Characterization of PD-L1 expression in Chinese non-small cell lung cancer patients with PTEN expression as a means for tissue quality screening

Abstract

The goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN IHC showed that 108 TMA samples and 105 whole-section samples qualified for PD-L1 IHC. With a clinically relevant cutoff, 41.7% of the TMA samples were PD-L1 positive. PD-L1 level was much lower in EGFR-mutant patients and seemed to be a favorable prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). These findings were confirmed in the whole-section samples except that their survival data were not mature enough for correlation analysis. In summary, PD-L1 expression was detected in approximately 40% of PTEN-qualified Chinese NSCLC samples, negatively correlated with EGFR mutation and seemed to be a favorable prognostic factor for both OS and RFS. Notably, the different results from PTEN-qualified and PTEN-disqualified samples underscore the importance of tissue quality control prior to biomarker testing.

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Comparative gene co-expression network analysis of epithelial to mesenchymal transition reveals lung cancer progression stages

Abstract

Background

The epithelial to mesenchymal transition (EMT) plays a key role in lung cancer progression and drug resistance. The dynamics and stability of gene expression patterns as cancer cells transition from E to M at a systems level and relevance to patient outcomes are unknown.

Methods

Using comparative network and clustering analysis, we systematically analyzed time-series gene expression data from lung cancer cell lines H358 and A549 that were induced to undergo EMT. We also predicted the putative regulatory networks controlling EMT expression dynamics, especially for the EMT-dynamic genes and related these patterns to patient outcomes using data from TCGA. Example EMT hub regulatory genes were validated using RNAi.

Results

We identified several novel genes distinct from the static states of E or M that exhibited temporal expression patterns or 'periods' during the EMT process that were shared in different lung cancer cell lines. For example, cell cycle and metabolic genes were found to be similarly down-regulated where immune-associated genes were up-regulated after middle EMT stages. The presence of EMT-dynamic gene expression patterns supports the presence of differential activation and repression timings at the transcriptional level for various pathways and functions during EMT that are not detected in pure E or M cells. Importantly, the cell line identified EMT-dynamic genes were found to be present in lung cancer patient tissues and associated with patient outcomes.

Conclusions

Our study suggests that in vitro identified EMT-dynamic genes capture elements of gene EMT expression dynamics at the patient level. Measurement of EMT dynamic genes, as opposed to E or M only, is potentially useful in future efforts aimed at classifying patient's responses to treatments based on the EMT dynamics in the tissue.

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Leukocytoclastic vasculitis complicating cisplatin + radiation treatment for laryngeal cancer: a case report

Abstract

Background

Leukocytoclastic vasculitis is typically mediated by deposition of immune complexes and is related to many causes, including medication. To the best of our knowledge, leukocytoclastic vasculitis related to cisplatin has not yet been described in the scientific literature.

Case presentation

We report a rare case of leukocytoclastic vasculitis after the first cycle of high-dose cisplatin chemotherapy in a patient with larynx carcinoma. A 48-year-old Caucasian man with larynx carcinoma received a high-dose of cisplatin monochemotherapy (100 mg/m² every 21 days), along with 70 Gy of radiotherapy divided into 35 sessions, as a therapeutic schedule. Twelve days after the first chemotherapy administration and after 8 sessions of radiotherapy (total of 16 Gy), the patient presented with acute onset of palpable purpura in the lower limbs. The patient was hospitalized for 10 days, and during this period, he underwent several examinations to rule out infectious, autoimmune, and neoplastic disorders. A skin biopsy showed leukocytoclastic vasculitis with a positive pattern for IgM and C3, as detected through direct immunofluorescence. Twenty-five days after cisplatin administration, the chemotherapy regimen was changed to carboplatin AUC 5, and the episodes of purpura ceased, reinforcing the hypothesis of an adverse reaction to cisplatin.

Conclusions

Cisplatin can induce leukocytoclastic vasculitis and clinicians should be aware of this potential effect for better case management and diagnosis.

http://ift.tt/2nzEnvE

Comparative gene co-expression network analysis of epithelial to mesenchymal transition reveals lung cancer progression stages

Abstract

Background

The epithelial to mesenchymal transition (EMT) plays a key role in lung cancer progression and drug resistance. The dynamics and stability of gene expression patterns as cancer cells transition from E to M at a systems level and relevance to patient outcomes are unknown.

Methods

Using comparative network and clustering analysis, we systematically analyzed time-series gene expression data from lung cancer cell lines H358 and A549 that were induced to undergo EMT. We also predicted the putative regulatory networks controlling EMT expression dynamics, especially for the EMT-dynamic genes and related these patterns to patient outcomes using data from TCGA. Example EMT hub regulatory genes were validated using RNAi.

Results

We identified several novel genes distinct from the static states of E or M that exhibited temporal expression patterns or 'periods' during the EMT process that were shared in different lung cancer cell lines. For example, cell cycle and metabolic genes were found to be similarly down-regulated where immune-associated genes were up-regulated after middle EMT stages. The presence of EMT-dynamic gene expression patterns supports the presence of differential activation and repression timings at the transcriptional level for various pathways and functions during EMT that are not detected in pure E or M cells. Importantly, the cell line identified EMT-dynamic genes were found to be present in lung cancer patient tissues and associated with patient outcomes.

Conclusions

Our study suggests that in vitro identified EMT-dynamic genes capture elements of gene EMT expression dynamics at the patient level. Measurement of EMT dynamic genes, as opposed to E or M only, is potentially useful in future efforts aimed at classifying patient's responses to treatments based on the EMT dynamics in the tissue.

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Leukocytoclastic vasculitis complicating cisplatin + radiation treatment for laryngeal cancer: a case report

Abstract

Background

Leukocytoclastic vasculitis is typically mediated by deposition of immune complexes and is related to many causes, including medication. To the best of our knowledge, leukocytoclastic vasculitis related to cisplatin has not yet been described in the scientific literature.

Case presentation

We report a rare case of leukocytoclastic vasculitis after the first cycle of high-dose cisplatin chemotherapy in a patient with larynx carcinoma. A 48-year-old Caucasian man with larynx carcinoma received a high-dose of cisplatin monochemotherapy (100 mg/m² every 21 days), along with 70 Gy of radiotherapy divided into 35 sessions, as a therapeutic schedule. Twelve days after the first chemotherapy administration and after 8 sessions of radiotherapy (total of 16 Gy), the patient presented with acute onset of palpable purpura in the lower limbs. The patient was hospitalized for 10 days, and during this period, he underwent several examinations to rule out infectious, autoimmune, and neoplastic disorders. A skin biopsy showed leukocytoclastic vasculitis with a positive pattern for IgM and C3, as detected through direct immunofluorescence. Twenty-five days after cisplatin administration, the chemotherapy regimen was changed to carboplatin AUC 5, and the episodes of purpura ceased, reinforcing the hypothesis of an adverse reaction to cisplatin.

Conclusions

Cisplatin can induce leukocytoclastic vasculitis and clinicians should be aware of this potential effect for better case management and diagnosis.

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Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

BACKGROUND

Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients.

METHODS

In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m² on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m² (10-day regimen).

RESULTS

Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m²/d, respectively [5-day regimen] and 53 patients who were assigned to 60 mg/m²/d [10-day regimen]). The 90 mg/m² dose showed no benefit in clinical outcomes in comparison with 60 mg/m² in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation.

CONCLUSIONS

Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2017. © 2017 American Cancer Society.

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Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases

BACKGROUND

Extrapulmonary neuroendocrine carcinomas (NECs) are poorly studied and are managed similar to lung NECs, which may not account for differences between the 2 groups of tumors as well as the heterogeneity within extrapulmonary NEC.

METHODS

Data from the Surveillance, Epidemiology, and End Results program between 1973 and 2012 were used to estimate the relative percentages of lung NECs and subgroups of extrapulmonary NECs, epidemiological patterns at these sites, and the median and 5-year overall survival rates.

RESULTS

Of 162,983 NEC cases, 14,732 were extrapulmonary; of these, 5509 were gastrointestinal (37.44%), 4151 were of unknown primary (28.2%), and 5072 were of other sites (34.4%). Lung NEC had the highest percentage of small cell morphology (95.2%) and gastrointestinal NEC had the least (38.7%), with the rest being other morphologies. Significant differences were noted with regard to median age (range, 48-74 years), percentage of cases of distant stage disease (24%-77%), and incidence according to sex and race. The median survival of patients with lung NEC was 7.6 months, that for patients with gastrointestinal NEC was 7.5 months (range, 25.1 months for NEC at the small intestine to 5.7 months for NEC at the pancreas), and that for patients with unknown NEC was 2.5 months. The 5-year survival rate for patients with local stage disease ranged from 58% to 60% for NECs of the female genital tract and small intestine to 25% for esophageal NECs. The primary tumor site remained statistically significant for survival even after adjusting for known prognostic variables (P<.0001).

CONCLUSIONS

To the authors' knowledge, the current study is the largest study of NECs performed to date and also the first with comprehensive epidemiological data. Significant differences in incidence patterns and large variations in survival depending on anatomical site and morphological subtype were noted. A curative approach is possible for patients with nonmetastatic NECs. Cancer 2017. © 2017 American Cancer Society.

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