (OR = 6.667, p = 0.007). A worse overall survival was noted in subjects with large tumours (OR = 4.87, p = 0.005) and locoregional metastatic disease (OR = 2.50, p = 0.018). Our data suggests that the presence of the A allele/AA haplotype in HNSCC individuals might contribute to the higher clinical aggressiveness of malignant disease.     

Prognostic significance of main bronchial lymph nodes involvement in non-small cell lung carcinoma: N1 or N2?

STUDY OBJECTIVES: Accurate TNM staging is the basis to evaluate prognosis and to plan treatment of patients with non-small cell lung cancer. Exact definition of N status is fundamental and the boundary line between N1 and N2 stations is one of the most controversial issue. Purpose of this study is to evaluate the prognostic significance of main bronchus nodes, that we classified as station number 10 (N1). METHODS: We reviewed retrospectively lymph node patterns and survival of 175 patients with N1 and 154 with N2 disease, that underwent surgical resection with hilar and mediastinal lymphadenectomy from January 1990 to December 2000. These two groups were subdivided in N1 without station number 10 involvement (N1-, n = 144), N1 with station number 10 involvement (N1+, n = 31), N2 single station (N2s, n = 107) and N2 multiple stations (N2m, n = 47), respectively. A univariate and multivariate analysis of prognostic factors predicting survival has been performed. RESULTS: Overall 5-year survival rate for 175 N1 patients and 154 N2 patients was 42 and 13%, respectively and the difference was statistically significant (P < 0.001). The prognosis between N1-, N1+, N2 was compared: 5-year survival rate was 44, 31 and 13%, respectively and the difference reached a statistical value between N1+ and N2 (P < 0.05), but not between N1- and N1+. When the comparison was made with N1-, N1+, N2s and N2m, the difference was significant between N1- and N2s (P = 0.0003), between N1+ and N2m (P = 0.0001), but not between N1+ and N2s. CONCLUSIONS: The aim of a uniform anatomical and clinical classification of nodal stations has not been thoroughly achieved, particularly regarding the boundary line between N1 and N2. Our study points out that the involvement of main bronchial nodes has a prognostic significance similar to that of N2 single station and should be considered as an early N2 disease.     

A randomized phase II study of docetaxel or vinorelbine in combination with cisplatin against inoperable, chemo-naïve non-small-cell lung cancer in Taiwan

Cisplatin plus a third-generation anti-cancer drug, such as vinorelbine, gemcitabine, or the taxanes, are the standard regimen used in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), and there is no significant difference in efficacy among the different regimens. Our aim was to evaluate the efficacy of docetaxel plus cisplatin (DC) versus vinorelbine plus cisplatin (VC) in chemo-na?ve NSCLC patients. From December 2003 to May 2005, 94 patients were enrolled. The treatment dose was D 60 mg/m2 and C 60 mg/m2 intravenous infusion (IV) on day 1, or V 25 mg/m2 IV on days 1 and 8, and C 60 mg/m2 IV on day 1, every 3 weeks. In all, 209 cycles of DC and 230 cycles of VC were given to the patients in the DC (median five cycles) and VC (median five cycles) arms, respectively. There were 19 partial responses and one complete response (overall 43.5%) in the DC arm, and no complete responses, but 22 partial responses (overall 45.8%), in the VC arm. Myelosuppression was the major toxicity occurring in both arms, with grades 3 or 4 neutropenia occurring in 72.9% and 71.7% of patients, respectively. Except for alopecia (p=0.005) and diarrhea (p<0.001), which were more common in the DC arm, no significant differences in toxicity profiles were found between the two treatment arms. The median time to disease progression was 4.7 months in the DC arm and 6.3 months in the VC arm (p=0.7355). Median survival time was 13 months in the DC arm and 13.8 months in the VC arm (p=0.9656). The 1-year survival rate was 55.5% and 51.7%, respectively. After treatment, the Lung Cancer Symptom Scales showed no significant difference between the two treatment arms. We concluded that both DC and VC are appropriate regimens for use in the first-line treatment of Chinese NSCLC patients. Asthenia, one of the major side effects of docetaxel, was not a major problem in the present study. Although both regimens produced a high incidence of severe neutropenia, the majority of patients recovered rapidly without sequelae; and VC treatment is still a standard chemotherapy for Chinese NSCLC patients in Taiwan.     

Overexpression of HPV16 E6/E7 mediated HIF-1α upregulation of GLUT1 expression in lung cancer cells

Tumor Biology - High-risk human papillomavirus (HPV) infection may play an important role in non-small cell lung carcinoma (NSCLC) development. However, some recent studies have proved that it was...     

Phase II study of carboplatin–paclitaxel alone or with bevacizumab in advanced sarcomatoid carcinoma of the lung: HOT1201/NEJ024

International Journal of Clinical Oncology - Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid...