Adjuvant treatment for patients with incidentally resected limited disease small cell lung cancer-a retrospective study.

Background With the exception of very early-stage small cell lung cancer (SCLC), surgery is not typically recommended for this disease; however, incidental resection still occurs. After incidental resection, adjuvant salvage therapy is widely offered, but the evidence supporting its use is limited. This study aimed to explore proper adjuvant therapy for these incidentally resected SCLC cases. Methods Patients incidentally diagnosed with SCLC after surgery at the Shanghai Pulmonary Hospital in China from January 2005 to December 2014 were included in this study. The primary outcome was overall survival. Patients were classified into different group according to the type of adjuvant therapy they received and stratified by their pathological lymph node status. Patients' survival was analyzed using a Kaplan-Meier analysis and Cox regression analysis. Results A total of 161 patients were included in this study. Overall 5-year survival rate was 36.5%. For pathological N0 (pN0) cases (n=70), multivariable analysis revealed that adjuvant chemotherapy (ad-chemo) was associated with reduced risk of death [hazard ratio (HR): 0.373; 95% confidence interval (CI): 0.141-0.985, P=0.047] compared to omission of adjuvant therapy. For pathological N1 or N2 (pN1/2) cases (n=91), taking no adjuvant therapy cases as a reference, the multivariable analysis showed that ad-chemo was not associated with a lower risk of death (HR: 0.869; 95% CI: 0.459-1.645, P=0.666), while adjuvant chemo-radiotherapy (ad-CRT) was associated with a lower risk of death (HR: 0.279; 95% CI: 0.102-0.761, P=0.013). Conclusions Patients who incidentally receive surgical resection and are diagnosed with limited disease SCLC after resection should be offered adjuvant therapy as a salvage treatment. For incidentally resected pN0 cases, ad-chemo should be considered and for pN1/2 cases, ad-CRT should be received

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC

Neuroblastoma: Triptolide Therapy

Neuroblastoma is the most common pediatric extracranial tumor, and advanced-stage cases are highly resistant to conventional chemotherapy. Heat-shock protein-70 (Hsp-70) is overexpressed in several human malignancies, and its inhibition has been shown to kill cancer cells. We have previously shown that triptolide, an inhibitor of Hsp-70, induces apoptotic cell death of pancreatic tumors. In this chapter, we explore the effectiveness of triptolide therapy in the treatment of neuroblastoma, both in vitro and in vivo. Additionally, we discuss the effect of triptolide treatment on levels of Hsp-70 and markers of apoptosis in neuroblastoma cell lines. We aim to clarify the mechanism by which triptolide induces cell death in neuroblastoma. After exposing neuroblastoma cells to triptolide, cellular viability was assessed, with results indicating that triptolide causes both dose- and time-dependent cell killing. In order to ascertain whether triptolide-mediated cell death occurs via an apoptotic pathway, caspase-3 and -9 activities as well as annexin staining were measured; these markers of apoptosis were found to be elevated, implicating an apoptotic pathway. As triptolide is a known inhibitor of Hsp-70, Western blot analysis and RT-PCR were performed following triptolide treatment, resulting in decreases of both Hsp-70 protein and mRNA levels. To clarify the cause-effect relationship, Hsp-70 was specifically silenced in neuroblastoma cells via siRNA, and viability, caspase activity, and phophatidylserine externalization were subsequently measured. The effects on cellular viability and markers of apoptosis were similar to those which are seen following triptolide therapy, supporting the hypothesis that Hsp-70 inhibition serves a key role in triptolide-mediated cell death. To examine the effects of triptolide on neuroblastoma in vivo, an orthotopic tumor model was developed, and, following randomization, mice in treatment and control groups received daily injections of triptolide and vehicle, respectively. At 21 days, mice were sacrificed, and tumors were measured. Mice receiving triptolide therapy had significantly smaller tumors than control, with average tumors in control mice 6 times the size of tumors in mice treated with triptolide. Immunohistochemisty and Western blotting were used to characterize Hsp-70 levels in residual tumors, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to identify cells undergoing apoptosis. Hsp-70 immunohistochemistry showed greater staining in control tumors than those from treated mice. Tumors from triptolide-receiving mice demonstrated significant TUNEL staining, while those receiving vehicle showed no evidence of apoptosis. In summary, treatment of neuroblastoma with triptolide shows efficacy in decreasing cellular viability in vitro and in inhibiting tumor growth in vivo through apoptotic pathways. Correlated drops in levels of Hsp-70 suggest that triptolide’s effects are associated with inhibition of Hsp-70 expression. Our findings suggest that triptolide may provide a novel therapy for neuroblastoma and further studies are certainly warranted

Active Learning in Medical Education: Application to the Training of Surgeons

Our article defines active learning in the context of surgical education and reviews the growing body of research on new approaches to teaching. We then discuss future perspectives and the challenges faced by the trainee and surgeon in applying active learning to surgical training. As modern surgical education faces numerous challenges, we hope our article will help surgical educators in the evaluation of curriculum development, methods of instruction, and assessment

Classifying Oligometastatic Non-Small Cell Lung Cancer

An oligometastatic cancer state was first postulated in the 1990s by Hellman and Weichselbaum and described limited metastatic spread to a single or few sites of disease. It was hypothesized that this metastatic entity falls along a continuum of the natural history of cancer progression from a localized primary tumor to widespread metastases. Support for oligometastatic non-small cell lung cancer (NSCLC) has since been provided by multiple retrospective studies and then prospective randomized trials demonstrating better survival in this patient population after aggressive consolidative treatment. However, the lack of a universal definition of oligometastatic NSCLC has hindered a comparison between different studies and prevented well-defined recommendations for local consolidative treatment in this patient population. Attempts have been made to establish a common definition for use in clinical management and for the identification of inclusion criteria for future trials. In this review, we seek to summarize the current definitions of oligometastatic NSCLC based on recent expert consensus statements, previous randomized trials, and current treatment guidelines and to highlight the continued variability in current practice