Methylated SHOX2 and RASSF1A genes are potential biomarkers for lung cancer diagnosis. Therefore, we explored the role of methylation detection combined with morphological bronchoscopic evaluation for lung cancer diagnosis. Bronchoscopy, methylation outcome, and pathological data were collected from 585 patients with lung cancer and 101 controls. The methylation status of the SHOX2 and RASSF1A genes were detected using real-time polymerase chain reaction quantification. Further, the sensitivity and area under the receiver operating characteristic curve of the three methods were analyzed. Among 686 patients, 57.1% had new lesions detected through bronchoscopy and 93.1% of these patients were diagnosed with malignant tumors. Besides, 42.9% of patients had no visible changes under bronchoscopy but there were still 74.8% of them diagnosed with malignant tumors. Bronchoscopy revealed that lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer mainly occurred in the upper and middle lobes. The sensitivity and specificity of methylation detection were 72.8% and 87.1% (vs. cytology 10.4% & 100%), respectively. Therefore, methylated SHOX2 and RASSF1A genes may be promising tumor markers in lung cancer diagnosis. Methylation detection can be an excellent supplementary tool for cytological diagnosis and, combined with bronchoscopy, could form a more effective diagnostic process.

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.

Small cell lung cancer is a relevant clinical issue as it is a highly malignant cancer, often diagnosed in advanced stage. Similarly to non-small cell lung cancer, tobacco smoking is currently the main risk factor. Its incidence, at least in males, has declined over the past decades, due to the worldwide decreased percentage of active smokers. The typical small cells of this tumor type are characterized by a high Proliferation Index, chromosomal deletions such as 3p(14-23) involving the tumor-suppressor gene FHIT, alterations of the MYC or Notch family proteins and the frequent expression of neuroendocrine markers. The combination of thoracic radiotherapy and chemotherapy is the standard treatment for limited stage disease, while platinum-based chemotherapy is the most effective choice for extensive stage disease. Unfortunately, whatever chemotherapy is used, the results are disappointing. No regimen has proved to be effective in the long run, indeed small cell lung cancer rapidly progresses after a frequent initial strong response, and the mortality rate remains still high. The advent of immunotherapy is actually changing the landscape in oncology. As well as in other cancers, recent trials have demonstrated the efficacy of the combination of immune checkpoint inhibitors and chemotherapy, opening new perspectives for the future of our patients.

The treatment of small cell lung cancer (SCLC) is a challenge for all specialists involved. New treatments have been added to the therapeutic armamentarium in recent months, but efforts must continue to improve both survival and quality of life. Advances in surgery and radiotherapy have resulted in prolonged survival times and fewer complications, while more careful patient selection has led to increased staging accuracy. Developments in the field of systemic therapy have resulted in changes to clinical guidelines and the management of patients with advanced disease, mainly with the introduction of immunotherapy. In this article, we describe recent improvements in the management of patients with SCLC, review current treatments, and discuss future lines of research.

The efficacy of prophylactic cranial irradiation (PCI) in treating patients with small cell lung cancer (SCLC) has not been clear, and recent randomized studies have demonstrated conflicting results from previously published findings. The purpose of this study was to reevaluate the efficacy of PCI in patients with SCLC and to assess factors associated with its efficacy.

We conducted a quantitative meta-analysis to explore the efficacy of PCI in patients with SCLC. A literature search was performed using EMBASE, MEDLINE, Cochrane and ClinicalTrials.gov databases. We pooled the data and compared overall survival (OS) and brain metastasis (BM) between patients treated with PCI (PCI group) and patients without PCI treatment (observation group).

Of the 1074 studies identified in our analysis, we selected seven studies including 2114 patients for the current meta-analysis. Our results showed that the PCI group showed decreased BM (HR = 0.45, 95% CI: 0.38-0.55, P < 0.001) and prolonged OS (HR = 0.81, 95% CI: 0.67-0.99, P < 0.001). However, in terms of OS, the pooled analysis showed a high heterogeneity (I² = 74.1%, P = 0.001). In subgroup analyses of OS, we found that the heterogeneity mainly came from patients with brain imaging after initial chemoradiotherapy (HR = 0.94, 95% CI: 0.74-1.18, P = 0.59).

The results of this study showed that PCI has a significant effect on decreasing BM but little benefit in prolonging OS when brain imaging was introduced to confirm lack of BM after initial chemoradiotherapy and before irradiation.

Although paclitaxel effectively treats various cancers, its debilitating peripheral neuropathic pain side effects often persist long after treatment has ended. Therefore, a compelling need exists for the identification of novel pharmacologic strategies to mitigate this condition. As inhibitors of monoacylglycerol lipase (MAGL), the primary hydrolytic enzyme of the endogenous cannabinoid, 2-arachidonyolglycerol, produces antinociceptive effects in numerous rodent models of pain, we investigated whether inhibitors of this enzyme (i.e., JZL184 and MJN110) would reverse paclitaxel-induced mechanical allodynia in mice. These drugs dose dependently reversed allodynia with respective ED50 values (95% confidence limit) of 8.4 (5.2-13.6) and 1.8 (1.0-3.3) mg/kg. Complementary genetic and pharmacologic approaches revealed that the antiallodynic effects of each drug require both cannabinoid receptors, CB1 and CB2 MJN110 reduced paclitaxel-mediated increased expression of monocyte chemoattractant protein-1 (MCP-1, CCL2) and phospho-p38 MAPK in dorsal root ganglia as well as MCP-1 in spinal dorsal horn. Whereas the antinociceptive effects of high dose JZL184 (40 mg/kg) underwent tolerance following 6 days of repeated dosing, repeated administration of a threshold dose (i.e., 4 mg/kg) completely reversed paclitaxel-induced allodynia. In addition, we found that the administration of MJN110 to control mice lacked intrinsic rewarding effects in the conditioned place preference (CPP) paradigm. However, it produced a CPP in paclitaxel-treated animals, suggesting a reduced paclitaxel-induced aversive state. Importantly, JZL184 did not alter the antiproliferative and apoptotic effects of paclitaxel in A549 and H460 non-small cell lung cancer cells. Taken together, these data indicate that MAGL inhibitors reverse paclitaxel-induced neuropathic pain without interfering with chemotherapeutic efficacy.

SCLC accounts for 15% and 20% of all lung cancers, with combined SCLC (CSCLC) comprising 2% to 5%. Little is known about the clinical characteristics and molecular changes associated with the various histologic components.

A total of 205 SCLC cases were resected between 2005 and 2015. Clinical and pathologic features were analyzed. All CSCLC cases were confirmed by histologic examination and immunohistochemistry. The individual components were microdissected using a novel automated dissection system, and DNA was extracted and subjected to targeted exome sequencing.

A total of 10 cases of CSCLC were identified out of 170 cases with adequate histologic material; squamous cell carcinoma comprised the second component in half of these (n = 5). There were no significant differences between CSCLC and pure SCLC with respect to clinical features. The median follow-up time was 36 months. The median survival times of patients with pure SCLC and CSCLC were 58 months and 26 months, respectively (p = 0.030). The different components of three cases of CSCLC were deemed adequate for microdissection and sequencing. Approximately 75% of the identified somatic mutations were present in both components. There were also 15 gene mutations or six amplifications unique to only one of the components.

We identified no significant clinical or pathologic differences between pure SCLC and CSCLC; CSCLC was associated with decreased overall survival compared with pure SCLC. The histologic components of CSCLC had high genetic concordance but also showed divergent genotypes. These findings may suggest a common precursor with subsequent acquisition of oncogenic changes in CSCLC.

Introduction: To investigate postoperative complications and the prognostic risk factors of patients underwent pneumonectomy. Methods: Four hundred and six patients underwent pneumonectomy were subjected to the study. All the clinicopathologic data including age, gender, smoking history, surgical treatment, postoperative complications, tumor staging and the follow-up information were investigated. Results: The 30-day and 90-day mortality rates were 3.2% and 6.2%, respectively. Postoperative complications developed in 149 patients (36.7%), mainly included arrhythmia, transfusion, pulmonary infection, bronchopleural fistula and acute respiratory distress syndrome. During the follow-up, 189 patients experienced a relapse, consisting of 51 patients with local recurrence and 138 with distant recurrence. The median survival time was 24.4 months and the overall 1-year, 3-year and 5-year survival rates were 82.7%, 50.9% and 32.5%, respectively. Moreover, the overall 1-year, 3-year, 5-year survival rates for patients with non-small cell lung cancer (NSCLC) were 84.1%, 52.1% and 32.5%, respectively and patients with small cell lung cancer (SCLC) were 56.1%, 38.5% and 28.8%, respectively. Among NSCLCs, adenocarcinomas had a worse prognosis than squamous carcinomas. Compared to right pneumonectomy, patients with left pneumonectomy had a better prognosis. Multivariable analysis revealed ICU stay, disease stage, nodal stage and adjuvant chemotherapy were all significant predictors of overall survival (OS). Conclusions: Pneumonectomy is still a valuable and effective treatment option for patients with advanced lung cancer. Surgeons should be more cautious when patients had higher disease stage, adenocarcinoma and right-side lung cancer. Neoadjuvant chemotherapy did not affect the prognosis. Pneumonectomy could also achieve acceptable survival outcomes in well-selected SCLC patients.

To elucidate the role of radiation therapy (RT) in the treatment of surgically resected limited-stage small cell lung carcinoma (LSCLC).

We queried the SEER database from 1998 to 2012 to identify patients who were diagnosed with LSCLC as their only primary tumor. Kaplan-Meier analysis was utilized to determine disease-specific survival (DSS) and overall survival (OS), while multivariate analysis was used to compare survival in terms of patients and treatment characteristics.

Eight hundred twenty-three LSCLC patients were identified for inclusion within the study. 12-month DSS for patients who did not receive surgery or RT was 31.9% (95% CI 27.7-36.3), 93.3% (95% CI 71.6-90.5) for surgery alone, and 81.0% (95% CI 69.3-88.6) for surgery + RT. 12-month OS was 27.2% (95% CI 23.4-31.1), 74.7% (95% CI 62.6-83.4), and 78.3% (95% CI 66.4-86.4) for no surgery or RT, for surgery alone, and for surgery + RT, respectively. In terms of multivariate analysis, patients receiving surgery alone and patients receiving surgery + RT had a better DSS and OS than those who received neither treatment. However, OS (HR 1.60; 95% CI 0.93-2.75, p = 0.09) and DSS (HR 1.34; 95% CI 0.72-2.51, p = 0.37) were not significantly associated with patients receiving surgery alone compared to surgery + RT.

Surgery alone and surgery + RT were positively associated with DSS and OS compared to patients who did not receive surgery or RT. However, the addition of RT to surgery did not significantly predict DSS or OS compared to surgery alone.

Small cell lung cancer (SCLC) is relative rare histology in lung cancer patients. The standard treatment, in patients with an intra-thoracic disease, is represented by the use of concurrent chemo-radiotherapy; while patients with early SCLC stage, surgical resection could be recommended. Stereotactic body radiotherapy (SBRT) is a recently introduced technique allowing the delivery of very high radiation doses to limited target volumes and it is considered the standard approach in the treatment of not operable stage I Non Small-Cell Lung Cancer (NSCLC). The successful role option of SBRT in early NSCLC in terms of local control and toxicity profile opened the issue in the use of this approach in early stage small cell lung cancer (SCLC). Aim of this review is to discuss the current literature in the safety and efficacy of SBRT in the treatment of patients with stage I SCLC.

The pretreatment albumin/globulin ratio (AGR) has been used as a prognostic factor in various cancers. This study aimed to evaluate the predictive value of AGR in small-cell lung cancer (SCLC).We tested albumin and total proteins in plasma samples from 276 SCLC patients from our cancer center between January 2003 and December 2006. The AGR was defined by the formula: albumin/(total proteins-albumin). The correlation between AGR and overall survival (OS) was examined by Kaplan-Meier and Cox regression methods. For validation, AGR was used to evaluate the prognosis of SCLC in another independent group.Total 276 patients (testing) and 379 patients (validation) were finally enrolled. The median OS was 15.31 months for testing patients and 15.06 months for validation patients, respectively. We determined 1.29 as the cutoff value by using the biostatistical tool (Cutoff Finder), then the patients in the testing group were classified into 2 groups. Kaplan-Meier curves showed high AGR group had significantly longer OS than low AGR group (P = 0.026). According to multivariate analyses, AGR was an independent prognostic factor for OS of SCLC patients in the testing group (HR, 1.35, 95% CI: 1.01-1.81, P = 0.046). In the validation group, AGR was also verified as a predictive factor for OS (P < 0.001), and the risk of SCLC in the low AGR group was 1.43 times higher than that in the high AGR group (HR, 1.43, 95% CI: 1.05-1.94, P = 0.022).AGR is an independent prognostic marker in SCLC patients. Furthermore, it could be of great value in the management of SCLC patients.

B cell lymphoma 2 (Bcl-2) is a central regulator of cell survival that is overexpressed in the majority of small-cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. The purpose of this work was to study the key factors that determine the sensitivity of SCLC cells to Bcl-2 homology domain-3 (BH3) mimetic S1 and the mechanism underlying the resistance of BH3 mimetics.

Western blot was used to evaluate the contribution of Bcl-2 family members to the cellular response of SCLC cell lines to S1. Acquired resistant cells were derived from initially sensitive H1688 cells. Quantitative PCR and gene silencing were performed to investigate Bcl-2 up-regulation.

A progressive increase in the relative levels of Bcl-2 and phosphorylated Bcl-2 (pBcl-2) characterized the increased de novo and acquired resistance of SCLC cell lines. Furthermore, acute treatment of S1 induced Bcl-2 expression and phosphorylation. We showed that BH3 mimetics, including S1 and ABT-737, induced endoplasmic reticulum (ER) stress and then activated MAPK/ERK pathway. The dual function of MAPK/ERK pathway in defining BH3 mimetics was illustrated; ERK1/2 activation leaded to Bcl-2 transcriptional up-regulation and sustained phosphorylation in naïve and acquired resistant SCLC cells. pBcl-2 played a key role in creating resistance of S1 and ABT-737 not only by sequestrating pro-apoptotic proteins, but also sequestrating a positive feedback to promote ERK1/2 activation.

These results provide significant novel insights into the molecular mechanisms for crosstalk between ER stress and endogenously apoptotic pathways in SCLC following BH3 mimetics treatment.

This retrospective cohort study was designed to analyze factors associated with administration of chemotherapy and to examine the impact of chemotherapy on survival among elderly patients with small-cell lung cancer (SCLC) in the community.

Elderly patients aged 65 years and older with SCLC diagnosed between 1992 and 2001 were selected from the Surveillance, Epidemiology, and End Results-Medicare database. Logistic regression was used to evaluate which covariates influenced receipt of chemotherapy. Cox proportional hazards regression was used to examine the influence of clinical and demographic variables on survival. The independent effect of chemotherapy on survival was determined using propensity scores and quantile regression.

In the final cohort of 10,428 patients, 67.1% received chemotherapy, 39.1% received radiation, 3.4% received surgery, and 21.8% received no treatment. The most common chemotherapy regimens included etoposide combined with either cisplatin or carboplatin. Patients aged 85 years and older were significantly less likely to receive chemotherapy compared with patients aged 65 to 69 years (odds ratio 0.17; 95% confidence interval 0.14-0.21). Median survival for all patients was 7 months. Factors associated with improved survival were being female, black race, having limited-stage disease, receiving any treatment, and having a lower comorbidity score. Quantile regression demonstrated that chemotherapy provided a 6.5-month improvement in median survival (95% confidence interval 6.3-6.6; p<0.001).

Statistically significant differences in the receipt of chemotherapy exist among elderly patients with SCLC. Chemotherapy is associated with a greater than 6-month improvement in median survival among elderly patients with SCLC, even in patients over the age of 80 years.

We investigated the correlation between circulating tumor cells and the incidence of brain metastases as a first site of recurrence among patients with small-cell lung cancer after systemic chemoradiotherapy and prophylactic cranial irradiation. In addition, we assessed the contribution of circulating tumor cells for planning the appropriate total dose of prophylactic cranial irradiation for small-cell lung cancer.

Patients (n = 112) with diagnosed Stage III small-cell lung cancer were treated with four cycles of platinum-based regimen and concurrent chest irradiation, and then prophylactic cranial irradiation. Blood samples for circulating tumor cell analysis were obtained before the initiation of chemotherapy and after the first and fourth cycle of chemotherapy.

Circulating tumor cells after the first cycle of chemotherapy correlated with tumor response after completion of chemotherapy (P = 0.012). Patients with brain as the first site suffered a higher rate of further metastases to other organs, and local recurrence, compared with those whose first site was the other organs (P < 0.001), and their survival rates were worse. Circulating tumor cells at baseline were the sole independent prognostic factor for specific progression-free survival. Receiver operating characteristic curves based on median specific progression-free survival revealed a circulating tumor cell cutoff at baseline of 218, and circulating tumor cells ≤218 at baseline correlated with significantly higher progression-free survival (P = 0.007), specific progression-free survival (P = 0.001) and overall survival (P = 0.001).

Circulating tumor cells prior to the initiation of chemotherapy are a valuable predictor of specific progression-free survival in Stage III small-cell lung cancer. For patients with circulating tumor cells >218, prophylactic cranial irradiation at a total dose of 30 Gy in 15 fractions is insufficient.

Ground-glass opacity (GGO) is reported to be characteristic to lepidic growth of neoplasm in subsolid nodules. In solid nodules of lung cancer, however, there is no characteristic feature to be reported.

To study if there are any thin-section CT findings characteristic to tumor histology or if they are only related to tumor size in solid nodules of the lung cancer.

This study included 106 solid peripheral lung cancers of 3 cm or smaller (56 adenocarcinomas, 33 squamous cell carcinomas, and 17 small cell carcinomas) in which 16-slice CT with 1 mm collimation was performed before surgery. Six morphologic findings (presence or absence of lobulation, coarse spiculation, air bronchogram, cavity, pleural tag, and pleural-based lesion) and four measurements (ratio of the greatest transverse and vertical diameter to the shortest transverse diameter and density of lobulation and coarse spiculation) on thin-section CT images were evaluated. Density of lobulation (coarse spiculation) was defined as the ratio of lobulation (coarse spiculation) number to the greatest transverse diameter of a nodule.

Air bronchogram (P < 0.01) was the only significant factor for predicting lung adenocarcinoma. The prevalence of air bronchogram was significantly greater in adenocarcinoma than in squamous cell carcinoma (P < 0.01) or small cell carcinoma (P < 0.01). As the tumor size advanced, significantly positive linear trends were seen in the prevalence of lobulation (P < 0.01), coarse spiculation (P < 0.01), and pleural tag (P < 0.01), and the mean values of density of lobulation (P < 0.01) and coarse spiculation (P < 0.01), while the significant negative linear trend was seen in the ratio of vertical diameter to the shortest transverse (P = 0.02).

Air bronchogram on thin-section CT is characteristic feature of solid adenocarcinoma of the lung. However, other thin-section CT findings are irrelevant to tumor histology and related only to tumor size.

The purpose of this study was to evaluate the treatment outcomes of stereotactic body radiotherapy (SBRT) for Stage I small-cell lung cancer (SCLC). From April 2003 to September 2009, a total of eight patients with Stage I SCLC were treated with SBRT in our institution. In all patients, the lung tumors were proven as SCLC pathologically. The patients' ages were 58-84 years (median: 74). The T-stage of the primary tumor was T1a in two, T1b in two and T2a in four patients. Six of the patients were inoperable because of poor cardiac and/or pulmonary function, and two patients refused surgery. SBRT was given using 7-8 non-coplanar beams with 48 Gy in four fractions. Six of the eight patients received 3-4 cycles of chemotherapy using carboplatin (CBDCA) + etoposide (VP-16) or cisplatin (CDDP) + irinotecan (CPT-11). The follow-up period for all patients was 6-60 months (median: 32). Six patients were still alive without any recurrence. One patient died from this disease and one died from another disease. The overall and disease-specific survival rate at three years was 72% and 86%, respectively. There were no patients with local progression of the lesion targeted by SBRT. Only one patient had nodal recurrence in the mediastinum at 12 months after treatment. The progression-free survival rate was 71%. No Grade 2 or higher SBRT-related toxicities were observed. SBRT plus chemotherapy could be an alternative to surgery with chemotherapy for inoperable patients with Stage I small-cell lung cancer. However, further investigation is needed using a large series of patients.

Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and the incidence has reduced over the last 20 years. Treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease. Chemotherapy remains the cornerstone of treatment for limited (LD) and extensive disease (ED), with concurrent chemotherapy and radical thoracic radiotherapy representing the best treatment option for fit patients with LD. Platinum-based chemotherapy is the treatment of choice in fit patients with good organ function, and the radiosensitizing effect of cisplatin is critically important for concurrent chemoradiotherapy in LD. Anthracycline-containing regimens represent a viable alternative for patients where platinum-based chemotherapy is contraindicated. Patients who relapse or progress after first-line chemotherapy have a very poor prognosis. Second-line therapy may produce a modest clinical benefit. Maintenance chemotherapy has not been shown to convincingly improve outcomes for SCLC. A number of targeted agents have been investigated in LD and ED, mostly in unselected populations, with disappointing results. Prophylactic cranial irradiation has been shown to reduce the incidence of brain metastases and prolong survival for both LD and ED without negative impact on quality of life (QOL) and cognitive function. Ongoing trials will shed some light on the impact of thoracic radiotherapy on QOL, symptom control and survival in ED SCLC patients who benefitted from first-line chemotherapy.

To investigate whether decrease in the serum levels of pro-gastrin releasing peptide (ProGRP) and neuron-specific enolase (NSE) were correlated with the radiological response in patients with small-cell lung cancer (SCLC).

Of the 196 patients, we retrospectively reviewed 118 patients elevated baseline levels of ProGRP and NSE prior to the initial therapy (IT) who survived for more than 1 month. The radiological response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Decrease in the serum ProGRP was strongly correlated with the decrease of the sum of the tumor diameters (SOD) before the third course (ρ=0.50) and after the fourth course (ρ=0.42) of IT. Decrease in the serum NSE was weakly correlated with the decrease of the SOD after the fourth course (ρ=0.27), but not before the third courses (ρ=0.22). In the receiver operating characteristic (ROC) curves predicting 1-year survivors, the area under the curve (AUC) for percent changes in serum ProGRP before the third course were significantly larger than those for NSE (0.714 vs. 0.527, p=0.004).

Percent changes in serum ProGRP showed better correlation to SOD and prognostic impact than that of NSE.

The incidence of small-cell lung cancer (SCLC) has decreased over several decades. Sixty-eight thousand six hundred eleven patients with SCLC in the National Cancer Data Base (NCDB) were analyzed to describe demographic, treatment, and survival changes between 1992 and 2007.

Four patient cohorts-diagnosed in 1992, 1997, 2002, and 2007-were examined. Univariate and multivariate analyses were performed to determine changes in demographic and treatment factors and their effect on survival of limited SCLC (LSCLC) and extensive SCLC (ESCLC).

The proportion of female patients increased, whereas the proportion of non-Hispanic white patients decreased. Median survival for patients with ESCLC and LSCLC was 6.1 and 12.9 months, respectively, and was not significantly improved between patients diagnosed in 1992 and 2002. Improved survival was associated with female sex, age < 70 years, and receipt of surgery for patients with LSCLC. Radiation therapy decreased the hazard ratio (HR) for patients with stage III LSCLC but not for patients with earlier stage disease. Chemotherapy decreased the HR for all patients with LSCLC. Patients with ESCLC treated with radiation in addition to chemotherapy had better survival than those who received only chemotherapy.

Despite changes in demographics and treatment, the median and 5-year survival rates for patients with SCLC have not significantly improved over the past 15 years. Surgery was associated with improved survival in LSCLC. The benefit of chemotherapy and/or radiation therapy was dependent on American Joint Committee on Cancer (AJCC) stage. AJCC staging information had prognostic and treatment ramifications and should be collected in future studies and databases.

Stage I or II small cell lung cancer is rare. We evaluated the contemporary incidence of early-stage small cell lung cancer and defined its optimal local therapy.

We analyzed the incidence, treatment patterns, and outcomes of 2214 patients with early-stage small cell lung cancer (1690 with stage I and 524 with stage II) identified from the Surveillance, Epidemiology, and End Results database from 1988 to 2005.

Early-stage small cell lung cancer constituted a stable proportion of all small cell lung cancers (3%-5%), lung cancers (0.10%-0.17%), and stage I lung cancers (1%-1.5%) until 2003 but, by 2005, increased significantly to 7%, 0.29%, and 2.2%, respectively (P < .0001). Surgery for early-stage small cell lung cancer peaked at 47% in 1990 but declined to 16% by 2005. Patients treated with lobectomy or greater resections (lobe) without radiotherapy had longer median survival (50 months) than those treated with sublobar resections (sublobe) without radiotherapy (30 months, P = .006) or those treated with radiotherapy alone (20 months, P < .0001). Patients undergoing sublobe without radiotherapy also demonstrated superior survival than patients receiving radiotherapy alone (P = .002). The use or omission of radiotherapy made no difference after limited resection (30 vs 28 months, P = .6). Multivariable analysis found survival independently related to age, year of diagnosis, tumor size, stage, and treatment (lobe vs sublobe vs radiotherapy alone).

Surgery is an underused modality in the management of early-stage small cell lung cancer. Lobectomy provides optimal local control and leads to superior survival. Although sublobar resection proved inferior to lobectomy, it conferred a survival advantage superior to radiotherapy alone. The addition of radiotherapy to resection provided no additional benefit.

Lung cancer, of which 15%-20% is small cell lung cancer, is the leading cause of cancer mortality and shows a high incidence worldwide. While pro-gastrin-releasing peptide (ProGRP) has been reported as a predictive diagnostic factor, it has not been widely accepted because of inconsistent conclusions. The aim of this study was to systematically evaluate ProGRP as the diagnostic standard for small cell lung cancer.

All published studies on ProGRP in the diagnosis of small cell lung cancer from January 1994 to April of 2010 were retrieved. By measuring methodological qualities, 11 papers were selected for this study. The overall diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate ProGRP as the diagnostic standard for small cell lung cancer using Meta DiSc statistical software.

There were 5146 subjects included in this meta-analysis. The sensitivity and specificity (95% confidence interval) of ProGRP was 0.716 (0.688-0.743) and 0.921 (0.909-0.932), respectively. The area under the summary receiver operating characteristic curve of ProGRP was 0.9236. The index of Q* was 0.8575.

ProGRP has better sensitivity and high specificity as an auxiliary indicator for the diagnosis of small cell lung cancer.

Besides new therapeutic drugs, effective diagnostic tools indicating early the efficacy of therapy are required to improve the individual management of patients with nonoperable cancer diseases.

In prospectively collected sera of 128 patients with newly diagnosed small cell lung cancer receiving first-line chemotherapy, the courses of nucleosomes, progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1), and carcinoembryonic antigen were investigated and correlated with therapy response objectified by computed tomography before start of the third treatment course.

In univariate analyses, high levels and insufficient decreases of nucleosomes, ProGRP, NSE, and CYFRA 21-1 during the first and second cycles of therapy correlated with poor outcome. Insufficient response to therapy was most efficiently indicated by the baseline values of nucleosomes, ProGRP, and CYFRA 21-1 before the second therapy cycle reaching areas under the curve (AUC) of 81.8%, 71.3%, and 74.9% in receiver operating characteristic curves, respectively. Combinations of nucleosomes with ProGRP (AUC 84.1%), CYFRA 21-1 (AUC 82.5%), and NSE (AUC 83.6%) further improved the diagnostic power in the high specificity range and yielded sensitivities of 47.1%, 35.3%, and 35.3% at 95% specificity, respectively. In multivariate analyses, including clinical and biochemical variables, only performance score and nucleosomes before cycle 2 were found to independently indicate therapy response.

Biochemical markers specifically identified patients with insufficient therapy response at the early treatment phase and showed to be valuable for diseases management of small cell lung cancer.

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models.

Complications induced by the chemotherapeutic agent cisplatin, such as neuropathy and cachexia, occur frequently, are often dose limiting, and have an impact on quality of life and survival in cancer patients. The recently discovered hormone ghrelin is a potent GH secretagogue with orexigenic and neuroprotective properties that may prevent or ameliorate these complications. The objective of this study was to determine the effects of ghrelin administration on mechanical hyperalgesia, anorexia, and cachexia induced by cisplatin. Adult male Sprague-Dawley rats were given cisplatin, ghrelin, ghrelin-cisplatin, or vehicle ip. Food intake and body weight were measured daily. Behavioral tests to assess the development of hyperalgesia were conducted by measuring mechanical and thermal sensitivity. Plasma ghrelin and IGF-I levels were also measured. Our results indicate that ghrelin coadministration inhibited the development of cisplatin-induced mechanical hyperalgesia, anorexia, and cachexia induced by cisplatin. Although ghrelin treatment had no effect on plasma IGF-I levels in control rats, it prevented the decrease in IGF-I levels induced by cisplatin. The attenuation of cisplatin-induced mechanical hyperalgesia induced by ghrelin was correlated with the prevention of cisplatin-induced lowering of IGF-I. In conclusion, ghrelin administration may be useful in the treatment or prevention of chemotherapy induced neuropathy and cachexia. Attenuation of mechanical hyperalgesia in the rat by the hormone ghrelin provides a unique model for elucidating the mechanisms involved, which are essential toward our understanding of these complications.

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which approximately 20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.

Over 95% of patients with small-cell lung cancer (SCLC) die within five years of diagnosis. The standard of care and the dismal prognosis for this disease have not changed significantly over the past 25 years. Some of the characteristics of SCLC that have defined it as a particularly virulent form of cancer -- rapid proliferation, excessive metabolic and angiogenic dependence, apoptotic imbalance and genetic instability -- are now being pursued as tumor-specific targets for intervention both in preclinical and early phase clinical studies. Here, we summarize areas of ongoing anti-cancer drug development, including classes of agents that target essential pathways regulating proliferation, angiogenesis, apoptotic resistance, chromosomal and protein stability, and cell-cell and cell-matrix interaction.