Lung Cancer Survival Trends in the Veterans Health Administration.

INTRODUCTION: Lung cancer survival is improving in the United States. We investigated whether there was a similar trend within the Veterans Health Administration (VHA), the largest integrated healthcare system in the United States. MATERIALS AND METHODS: Data from the Veterans Affairs Central Cancer Registry were analyzed for temporal survival trends using Kaplan-Meier estimates and linear regression. RESULTS: A total number of 54,922 Veterans were identified with lung cancer diagnosed from 2010 to 2017. Histologies were classified as non-small-cell lung cancer (NSCLC) (64.2%), small cell lung cancer (SCLC) (12.9%), and 'other' (22.9%). The proportion with stage I increased from 18.1% to 30.4%, while stage IV decreased from 38.9% to 34.6% (both P < .001). The 3-year overall survival (OS) improved for stage I (58.6% to 68.4%, P < .001), stage II (35.5% to 48.4%, P < .001), stage III (18.7% to 29.4%, P < .001), and stage IV (3.4% to 7.8%, P < .001). For NSCLC, the median OS increased from 12 to 21 months (P < .001), and the 3-year OS increased from 24.1% to 38.3% (P < .001). For SCLC, the median OS remained unchanged (8 to 9 months, P = .10), while the 3-year OS increased from 9.1% to 12.3% (P = .014). Compared to White Veterans, Black Veterans with NSCLC had similar OS (P = .81), and those with SCLC had higher OS (P = .003). CONCLUSION: Lung cancer survival is improving within the VHA. Compared to White Veterans, Black Veterans had similar or higher survival rates. The observed racial equity in outcomes within a geographically and socioeconomically diverse population warrants further investigation to better understand and replicate this achievement in other healthcare systems.

Disparities and Underutilization of Surgery for Early Stage Small Cell Lung Cancer.

BACKGROUND: The National Comprehensive Cancer Network recommends surgical resection for stage I small cell lung cancer (SCLC). Despite these recommendations and the curative potential of such surgery, many continue to underutilize surgery. Our aim is to investigate factors that contribute to underutilization of surgery for stage I SCLC. METHODS: The National Cancer Database was queried to identify patients with SCLC stage I-IV from 2004 to 2018. Staging was defined by the American Joint Committee on Cancer guidelines. Cochran-Armitage analysis was performed to analyze trends in surgical treatment for patients diagnosed with stage I SCLC. Multivariable logistic regression assessed relationships between patient factors and surgical treatment. RESULTS: A total of 296,583 patients were diagnosed with SCLC. Of the stage I patients (n = 13,003), only 29.4.% (n = 3823) underwent surgery. Trend analysis demonstrated increased frequency of surgical treatment for stage I SCLC over years 2004 to 2017, from 14.9% to 39.6% (P < .0001). Factors that were associated with underutilization of surgery for stage I SCLC include African American race, lower median income, nonprivate insurance or Medicare, community facility, and geographic regions other than the Northeast. CONCLUSIONS: Surgical treatment for stage I SCLC remains underutilized and our study identifies notable associated factors. The recognition of these factors may help patients overcome barriers to receiving recommended treatments, improve guideline adherence, and overall quality of care for stage I SCLC patients.

Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer.

Background: Durvalumab is an immune checkpoint Inhibitor (ICIs) that is used in the treatment of malignant tumors, such as lung cancer and melanoma. ICIs are associated with immune-related adverse events including autoimmune encephalitis, although both paraneoplastic phenomena and ICI treatment may lead to autoimmunity. Case presentation: We describe a 72-year old male patient with small-cell lung cancer, who during adjuvant treatment with Durvalumab developed GABABR1 and GAD65 antibodies and both diabetes and autoimmune limbic encephalitis. Because he was followed prospectively as part of a treatment study, we had access to repeated serum samples and cognitive assessments over time prior to developing encephalitis and diabetes, in addition to later assessments. A high titer of GABABR1 antibodies appeared early, while GAD65 antibodies appeared later with a lower titer in parallel with the development of diabetes. As he subsequently developed clinical signs of encephalitis, verified by EEG and brain MRI, he also had CSF GABABR1 antibodies. Durvalumab was discontinued and steroid treatment with subsequent plasmapheresis were started, resulting in reduction of both CSF and serum antibody levels. Clinical signs of encephalitis gradually improved. Conclusion: This case illustrates the importance of being aware of possible serious autoimmune adverse reactions, including neurological syndromes such as encephalitis, when treating patients with high risk of para-neoplasia with ICIs. In addition, the case shows the development of autoantibodies over time.

Integrative Analysis of Ferroptosis-Related Genes in Small Cell Lung Cancer for the Identification of Biomarkers and Therapeutic Targets.

BACKGROUND: Ferroptosis is an iron-dependent programmed cell death mode induced by the toxic buildup of phospholipid peroxidation. Although it is known to affect the initiation and growth of tumors, the association between ferroptosis-related genes (FRGs) and small cell lung cancer (SCLC) has yet to be established. METHODS: We used the gene expression omnibus (GEO) and ferroptosis database (FerrDb) to acquire information on SCLC and its associated FRGs. Marker genes were subsequently identified using Least Absolute Shrinkage and Selection Operator (LASSO) and support vector machine recursive feature eilmination (SVM-RFE) algorithms and analyzed for single-gene function and pathway enrichment. Using the drug-gene interaction database (DGIdb), we identified forty drugs targeting six marker genes. The competing endogenous RNA (ceRNA) network revealed the regulation pattern for long non-coding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) based on marker genes. RESULTS: Six differentially expressed FRGs (ATG3, MUC1, RRM2, IDH2, PARP1, and EZH2) were identified as marker genes with accurate diagnostic capabilities. According to single-gene function and pathway enrichment analyses, these marker genes may be involved in immunomodulation and the cell cycle, as well as numerous pathways connected to tumorigenesis, including the JAK-STAT and PPAR signal pathways. In addition, CIBERSORT analysis showed that MUC1 and PARP1 expression may affect the immune microenvironment in SCLC. CONCLUSIONS: We confirmed the accuracy of marker genes for the diagnosis of SCLC using a logistic regression model, thus providing further opportunities to study SCLC-related mechanisms. The accuracy of these results for the diagnosis of SCLC must now be confirmed by further research prior to clinical application.

Efficacy of Tyrosine Kinase Inhibitors in Primary Driver-Gene-Positive Combined Small-Cell Lung Cancer: A Retrospective Study.

BACKGROUND: Combined small-cell lung cancer (c-SCLC) with gene mutations is a rare subtype often found alongside adenocarcinoma. Targeted therapy may be effective because of the presence of specific molecular targets. However, due to its rarity and unconventional genetic testing, the efficacy remains uncertain. METHODS: A total of 31 c-SCLC patients with gene mutations were retrospectively included and grouped according to their treatment regimens. Treatment outcomes were evaluated. Kaplan-Meier method was used for survival analysis, with Log Rank test applied for comparison between groups. RESULTS: We divided the 31 patients into 3 groups according to first-line treatment: group A (chemotherapy, n = 16), group B (targeted monotherapy, n = 7), and group C (targeted combination therapy, n = 8). The overall response rates (ORR) were 43.8%, 42.9%, and 62.5%. The disease control rates (DCR) were 87.5%, 85.7%, and 100%. The median progression-free survival (PFS) was 4.0, 5.0, and 7.93 months (P = .024), with a significant difference between group A and C (P = .010). The median overall survival (OS) was 14.10, 17.43, and 12.93 months (P = .313). Seven patients in group A received targeted therapy in later-line. Of the total 22 patients received targeted monotherapy or combination therapy, the ORR and DCR were 54.5% and 90.9%. The median PFS and OS were 5.87 and 17.30 months. Additionally, adverse events (AEs) occurred in 53.8% and 88.9% of monotherapy and combination therapy. The most common AEs in monotherapy were elevated transaminases (23.1%) and in combination anemia (66.7%). CONCLUSIONS: TKIs showed encouraging efficacy in driver-gene-positive c-SCLC. While monotherapy may be a supplementary option, combination with chemotherapy appears to be preferable and superior.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

Efficacy Analysis of Wandai Decoction Combined with Traditional Chinese Medicine Fumigation and Washing in Patients with Chronic Vaginitis After Sintilimab Treatment for Small Cell Lung Cancer.

Objective: To investigate the effect of Wandai decoction combined with traditional Chinese medicine fumigation and washing in patients with chronic vaginitis after sintilimab treatment for small cell lung cancer. Methods: We recruited 80 patients who developed chronic vaginitis after sintilimab treatment for small cell lung cancer from Hainan General Hospital from January 2020 to June 2022; using a random number table, 40 were assigned to a control group and 40 were assigned to an observation group. The control group was treated with Wandai decoction, and the observation group was treated with Wandai decoction combined with traditional Chinese medicine fumigation and washing. The 2 groups were compared for improvement of the symptoms of vulvar pruritus subsidence time, leukorrhea recovery time, and traditional Chinese medicine symptom score; levels of the vaginal microecological environment factors immunoglobulin G, secretory immunoglobulin A, and pH; levels of the serum inflammatory factors C-reactive protein, tumor necrosis factor, and interleukin-6; and clinical efficacy. Results: After treatment, the observation group had significantly higher vulvar pruritus subsidence time, leukorrhea recovery time, traditional Chinese medicine symptom score, and pH value; significantly lower levels of C-reactive protein, tumor necrosis factor, and interleukin-6; and significantly higher levels of immunoglobulin G, secretory immunoglobulin A, and total effective rate compared with the control group (all P < .0.001). Conclusions: Wandai decoction combined with traditional Chinese medicine fumigation and washing was effective in treating chronic vaginitis after sintilimab treatment for small cell lung cancer. The treatment ameliorated symptoms of leukorrhea abnormalities, vulvar pruritus, and local inflammation, and promoted the recovery of the vaginal microbial environment. Despite the limitations of our study (small sample size and lack of comparison between different types of chronic vaginitis, which hinders the confirmation of extensive efficacy), we consider Wandai decoction combined with traditional Chinese medicine fumigation and washing worthy of promotion and application in clinical practice.

Pathological complete response to neoadjuvant tislelizumab plus chemotherapy in stage IIIB small cell lung cancer: A case report and literature review.

Immunotherapy plus chemotherapy has been approved for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC, stage IV). Recently, the 2023 version of the National Comprehensive Cancer Network Guidelines recommended immunotherapy plus chemotherapy as the neoadjuvant regimen in patients with resectable non-small cell lung cancer (NSCLC). However, it is still unclear whether the combination regimen of immunotherapy plus chemotherapy is also beneficial for SCLC in the neoadjuvant context. Here, we report the case of a patient with stage IIIB SCLC who showed long-term survival and good tolerance to the neoadjuvant chemoimmunotherapy consisting of tislelizumab (an anti-PD-1 monoclonal antibody) plus etoposide-carboplatin. The patient achieved pathological complete response after receiving two cycles of neoadjuvant tislelizumab and chemotherapy followed by surgery. Two courses of post-operative tislelizumab and etoposide-carboplatin treatment were performed. The patient has survived for more than 23 months with no recurrence or metastases after neoadjuvant therapy. Multiplexed immunofluorescence and immunohistochemistry staining showed that the post-treatment specimens had remarkable immune cells infiltration, including CD3+ T cells, CD4+ T cells, and CD8+ T cells, which contrasted with very low levels of these cells in the pre-treatment samples. This study is, to the best of our knowledge, the first attempt to present the neoadjuvant chemoimmunotherapy of tislelizumab in combination with etoposide-carboplatin in SCLC. Our study suggested that neoadjuvant tislelizumab plus chemotherapy may facilitate radical resection and benefit patients with locally advanced (stage IIB-IIIC) SCLC.

Retrospective Clinical Study on Integrated Chinese and Western Medicine in Treatment of Limited-Stage Small Cell Lung Cancer.

OBJECTIVE: To investigate the efficacy of integrated Chinese and Western medicine extending the progression-free survival (PFS) and overall survival (OS) of limited-stage small cell lung cancer (LS-SCLC) patients after the first-line chemoradiotherapy. METHODS: The data of 67 LS-SCLC patients who received combined treatment of CM and Western medicine (WM) between January 2013 and May 2020 at the outpatient clinic of Guang'anmen Hospital were retrospectively analyzed. Thirty-six LS-SCLC patients who received only WM treatment was used as the WM control group. The medical data of the two groups were statistically analyzed. Survival analysis was performed using the product-limit method (Kaplan-Meier analysis). The median OS and PFS were calculated, and survival curves were compared by the Log rank test. The cumulative survival rates at 1, 2, and 5 years were estimated by the life table analysis. Stratified survival analysis was performed between patients with different CM administration time. RESULTS: The median PFS in the CM and WM combination treatment group and the WM group were 19 months (95% CI: 12.357-25.643) vs. 9 months (95% CI: 5.957-12.043), HR=0.43 (95% CI: 0.27-0.69, P<0.001), respectively. The median OS in the CM and WM combination group and the WM group were 34 months (95% CI could not be calculated) vs. 18.63 months (95% CI: 16.425-20.835), HR=0.40 (95% CI: 0.24-0.66, P<0.001), respectively. Similar results were obtained in the further stratified analysis of whether the duration of CM administration exceeded 18 and 24 months (P<0.001). CONCLUSION: The combination treatment of CM and WM with continuing oral administration of CM treatment after the first-line chemoradiotherapy for LS-SCLC patients produced better prognosis, lower risks of progression, and longer survival than the WM treatment alone. (Registration No. ChiCTR2200056616).

Efficacy and mechanism study of cordycepin against brain metastases of small cell lung cancer based on zebrafish.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive tumor with high brain metastasis (BM) potential. There has been no significant progress in the treatment of SCLC for more than 30 years. Cordycepin has shown the therapeutic potential for cancer by modulating multiple cellular signaling pathways. However, the effect and mechanism of cordycepin on anti-SCLC BM remain unknown. PURPOSE: In this study, we focused on the anti-SCLC BM effect of cordycepin in the zebrafish model and its potential mechanism. STUDY DESIGN AND METHODS: A SCLC xenograft model based on zebrafish embryos and in vitro cell migration assay were established. Cordycepin was administrated by soaking and microinjection in the zebrafish model. RNA-seq assay was performed to analyze transcriptomes of different groups. Geno Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed to reveal the underlying mechanism. Real-time qPCR was used to verify the effects of cordycepin on the key genes. RESULTS: Cordycepin showed lower cytotoxicity in vitro compared with cisplatin, anlotinib and etoposide, but showed comparable anti-proliferation and anti-BM effects in zebrafish SCLC xenograft model. Cordycepin showed significant anti-SCLC BM effects when administrated by both soaking and microinjection. RNA-seq demonstrated that cordycepin was involved in vitamin D metabolism, lipid transport, and proteolysis in cellular protein catabolic process pathways in SCLC BM microenvironment in zebrafish, and was involved in regulating the expressions of key genes such as cyp24a1, apoa1a, ctsl. The anti-BM effect of cordycepin in SCLC was mediated by reversing the expression of these genes. CONCLUSION: Our work is the first to describe the mechanism of cordycepin against SCLC BM from the perspective of regulating the brain microenvironment, providing new evidence for the anti-tumor effect of cordycepin.

Holistic immunomodulation for small cell lung cancer.

Small cell lung cancer (SCLC) is characterized by a high mortality rate, rapid growth, and early metastasis, which lead to a poor prognosis. Moreover, limited clinical treatment options further lower the survival rate of patients. Therefore, novel technology and agents are urgently required to enhance clinical efficacy. In this review, from a holistic perspective, we summarized the therapeutic targets, agents and strategies with the most potential for treating SCLC, including chimeric antigen receptor (CAR) T therapy, immunomodulating antibodies, traditional Chinese medicines (TCMs), and the microbiota, which have been found recently to improve the clinical outcomes and prognosis of SCLC. Multiomics technologies can be integrated to develop effective diagnostic methods and identify new targets for new drug discovery in SCLC. We discussed in depth the feasibility, potential, and challenges of these new strategies, as well as their combinational treatments, which may provide promising alternatives for enhancing the clinical efficacy of SCLC in the future.

Opium use and risk of lung cancer: A multicenter case-control study in Iran.

Opium use was recently classified as a human carcinogen for lung cancer by the International Agency for Research on Cancer. We conducted a large, multicenter case-control study evaluating the association between opium use and the risk of lung cancer. We recruited 627 cases and 3477 controls from May 2017 to July 2020. We used unconditional logistic regression analyses to estimate the odds ratios (OR) and 95% confidence intervals (CI) and measured the association between opium use and the risk of lung cancer. The ORs were adjusted for the residential place, age, gender, socioeconomic status, cigarettes, and water pipe smoking. We found a 3.6-fold risk of lung cancer for regular opium users compared to never users (95% CI: 2.9, 4.6). There was a strong dose-response association between a cumulative count of opium use and lung cancer risk. The OR for regular opium use was higher for small cell carcinoma than in other histology (8.3, 95% CI: 4.8, 14.4). The OR of developing lung cancer among opium users was higher in females (7.4, 95% CI: 3.8, 14.5) than in males (3.3, 95% CI: 2.6, 4.2). The OR for users of both opium and tobacco was 13.4 (95% CI: 10.2, 17.7) compared to nonusers of anything. The risk of developing lung cancer is higher in regular opium users, and these results strengthen the conclusions on the carcinogenicity of opium. The association is stronger for small cell carcinoma cases than in other histology.

Combinatory therapy of MRP1-targeted photoimmunotherapy and liposomal doxorubicin promotes the antitumor effect for chemoresistant small cell lung cancer.

Small cell lung cancer (SCLC), considered a mortal recalcitrant cancer, is a severe healthcare issue because of its poor prognosis, early metastasis, drug resistance and limited clinical treatment options. In our previous study, we established a MRP1-targeted antibody-IR700 system (Mab-IR700) for near infrared photoimmunotherapy (NIR-PIT) which exhibited a promising therapeutic effect on drug resistant H69AR cells both in vitro and in vivo, though the tumor growth suppression effect did not last long with a single round of PIT treatment. To achieve a better anticancer effect, we have combined Mab-IR700-mediated NIR-PIT with liposomal doxorubicin (Doxil®) and investigated the in vitro and in vivo cytotoxicity by using a H69AR/3T3 cell co-culture model in which 3T3 cells were used to mimic stromal cells. Cytotoxicity experiments demonstrated the specificity of Mab-IR700 to H69AR cells, while cytotoxicity and flow cytometry experiments confirmed that H69AR cells were doxorubicin-resistant. Compared with Mab-IR700-mediated PIT or Doxil-mediated chemotherapy, the combination therapy exhibited the best cell killing effect in vitro and superior tumor growth inhibition and survival prolongation effect in vivo. Super enhanced permeability and retention (SUPR) effect was observed in both co-culture spheroids and tumor-bearing mice. Owing to an approximately 9-fold greater accumulation of Doxil within the tumors, NIR-PIT combined with Doxil resulted in enhanced antitumor effects compared to NIR-PIT alone. This photoimmunochemotherapy is a practical strategy for the treatment of chemoresistant SCLC and should be further investigated for clinical translation.

Tumors derived from lung cancer cells respond differently to treatment with sodium valproate (a HDAC inhibitor) in a chicken embryo chorioallantoic membrane model.

Lung cancer is the most frequent cause of cancer death. Some human lung malignant tumors have a combined small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) histology, with tumor cell phenotype changing during tumor progression. Valproic acid is used as an anti-seizure medication to treat migraine, and bipolar mood disorders. Recently, its efficacy as an adjuvant therapy was shown in cancer due to its histone deacetylase (HDAC) inhibitory property. HDACs are upregulated in lung tumors, and HDAC inhibitors, including valproic acid, inhibit endothelial cell proliferation in vitro and in vivo and have antiproliferative and antimigratory properties. We tested valproic acid for possible antiangiogenic and antimigratory effects on experimental lung tumors grafted onto the chicken embryo chorioallantoic membrane (CAM). Tumors were formed from two NSCLC cell lines and a single SCLC cell line. To investigate tumor and CAM interactions, in vivo biomicroscopy, visualization of blood vessels with injected fluorescent dextran, histological, immunohistochemical and histomorphometric methods were applied. Our results showed that a sodium valproate (NaVP) treatment-induced a dose-dependent decrease of experimental tumor invasion into the CAM mesenchyme and a reduction in angiogenesis. Both the invasion and the angiogenic response were dependent on the type of cell line used: invasion and angiogenesis of tumors derived from A549 and NCI-H146 cell lines responded to increasing doses of NaVP from 4 to 8 mM, whereas Sk_Lu_1 cells response were antimigratory and antiangiogenic when NaVP was used up to 6 mM. When 8mM NaVP was used, stimulated invasion and angiogenesis in tumors from Sk_Lu_1 cells were observed.

Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities.

BACKGROUND: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. MATERIALS AND METHODS: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes. RESULTS: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. CONCLUSIONS: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).

Low level of complement factor H increases the risk of cancer-related death in patients with small-cell lung cancer.

INTRODUCTION: Pulmonary cancer is a kind of deeply invasive tumour which is difficult to treat, and its mortality rate is high. Previous research has shown that activation of complement could contribute to the progression of non-small-cell lung cancer (SCLC). However, little research has been done on SCLC. METHODS: Complement factor H (CFH), complements C3 as well as C4 were measured in patients, and the prognostic impact of different parameters was assessed by log-rank function analysis and Cox multifactor models. Besides, we constructed a predictive model based on complement fractions and validated the accuracy of the model. RESULTS: Among these 242 patients, 200 (82.6%) died. The median survival time was 18.3 months. We found by multifactorial analysis that high levels of CFH decreased the risk of death (HR 0.23, 95% CI 0.10 to 0.57, p<0.001), while elevated complement C4 displayed poor prognosis (HR 2.28, 95% CI 1.66 to 3.13, p<0.001). We screened variables by Cox models and constructed CFH-based prediction models to plot a nomogram by internal validation. The nomogram showed excellent accuracy in assessing the probability of death, yielding an adjusted C-statistics of 0.905. CONCLUSIONS: CFH can be recognised as a biomarker to predict the risk of death in SCLC. The prediction model established based on CFH, C3 and C4 levels has good accuracy in patients' prognostic assessment.

HER2 targeting near-infrared photoimmunotherapy for a CDDP-resistant small-cell lung cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is tyrosine kinase receptor that belongs to the ErbB family and is overexpressed on the membrane surface of various cancer cells, including small cell lung cancer (SCLC); however, no HER2 targeted therapy for SCLC have yet been established. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on photo-absorber, IRDye-700DX (IR700), -antibody conjugates, and near-infrared (NIR) light. METHODS: We used HER2-positive SCLC parental cell lines (SBC-3) and its chemoresistant cell lines, and examined therapeutic efficacy of HER2 targeting NIR-PIT using anti HER2 antibody trastuzumab. RESULTS: We found that HER2 expression was upregulated on chemoresistant cell lines, especially cisplatin-resistance (SBC-3/CDDP). In vitro, the rate of cell death increased with the amount of NIR-light irradiation, and it was significantly higher in SBC-3/CDDP than in SBC-3. In vivo, tumor growth was more suppressed in SBC-3/CDDP group than in SBC-3 group, and survival period tended to be prolonged. CONCLUSION: In this study, we demonstrated that HER2 targeting NIR-PIT using trastuzumab is promising therapy for HER2-positive SCLC, and is more effective when HER2 expression is upregulated due to CDDP resistance, suggesting that the HER2 expression level positively corelated with the efficacy of NIR-PIT.

MRP1-targeted near infrared photoimmunotherapy for drug resistant small cell lung cancer.

Small cell lung cancer (SCLC), one of the most aggressive cancers, has a high mortality rate and poor prognosis, and the clinical therapeutic outcomes of multidrug resistant SCLC are even worse. Multidrug resistance protein 1 (MRP1), one of the ATP-binding cassette (ABC) transporter proteins that cause decreased drug accumulation in cancer cells, is overexpressed in drug resistant SCLC cells and could be a promising target for treating the patients suffering from this illness. Near infrared photoimmunotherapy (NIR-PIT) is a newly developed approach for targeted cancer treatment which uses a conjugate of a monoclonal antibody and photoabosorber IR700 followed by NIR light irradiation to induce rapid cancer cell death. In the present study, an anti-MRP1 antibody (Mab) -IR700 conjugate (Mab-IR700) was synthesized, purified and used to treat chemoresistant SCLC H69AR cells that overexpressed MRP1, while non-MRP1-expressing H69 cells were used as a control. Then, the photokilling and tumor suppression effect were separately evaluated in H69AR cells both in vitro and in vivo. Higher cellular delivery of Mab-IR700 was detected in H69AR cells, whereas there was little uptake of IgG-IR700 in both H69 and H69AR cells. Due to the targeting activity of Mab, stronger photokilling effect was found both in H69AR cells and spheroids treated with Mab-IR700, while superior tumor suppression effect was also observed in the mice treated with Mab-IR700 and light illumination. Photoacoustic imaging results proved that oxygen was involved in NIR-PIT treatment, and TUNEL staining images showed the occurrence of cell apoptosis, which was also testified by HE staining. This research provides MRP1 as a novel target for PIT and presents a prospective way for treating drug resistant SCLC and, thus, should be further studied.

The efficacy of music therapy to relieve pain, anxiety, and promote sleep quality, in patients with small cell lung cancer receiving platinum-based chemotherapy.

PURPOSE: Chemotherapy induces a range of physical and psychological symptoms, including pain, sleep disorders, fatigue, and anxiety. We aimed to assess the efficacy of six-step music therapy in relieving pain and anxiety and improving sleep quality in lung cancer patients receiving platinum-based chemotherapy. METHODS: Between March 2013 and October 2015, we enrolled a total of 100 patients who were diagnosed with small cell lung cancer and scheduled for platinum-based chemotherapy. Patients were randomly assigned to two groups: the music therapy group (received six-step music therapy, n=50) and the control group (not received six-step music therapy, n=50). The anxiety, pain, and sleep quality of all patients were assessed using the self-rating anxiety scale (SAS), the visual analogue scale (VAS), and the Pittsburgh Sleep Quality Index (PSQI), respectively. RESULTS: There were no significant differences in the demographic characteristics and music background between the two groups. The SAS and VAS scores in the two groups were not statistically different before chemotherapy. However, patients in the music therapy group showed significantly lower SAS and VAS scores compared with the control group at both 1 day and 5 days after chemotherapy. (SAS score at 1-day post-therapy, 49.48±2.14 vs 61.46±8.8, P=0.011; SAS score at 5-day post-therapy, 39.73±1.79 vs 62.02±8.83, P=0.005; VAS score at 1-day post-therapy, 2.14±0.78 vs 4.74±1.01, P=0.005; VAS score at 5-day post-therapy, 2.06±0.79 vs 4.74±1.08, P=0.004). In addition, the total PSQI score of patients who received music therapy was also significantly higher than that of the control group after therapy (total PSQI score at 1-day post-therapy, 8.50±1.69 vs 17.81±3.01, P=0.006; total PSQI score at 5-day post-chemotherapy, 9.84±3.02 vs 18.66±2.91, P=0.012). CONCLUSION: The music therapy was an effective approach in alleviating pain and anxiety and promoting sleep quality in lung cancer patients receiving platinum-based chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (registration number: ChiCTR-TRC-13003993).