Adjuvant chemotherapy improves the prognosis of early stage resectable pulmonary large cell carcinoma: analysis of SEER data.

BACKGROUND: Pulmonary large cell carcinoma (LCC) is a poorly differentiated and rare tumor with dismal outcome, and there are no recommended treatments for LCC. Little is known about the efficacy of postoperative chemotherapy in patients with early stage LCC. METHODS: The patients with early stage I/II LCC in the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2015 were retrospectively reviewed. The overall survival (OS) of patients with LCC at different stages and treatments were evaluated by Kaplan-Meier analysis with log-rank test. Univariate and multivariate Cox proportional risk regression analysis were employed to determine the independent risk factors of OS. Finally, a nomogram was constructed to predict the 1 -, 3- and 5-year OS of early stage LCC patients. RESULTS: A total of 1,099 pulmonary LCC cases were included in this study. 71.8% of patients were over 60 years old, and 66.7% of the tumor lesions located in the upper lobe, followed by the lower lobe (25.7%). Meanwhile, the majority of tumors showed poor differentiation (96.1%). The median OS of surgical patients with or without post-operative adjuvant chemotherapy was 61 and 47 months, respectively. Post-operative chemotherapy was associated with better OS (HR: 0.805; 95% CI: 0.676-0.959, P=0.020). For patients with tumor size >3 cm or IB stage tumor, the prognosis of postoperative chemotherapy was better than that of patients without chemotherapy. Multivariate Cox analysis revealed the age, stage and treatments were independent risk factors of OS for early stage LCC. The nomogram had a calibration index of 0.581. CONCLUSIONS: The incidence of LCC was high in the elderly, and it generally had poor differentiation. Post-operative chemotherapy is strongly recommended for patients with LCC at stage IB or higher.

Lung Cancer in the Young.

INTRODUCTION: Median age at diagnosis of lung cancer is 70 years. Its presentation in patients 40 or younger is uncommon and it has been proposed that maybe it is a different disease due to its clinical characteristics and genetic makeup. There are a limited number of studies in this population and they report different clinic-pathological characteristics in comparison with older patients. METHODS: We described the incidence of lung cancer patients diagnosed at age 40 or younger at the Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima-Peru; from 2009 to 2017 and evaluated the characteristic of NSCLC. Epidemiologic and clinic-pathological data was collected from clinical files. Analysis was carried out using SPSSvs19 software. RESULTS: We identified 3823 patients with lung cancer seen at INEN during the study period. Among these, 166 (4.3%) patients were 40 years or younger, and 137/166 (82.5%) were NSCLC. Median age at diagnosis was 36 years (range 14-40 years) and 59.1% of patients were female. A smoking history was present in 14.4% of patients. Frequent symptoms at diagnosis were cough (62.0%), chest pain (51.8%) and dyspnea (40.9%). Adenocarcinoma was the most common histological type (63.3%). Most patients had advanced disease at diagnosis (84.7%). The median overall survival was 8.2 months. CONCLUSIONS: The proportion of young patients with lung cancer in our population is higher than that reported in the most recent literature. Lung cancer in the young is mostly sporadic, more frequent in women, usually adenocarcinoma type and it presents with advanced disease, resulting in a very poor survival.

Miliary Lung Metastases from Genital Large Cell Neuroendocrine Carcinomas.

We herein report two cases of miliary lung metastases from genital carcinoma in uterine cervix and endometrium. Notably, these patients were unable to receive any anti-tumor chemotherapy due to rapid progression causing respiratory failure, and they ultimately died of disease progression within only a month after the first visit to our hospitals. A postmortem examination confirmed the diagnosis of genital large-cell neuroendocrine carcinoma (LCNEC). Chest physicians should be aware of genital LCNEC with a dismal prognostic entity as an important differential diagnosis of miliary lung metastases.

Lung Cancer: Clinical Presentation and Diagnosis.

In the absence of screening, most patients with lung cancer are not diagnosed until later stages, when the prognosis is poor. The most common symptoms are cough and dyspnea, but the most specific symptom is hemoptysis. Digital clubbing, though rare, is highly predictive of lung cancer. Symptoms can be caused by the local tumor, intrathoracic spread, distant metastases, or paraneoplastic syndromes. Clinicians should suspect lung cancer in symptomatic patients with risk factors. The initial study should be chest x-ray, but if results are negative and suspicion remains, the clinician should obtain a computed tomography scan with contrast. The diagnostic evaluation for suspected lung cancer includes tissue diagnosis, staging, and determination of functional capacity, which are completed simultaneously. Tissue samples should be obtained using the least invasive method possible. Management is based on the individual tumor histology, molecular testing results, staging, and performance status. The management plan is determined by a multidisciplinary team consisting of a pulmonology subspecialist, medical oncology subspecialist, radiation oncology subspecialist, and thoracic surgeon. The family physician should remain involved with the patient to ensure that patient priorities are supported and, if necessary, to arrange for end-of-life care.

An African American Man in His Late 30s With Lung Cancer Presenting With Persistent Cough and Hemoptysis.

CASE PRESENTATION: An African American man in his late 30s was referred to the pulmonary clinic for evaluation of a persistent cough of several weeks' duration. Cough was productive of mucopurulent sputum mixed with blood. He also noted generalized weakness and dyspnea with minimal exertion.

Which is the Role of Pneumonectomy in the Era of Parenchymal-Sparing Procedures? Early/Long-Term Survival and Functional Results of a Single-Center Experience.

AIM: Despite the increasing adoption of parenchymal-sparing procedures, pneumonectomy is still necessary in several pleural and pulmonary (benign or malignant) diseases. We reviewed clinical data of a large cohort of patients treated by pneumonectomy with the aim of better define its impact on early and long-term results. METHODS: Clinical and pathological characteristics of all consecutive patients treated by pneumonectomy between January 2005 and May 2012 were retrospectively reviewed. Thirty- and 90-day mortality, as well as long-term survival was assessed. Factors associated to long-term survival were analyzed by univariate and multivariate analyses. Evaluation of quality of life was carried out by a standard questionnaire (SF-12) administrated by phone to patients surviving beyond 1 year. RESULTS: A total of 398 patients (293 men; mean age 61 ± 10.9 years) were operated on in the study period. Indication was malignancy in 380 patients (350 primary lung cancers). Thirty-day mortality was 9 % (right: 12.6 % vs. left: 6.3 %, p = 0.013), significantly correlating with age (p = 0.021), comorbidities (p = 0.034), PS > 1 (p = 0.018), preoperative dyspnea (p = 0.0013), and FEV1 (p = 0.0071). Overall 1-, 3-, 5-, and 7-year survival rates were 76.6, 46.6, 34.4, and 29.2 %. In case of primary lung cancer, these figures were 76.8, 46.4, 34.5, and 29.7 %. At univariate analysis, a less favorable survival was associated to PS > 1 (p = 0.0078), right side (p = 0.044), occurrence of postoperative complications (p = 0.00079), and T3-4 status (p = 0.013). At multivariate analysis, PS > 1, right side, and occurrence of postoperative complications were identified as independent worse prognostic factors. SF12 physical score was 39.1 ± 9.0 and was correlated to the presence of preoperative symptoms (p = 0.013). Mental score was 50.68 ± 9.63 and was correlated to preoperative FEV1/FVC ratio (p = 0.023) and side of disease (p = 0.023). CONCLUSION: In current practice, pneumonectomy is still performed for malignancy, sometimes after induction treatment. High postoperative morbidity and mortality are observed; however, at a farer interval time point, long-term survival with preserved quality of life can be observed.

Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung.

BACKGROUND: In terms of prognosis, large cell neuroendocrine carcinoma (LCNEC) differs distinctively from other non-small cell lung cancers, with the prognosis of LCNEC being poor, even for early-stage disease. Improvements in survival require a biomarker capable of defining a subset of patients destined to do poorly so that these patients can be targeted for additional therapies, including chemotherapy. In this study, we focused on the Klotho gene, which is an anti-aging gene known to be a potential tumor suppressor. We investigated whether the immunohistochemical expression of Klotho can predict survival patients with resected LCNEC. METHODS: The histological characteristics of patients receiving an initial diagnosis of LCNEC (n=30) at Tokyo Medical University Hospital were retrospectively reviewed, and multiple variables including stage, lymphangioinvasion, lymph node status and the expression of Klotho as identified using an immunohistochemical analysis, were assessed. RESULTS: Immunostaining for Klotho was mostly cytoplasmic, and Klotho expression was seen in 10 patients (33.3%) but not in 20 patients (66.7%). The expression of Klotho was significantly associated with a good outcome of resected patients with LCNEC and Klotho(-) was associated with increased LCNEC risk by multivariate analysis (hazard ratio 4.92, 95% confidence interval 1.04-23.24, p=0.044). Neither lymph node status nor lymphangioinvasion were significantly associated with a poor survival. However, among patients without lymph node metastasis or angioinvasion, the survival benefit of Klotho expression in the primary tumor was significantly higher, compared with that of patients without Klotho expression. CONCLUSION: Klotho staining provides a new biomarker for a good outcome in patients with LCNEC, especially among patients without lymph node metastasis or lymphangioinvasion.

Large cell/neuroendocrine carcinoma.

Large cell neuroendocrine tumors of the lung represent a recently reclassified subtype of lung cancer with features of both small cell and non-small cell lung cancer. We review diagnostic difficulties, typical presentations, and the natural history of this tumor. We review treatment data, and suggest that as in more common types of lung cancer, multi-modality therapy may be the most promising course of treatment.

Toona sinensis extracts induced cell cycle arrest and apoptosis in the human lung large cell carcinoma.

Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the supernatant of centrifuged crude extract from Toona sinensis leaves (TSL-1) to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose) polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.

Fall in diffusing capacity associated with induction therapy for lung cancer: a predictor of postoperative complication?

BACKGROUND: Pulmonary resection after induction therapy is associated with high rates of pulmonary morbidity and mortality. However, the impact of induction therapy on the pulmonary toxicity and associated pulmonary complications has not been fully investigated in the setting of lung cancer surgery. METHODS: We assessed the 66 consecutive patients who underwent a pulmonary resection after induction therapy, 48 of whom received chemoradiotherapy and 18, chemotherapy alone. Results of pulmonary function before and after induction therapy were compared, and logistic regression analyses utilized to explore the risk factors of pulmonary morbidity. RESULTS: After induction therapy, forced expiratory volume in 1 second (FEV1) was increased significantly (from 2.28 +/- 0.61 L to 2.40 +/- 0.62 L; p < 0.05); however, percent vital capacity (%VC) and FEV1/FVC did not change significantly. The diffusing capacity of lung for carbon monoxide (D(LCO)) was decreased significantly by 21% (from 90.3% +/- 18.3% to 71.1% +/- 12.5%; p < 0.0005). Patients with respiratory complication showed lower predicted postoperative %FEV1 (49.5% +/- 11.1% versus 57.2% +/- 14.2%; p = 0.031) and predicted postoperative %Dlco (41.9% +/- 8.0% versus 55.4% +/- 10.1%; p < 0.0001) results than those without complications. Univariate and multivariate analyses revealed that predicted postoperative %D(LCO) alone was an independent factor to predict postoperative pulmonary morbidity. CONCLUSIONS: For patients who undergo a pulmonary resection after induction therapy, predicted postoperative %D(LCO) is more important to predict pulmonary morbidity rather than static pulmonary function (predicted postoperative %VC or %FEV1). The decrease in D(LCO) is thought to reflect a limited gas exchange reserve, caused by the potential toxicity of chemotherapy or chemoradiotherapy. We believe that the impact of diffusion limitation after induction therapy should to be emphasized to decrease the pulmonary morbidity.

Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status: a Minnie Pearl Cancer Research Network Phase II Trial.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) and poor performance status (PS) are often excluded from trials. Gefitinib is a safe oral agent that may benefit these patients. PATIENTS AND METHODS: Seventy-two patients with poor PS and advanced NSCLC were enrolled onto this study of gefitinib 250 mg per day given orally until disease progression, with evaluation at 8 weeks. Eligible patients had no previous chemotherapy, an Eastern Cooperative Oncology Group PS of 2/3, and stage IIIB/IV NSCLC. Quality of life (QOL) and symptom response (SR) scores were calculated using the Functional Assessment of Cancer-Lung questionnaire. Patient characteristics included a median age of 75 years; PS of 2/3; and bronchoalveolar (n=3), adenocarcinoma (n=29), squamous cell (n=21), large-cell (n=11), and unspecified histology (n=6). Mean treatment duration was 4 months (range, 3 days to 18 months), and median duration of follow-up was 12 months. Grade 3/4 toxicities included rash and diarrhea. RESULTS: Among 70 patients assessed for response, there were 3 partial responses (4%), 32 patients with stable disease (46%), and 18 with progressive disease (26%). Median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.3 months, respectively. Six-month and 1-year PFS and OS rates were 35% and 21% and 50% and 24%, respectively. Eighty-two percent and 48% of patients reported improvements or no change in QOL and SR, respectively. CONCLUSION: Gefitinib demonstrates modest efficacy and is well tolerated as initial therapy in advanced NSCLC for patients with poor PS.

Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer.

BACKGROUND: We designed a prospective study to test epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) in resected stage I-IIIA non-small-cell lung cancer (NSCLC) and to correlate overexpression with survival. PATIENTS AND METHODS: EGFR expression was evaluated in 130 consecutive NSCLC patients after radical surgery (60 squamous cell carcinomas, 48 adenocarcinomas, 22 large cell carcinomas: stage I, 41 (31%); stage II, 37 (29%) and stage IIIA, 52 (40%). RESULTS: Overall, 101 of 130 (78%) specimens expressed EGFR, and with a cut-off value of 10% positive cells 48 cases (37%) were classified as positive. At univariate analysis, EGFR was significantly more expressed in stage III (50%) than stage I (20%) and stage II (25%) (P <0.03). No correlation with histotype was found. After a median follow-up of 84 months, both median survival time (18 versus 50 months), 2-year (43% versus 70%) and 5-year (31% versus 46%) survival rates of positive cases were significantly lower than negative ones [P <0.001; hazard ratio 1.96; 95% confidence interval (CI) 1.16-3.30]. At the multivariate analysis, EGFR overexpression and stage emerged as independent factors for cancer-related mortality. CONCLUSION: In patients with radically resected stage I-IIIA NSCLC, EGFR overexpression predicts shorter survival, thus representing a valuable prognostic factor.

Gene expression profiling of cultured human bronchial epithelial and lung carcinoma cells.

Lung cancer is a complex collection of diseases that is thought to begin with single mutated progenitor cells and culminates in any of several clinically described pathologies. Our knowledge of the molecular events that lead to different lung cancer types--small cell carcinoma, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma--is incomplete. Nonetheless, it is evident that genetic changes that impact multiple molecular networks are involved in the generation of each specific phenotype. Due to the obvious complexity of these processes, the simultaneous quantitative monitoring of changes in the expression of genes that define these networks can provide mechanistic information to increase our understanding of the molecular basis for human pulmonary carcinogenesis. To this end, we have employed a commercially available human cDNA array (Atlas Human Array, Clontech Laboratories) to systematically screen for alterations in the expression of 600 genes in normal human bronchial epithelial (NHBE) cells as well as in several lung carcinoma lines. Studies on the reproducibility and variability of array results indicate that a 2-fold or greater difference in the expression of a particular gene could be considered a real difference in transcript abundance. Accuracy of gene expression as measured in the array was verified by comparing mRNA levels of the proto-oncogene c-myc in the array with results obtained by traditional Northern blot analysis and by quantitative RT-PCR. Gene expression profiles were compared within and among cell types. The differential expression of 17 genes, including downregulation of MRP8 and MRP14 and upregulation of CYP1B1, was observed in all four carcinoma lines compared to NHBE cells. The direction of all 17 gene expression differences, either upregulation or downregulation relative to NHBE cells, was the same for all four carcinoma lines, underscoring their common molecular features. Each lung tumor line also exhibited a number of unique differences compared to both normal cells and the other tumor cell lines. These differences may be due to differences in the cellular origin and/or pathology of the cell lines studied.

Pulmonary neuroendocrine cells in physiology and pathology.

Pulmonary neuroendocrine cells are scant and widespread within the pulmonary epithelium. The function they play is not fully known, more studies are needed to clearly define it. They have been implicated however, as either the culprit or victim of many pulmonary diseases. That is the reason, why so many scientists take interest in the pulmonary neuroendocrine system. This paper reviews current information regarding pulmonary neuroendocrine cells, their origin, morphology, ontogeny, role, neuroendocrine cell markers, dysplasia and hyperplasia of pulmonary neuroendocrine cells in various conditions, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, typical carcinoid, atypical carcinoid, small-cell lung carcinoma, large-cell neuroendocrine carcinoma and the unusual spectrum of pulmonary neuroendocrine tumours.

Neurally mediated syncope induced by lung cancer--a case report.

The authors present hemodynamic and autonomic features of recurrent and episodic neurally mediated syncope in a man with lung cancer involving afferent vagus. He revealed extreme hypotension with bradycardia occurring during sitting or standing. A head-up tilt test also induced syncope. However, syncope attacks no longer occurred 2 weeks after admission. Alternatively, the paralyses of the left recurrent laryngeal nerve and the left phrenic nerve developed. It is suggested that the lung cancer involved upper rootlets of the left vagus and caused transient hypersensitivity of baroreceptor function that resulted in neurally mediated syncope.

Aggressive surgical treatment of multiple primary lung cancers.

A case of triple primary lung cancers--squamous cell carcinoma, adenocarcinoma and large-cell carcinoma--is presented. Surgical treatment comprised, respectively, left pneumonectomy, partial resection of the right upper lobe and completion right upper lobectomy. The postoperative courses were uneventful and the patient remains well, with no sign of recurrence, 20 months after the third operation.

Spontaneous regression of large-cell carcinoma of the lung--a rare observation in clinical practice.

Spontaneous regression of non-small-cell lung carcinoma is extremely rare and there are few documented cases. We report a 59-year-old man with a right upper lobe tumour which showed progressive regression while hilar adenopathy appeared 2 months after the initial tumour detection. At operation, only scar tissue was found in the lung but a hilar lymph node contained large-cell undifferentiated carcinoma. This report indicates that a decrease in size of a pulmonary mass does not exclude the diagnosis of carcinoma and that metastatic disease can occur even if the primary tumour regresses.

Frequent reduction of gap junctional intercellular communication and connexin43 expression in human and mouse lung carcinoma cells.

The reduced gap junctional intercellular communication (GJIC) and gap junction protein (connexin) expression that have been noted in many neoplastic cell types may contribute to the neoplastic phenotype. We assessed GJIC (by fluorescent dye micro-injection) and connexin expression (by Northern blotting, Western blotting and immunohistochemistry) in five mouse and 17 human lung carcinoma cell lines; both measures were lower in neoplastic cells compared to non-transformed lung epithelial cells. Other connexins were not detected in these cells. Co-culture experiments indicated that carcinoma cell lines able to transfer dye among themselves (homologous GJIC) had little capacity for dye-coupling with non-transformed cells (heterologous GJIC). Southern blot analyses indicated that reductions in GJIC and connexin43 expression were not due to deletions or rearrangements of this gene, but were more likely accounted for by transcriptional down-regulation and/or post-transcriptional factors. No correlations between GJIC and known oncogene and tumor suppressor gene alterations in the human lung carcinoma cells were apparent, suggesting that other mechanisms down-regulate GJIC in these cells. Since the neoplastic cell lines exhibited low GJIC (either homologous or heterologous), this characteristic may be involved in expression of the neoplastic phenotype.

Evaluation of abnormal regional ventilation in patients with lung cancer using three-dimensional display of dynamic 133Xe SPET.

Preliminary studies were carried out of regional ventilation in lung cancer using three-dimensional (3D) display of dynamic pulmonary 133Xe single photon emission tomography (SPET). Transaxial equilibrium and washout images were obtained from SPET data acquired with an acquisition time of 30 s using a triple-detector SPET system in 39 patients with lung cancer. After reconstructing colour-illuminated, surface-rendered 3D images of equilibrium and 3-min washout (WO3), a single 3D fusion display was created from these two different time-course image sets, in which the 3D WO3 image indicating 133Xe retention was visible through the 3D equilibrium image delineating lung contours. The extent of retention was assessed using the 133Xe retention index, defined as the ratio of summed pixels of the segmented WO3 data to those of the segmented equilibrium data. 133Xe SPET was highly sensitive and specific for the presence of regional ventilation abnormalities associated with endobronchial tumour or bronchial compression due to enlarged lymph nodes. These abnormalities were demonstrated irrespective of the presence or absence of secondary changes distal to the tumour on the chest computed tomography scan. The geometrically realistic 3D fusion display enhanced anatomic localization of the regional ventilation abnormalities compared to the information from multislice tomograms, and the 133Xe retention index correlated well with %FEV1 (r = 0.828). This topographic 3D display for 133Xe SPET allows better perception of anatomic localization and extent of 133Xe retention. It will be useful for assessing regional ventilatory function in patients with lung cancer.