Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and ...nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.
Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year.
The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval CI, 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02).
Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.
Our goal was to determine whether tumour radiosensitivity is associated with activation of the immune system across all tumour types as measured by two gene expression signatures (GESs).
We ...identified 10,240 genomically profiled distinct solid primary tumours with gene expression analysis available from an institutional de-identified database. Two separate GESs were included in the analysis, the radiosensitivity index (RSI) GES (a 10-gene GES as a measure of radiosensitivity) and the 12-chemokine (12-CK) signature (a 12-gene GES as a measure of immune activation). We tested whether the RSI and 12-CK were associated with each other across all tumour samples and, in an exploratory analysis, their prognostic significance in predicting distant metastasis-free survival (DMFS) among a well-characterised, independent cohort of 282 early-stage breast cancer cases treated with surgery and post-operative radiation alone without systemic therapy. The lower the RSI score, the higher the tumour radiosensitivity; whereas, the higher the 12-CK score the higher the immune activation.
Using an RSI cut-point of ≤0.3745, RSI-low tumours (n = 4,291, 41.9%) had a significantly higher median 12-CK GES value (0.54 −0.136, 1.095) compared with RSI-high tumours (−0.17 –0.82, 0.42; p < 0.001) across all tumour samples, indicating that radiosensitivity is associated with immune activation. In an exploratory analysis of early-stage breast cancer cases, a multivariable model with patient age, RSI and 12-CK provided a strong composite model for DMFS (p = 0.02), with RSI (hazard ratio HR 0.63 95% confidence interval 0.36, 1.09) and 12-CK (HR 0.66 0.41, 1.04) each providing comparable contributions.
Tumour radiosensitivity is associated with immune activation as measured by the two GESs.
•There are data that suggest an interplay between response to radiation therapy and immune activation.•If a gene expression signature (GES) could improve the identification of this interplay it would likely be deemed a success.•We compared two GES for tumour radiosensitivity index (RSI) and immune activation (12-CK).•RSI and 12-CK GES are associated across all tumour types.•The combined RSI and 12-CK GES phenotype has the potential to improve our prognostic ability.
In the less than 70 years since Korean liberation, Korea has grown to be one of the world’s top five ship-owning countries in 2014. This can be attributed to a few factors such as government policy, ...Korea Shipping Corporation (KSC, hereafter) and merchant marine officers. This paper will expound the true motivations of the establishment and the privatization of KSC in 1950 and in 1968, respectively. KSC, as Korea’s national shipping company, sailed along a very unusual course of development. It was established in 1950 not to foster and develop Korea’s shipping industry but to help alleviate the financial burdens of the fledgling Korean government. The main cause of privatizing KSC in 1968 was a purely political decision, not an economic one as it overlapped with the rapid growth period of the shipping industry in the world, as well as in Korea. In sum, KSC, a state-run enterprise, was a bane in the short run but a boon in the long run for both the Korean government and Korea’s shipping industry. If we can believe KSC followed the ordinary sailing route as a state-run enterprise, we might develop a new opinion that the national shipping company might be a financial burden in a short period, but various benefits over a long period. KCI Citation Count: 0
Background
Following wide excision of Merkel cell carcinoma (MCC), postoperative radiation therapy (RT) is typically recommended. Controversy remains as to whether RT can be avoided in selected ...cases, such as those with negative margins. Additionally, there is evidence that RT can influence survival.
Methods
We included 171 patients treated for non-metastatic MCC from 1994 through 2012 at a single institution. Patients without pathologic nodal evaluation (clinical N0 disease) were excluded to reflect modern treatment practice. The endpoints included local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS).
Results
Median follow-up was 33 months. Treatment with RT was associated with improved 3-year LC (91.2 vs. 76.9 %, respectively;
p
= 0.01), LRC (79.5 vs. 59.1 %;
p
= 0.004), DFS (57.0 vs. 30.2 %;
p
< 0.001), and OS (73 vs. 66 %;
p
= 0.02), and was associated with improved 3-year DSS among node-positive patients (76.2 vs. 48.1 %;
p
= 0.035), but not node-negative patients (90.1 vs. 80.8 %;
p
= 0.79). On multivariate analysis, RT was associated with improved LC hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.07–0.46;
p
< 0.001, LRC (HR 0.28, 95 % CI 0.14–0.56;
p
< 0.001), DFS (HR 0.42, 95 % CI 0.26–0.70;
p
= 0.001), OS (HR 0.53, 95 % CI 0.31–0.93;
p
= 0.03), and DSS (HR 0.42, 95 % CI 0.26–0.70;
p
= 0.001). Patients with negative margins had significant improvements in 3-year LC (90.1 vs. 75.4 %;
p
< 0.001) with RT. Deaths not attributable to MCC were relatively evenly distributed between the RT and no RT groups (28.5 and 29.3 % of patients, respectively).
Conclusions
RT for MCC was associated with improved LRC and survival. RT appeared to be beneficial regardless of margin status.
Epigenetic changes associated with human papillomavirus (HPV)-driven tumors have been described; however, HPV type-specific alterations are less well understood. We sought to compare HPV16-specific ...methylation changes with those in virus-unassociated head and neck squamous cell carcinomas (HNSCC).
Within The Cancer Genome Atlas, 59 HPV16+ HNSCC, 238 nonviral HNSCC (no detectable HPV or other viruses), and 50 normal head and neck tissues were evaluated. Significant differentially methylated regions (DMR) were selected, and key associated genes were identified. Partial least squares models were generated to predict HPV16 status in additional independent samples.
HPV infection in HNSCC is associated with type-specific methylomic profiles. Multiple significant DMRs were identified between HPV16+, nonviral, and normal samples. The most significant differentially methylated genes, SYCP2, MSX2, HLTF, PITX2, and GRAMD4, demonstrated HPV16-associated methylation patterns with corresponding alterations in gene expression. Phylogenetically related HPV types (alpha-9 species; HPV31, HPV33, and HPV35) demonstrated a similar methylation profile to that of HPV16 but differed from those seen in other types, such as HPV18 and 45 (alpha-7).
HNSCC linked to HPV16 and types from the same alpha species are associated with a distinct methylation profile. This HPV16-associated methylation pattern is also detected in cervical cancer and testicular germ cell tumors. We present insights into both shared and unique methylation alterations associated with HPV16+ tumors and may have implications for understanding the clinical behavior of HPV-associated HNSCC.
HPV type-specific methylomic changes may contribute to understanding biologic mechanisms underlying differences in clinical behavior among different HPV+ and HPV- HNSCC.
We herein report the optimization and application of silver cationization (Ag
+
) in combination with laser desorption ionization (LDI) ultrahigh-resolution mass spectrometry (UHR-MS) to determine ...the structures of the sulfur-containing compounds present in heavy crude oil. A number of sulfur-containing model compounds were used to optimize the positive-ion mode LDI-MS conditions in the presence of a silver-complexing agent. Under the optimized LDI conditions, sulfur-rich heavy oil fractions were treated with the silver salt, where Ag
+
coordinated with the sulfur atoms to speciate the sulfur species. The obtained results suggested that benzothiophenic, naphtheno-non-aromatic sulfides, and non-aromatic thiols were the major components present in the analyzed oil sample.
Graphical abstract
Abstract
BACKGROUND
We hypothesized treatment with nivolumab and SRS would be feasible and well tolerated and may improve intracranial tumor control over SRS alone for breast cancer brain metastases.
...METHODS
The study is a phase Ib trial of nivolumab and SRS for breast cancer brain metastases. Clinical trial information: NCT03807765. Key eligibility criteria include breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≥ 10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and q4 weeks.
RESULTS
A total of 12 patients were treated to 17 brain metastases. Breast cancer subtypes included triple negative (50%), HR+/HER2- (33%), and HR-/HER2+ (17%). Median follow-up from start of protocol therapy is 44 months. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12 month control rate of 33%. Median systemic progression free survival was 7.7 months with a 12 month rate of 42%. Median overall survival (OS) was 24.7 months with a 12 month OS of 75%. No cases of radionecrosis were noted. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared to baseline (83%), week 25 compared to baseline (89%), and 100% at first follow-up. An increase in cfDNA 4 weeks post SRS was found to predict worse intracranial control (HR: 4.4; 95% CI: 1.1-18.5; p = 0.04).
CONCLUSIONS
Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. An increase in cfDNA 4 weeks post SRS was found to predict worse intracranial control and was eventually seen in all patients.
Radiation therapy (RT) can prime and boost systemic anti-tumor effects via STING activation
,
resulting in enhanced tumor antigen presentation and antigen recognition by T cells
.
It is increasingly ...recognized that optimal anti-tumor immune responses benefit from coordinated cellular (T cell) and humoral (B cell) responses. However, the nature and functional relevance of the RT-induced immune response are controversial, beyond STING signaling, and agonistic interventions are lacking. Here, we show that B and CD4
+
T cell accumulation at tumor beds in response to RT precedes the arrival of CD8
+
T cells, and both cell types are absolutely required for abrogated tumor growth in non-irradiated tumors. Further, RT induces increased expression of 4-1BB (CD137) in both T and B cells; both in preclinical models and in a cohort of patients with small cell lung cancer treated with thoracic RT. Accordingly, the combination of RT and anti-41BB therapy leads to increased immune cell infiltration in the tumor microenvironment and significant abscopal effects. Thus, 4-1BB therapy enhances radiation-induced tumor-specific immune responses via coordinated B and T cell responses, thereby preventing malignant progression at unirradiated tumor sites. These findings provide a rationale for combining RT and 4-1bb therapy in future clinical trials.
BackgroundThe Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating the immune system through cytokine receptors by modulating T ...cell polarization and effector functions. Cytokine binding to the cognate receptors activates JAKs that phosphorylates STATs which in turn translocate to the nucleus in order to activate or suppress the transcription of genes. This pathway is regulated by an array of regulator proteins, determining the initiation, duration, and termination of the signaling. However, the roles of these protein regulators other than phosphorylation-dephosphorylation remain unclear.Sirt2 is an (NAD+)-dependent histone deacetylase with conflicting reports on its tumor suppressor or oncogenic roles. We previously showed that Sirt2 is a suppressor of T cell metabolism that deacetylates key metabolic targets and negatively impacts their enzymatic activity. Accordingly, Sirt2 deficient T cells exhibited a hyper-metabolic status with a profound upregulation of glycolysis.MethodsThe role of Sirt2 in T cell immune response was investigated using RNA-sequencing, CFSE proliferation assay, DAPI/AnnexinV staining, IFN-γ ELISpot assay, intracellular staining of effector molecules and LDH cytotoxicity assay in Wild-type and Sirt2 knockout mice. Sirt2 interactome was identified via mass spectrometry (MS) and immunoprecipitation/Wb analyses. Phosphorylation and acetylation of JAK/STAT effector molecules following cytokine stimulation were assessed by Wb. Pharmacologic inhibition of Sirt2 in human T cells was achieved using Thiomyristoyl, a Sirt2 selective inhibitor.ResultsSirt2 expression is induced following T cell activation. Our molecular studies revealed that Sirt2 directly interacts with JAK1/2/3 and STAT1/3/5 and negatively impacting their acetylation status.Strikingly Sirt2 inhibition resulted in increased phosphorylation of JAK1/2/3 and STAT3/5 following IL2 stimulation and increased phosphorylation of JAK1/2 and STAT1 following IFN-γ stimulation in murine and human T cells.Accordingly, RNA-sequencing analysis revealed upregulation of IL-2 signaling and IFN-γ response with Sirt2 deficiency in activated T cells.As a consequence of enhanced JAK/STAT activation, Sirt2 deficient T cells displayed enhanced T cell proliferation and effector functions.ConclusionsOur findings indicate Sirt2 as a suppressor of JAK/STAT pathways and show that protein acetylation plays an important role in the modulation of cytokine signaling and T cell fate. Therefore, Sirt2 constitutes a potential target to manipulate the immune response and to treat immune-related diseases or enhance antitumor immunity.AcknowledgementsThis work was supported in part by K08 CA194273, ACS IRG-17-173-22, NCI Cancer Center Support Grant (P30-CA076292) and the Moffitt Foundation.
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