Circulating Tumor Biomarkers Research Articles

Circulating tumor DNA - Current state of play and future perspectives.

Cancer management paradigms are shifting towards a personalized approach thanks to the advent of the -omics technologies. Liquid biopsies, consisting in the sampling of blood and other bodily fluids, are emerging as a valid alternative to circulating tumor biomarkers and tumor tissue biopsies for cancer diagnosis, routine monitoring and prognostication. The content of a liquid biopsy is referred to as the "tumor circulome". Among its components, circulating tumor DNA (ctDNA), including both cell-free and exosome-associated DNA, is the most widely characterized element. ctDNA analysis has a tremendous capability in the diagnostic arena. Its potential has been demonstrated at each level of disease staging and management and supported by a recent FDA approval for companion diagnostic, and the investments being made by pharmaceutical companies in this sector are numerous. The approaches available for ctDNA analysis allow both quantitative and qualitative studies and range from PCR and dPCR-mediated single/multiple gene mutational assessment to whole genome next generation sequencing and methylation mapping. Although the principal object of a liquid biopsy is blood, other body fluids such as urine and saliva show potential as complementary DNA sources for tumor analysis. In this review we provide a synopsis on the state of play of current ctDNA application. We discuss the clinical significance of ctDNA analysis and review the state of the art of technologies being currently developed to this aim. We also discuss the current issues limiting ctDNA application and highlight the promising approaches being developed to overcome these.

The Use of Microfluidic Technology for Cancer Applications and Liquid Biopsy.

There is growing awareness for the need of early diagnostic tools to aid in point-of-care testing in cancer. Tumor biopsy remains the conventional means in which to sample a tumor and often presents with challenges and associated risks. Therefore, alternative sources of tumor biomarkers is needed. Liquid biopsy has gained attention due to its non-invasive sampling of tumor tissue and ability to serially assess disease via a simple blood draw over the course of treatment. Among the leading technologies developing liquid biopsy solutions, microfluidics has recently come to the fore. Microfluidic platforms offer cellular separation and analysis platforms that allow for high throughout, high sensitivity and specificity, low sample volumes and reagent costs and precise liquid controlling capabilities. These characteristics make microfluidic technology a promising tool in separating and analyzing circulating tumor biomarkers for diagnosis, prognosis and monitoring. In this review, the characteristics of three kinds of circulating tumor markers will be described in the context of cancer, circulating tumor cells (CTCs), exosomes, and circulating tumor DNA (ctDNA). The review will focus on how the introduction of microfluidic technologies has improved the separation and analysis of these circulating tumor markers.

GD2 as a circulating tumor biomarker (CTB) for neuroblastoma (NBL).

10538Background: CTBs that reflect tumor burden or viability can improve the accuracy and sensitivity of assessing tumor response in phase 2 trials and substantially shorten the timeline of phase 3...

Abstract OT2-06-03: METAMORPH: METAstatic markers of recurrent tumor PHenotype for breast cancer

Abstract Up to 30% of patients diagnosed with breast cancer will develop recurrent disease within their lifetime, and currently this form of the disease is incurable. There are unmet needs to better understand underlying metastatic biology, identify new therapeutic targets and develop better methods for monitoring changes in disease, both to monitor response and elucidate resistance mechanisms. To address these needs, the METAMORPH Study encompasses a comprehensive approach that combines serial molecular tissue profiling at the RNA and DNA level with circulating markers (DTCs, CTCs, plasma tumor DNA), and ongoing assessment of therapeutic response. METAMORPH is a prospective cohort study of women with suspected or confirmed recurrent breast cancer and accessible tumor by standard clinical biopsy, who are enrolled at the University of Pennsylvania prior to starting a new therapy for recurrent metastatic disease. The aims of this trial are to (1) evaluate the mechanisms through which recurrent breast cancer are genetically distinct from the primary tumor, (2) evaluate the circulating tumor biomarker trajectory of recurrent disease, (3) elucidate “escape pathways” of progressing tumors that emerge during the selective pressure of therapy, and (4) explore clinical utility of tumor and blood testing. The study protocol integrates research aims into clinical care, including a standardized approach to disease assessment and biopsy, pathologic confirmation of histology and receptor subtype, panel-based CLIA-approved genomic profiling, collection of research specimens, and standardized reporting of results, which are returned to patients and physicians. Patients are followed for treatment and outcome, and serial samples are collected at progression. A companion protocol, COMET, provides education about genomic testing and assesses patient understanding and impact of results. To date, 155 patients have enrolled, 142 (92%) have been biopsied, 120 (77%) have had sufficient DNA for molecular profiling and 109 (70%) have had genomic panel testing. Accrual is ongoing, with an initial target of 300 patients. Multiple sites within the UPHS Health System are enrolling. Contact information: angela.demichele@uphs.upenn.edu. Key words: Metastatic disease, tumor profiling. Citation Format: DeMichele A, Soucier-Ernst DJ, Clark C, Shih N, Stavropoulos W, Maxwell KN, Feldman M, Lierbamen D, Morrissette JJD, Paul MR, Pan T-C, Wang J, Belka GK, Chen Y, Yee S, Carpenter E, Fox K, Matro J, Clark A, Shah P, Domchek S, Bradbury A, Chodosh L. METAMORPH: METAstatic markers of recurrent tumor PHenotype for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-06-03.

Microfluidics-enabled rational design of immunomagnetic nanomaterials and their shape effect on liquid biopsy.

Microfluidics brings unique opportunities for the synthesis of nanomaterials toward efficient liquid biopsy. Herein, we developed the microreactor-enabled flow synthesis of immunomagnetic nanomaterials with controllable shapes (sphere, cube, rod, and belt) by simply tuning the flow rates. The particle shape-dependent screening efficiency of circulating tumor cells was first investigated and compared with commercial ferrofluids, providing new insights into the rational design of a particulate system toward the screening and analysis of circulating tumor biomarkers.

Abstract OT2-01-03: A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC)

Abstract VT-464, an oral dual lyase-selective CYP17 inhibitor and AR antagonist (wild-type and mutated forms [e.g., F876L and T877A]), is in multiple Phase (Ph) 2 studies as treatment for men with castration-resistant prostate cancer (CRPC). VT-464 inhibits the growth of multiple BC cell lines in vitro including MCF7 (ER(+)/AR low), tamoxifen-resistant MCF7, and MDA-MB-453 (ER(-)/AR(+)) in a dose-dependent manner and with greater potency/efficacy than enzalutamide (submitted, Ellison et al., 2015). A subset of TNBC and most ER(+) BC express AR, making them potential targets for VT-464 since it directly inhibits both androgen/estrogen synthesis and AR transcriptional activity. Objectives: The primary objective of Ph 1, now enrolling, is to establish the once-daily dose of VT-464 in women. Secondary objectives include safety, PK and efficacy endpoints, including determination of clinical benefit rate (CBR) which is the primary objective of Ph 2. Exploratory objectives include the determination of the extent of AR expression and signaling in breast tissue and to evaluate the relationship of expression with VT-464 effects on circulating tumor biomarkers, circulating hormones and clinical outcomes. Study Design: This study is an open-label, single arm, Ph 1/2 study of VT-464 in women with AR(+) TNBC or ER(+)/HER2 normal unresectable locally advanced or metastatic BC. Ph 1 will follow a modified 3+3 Fibonacci design with cohort expansion to 6 patients following a single DLT in the first 28-days of treatment. Approximately 2-3 dose-levels will be explored in Ph 1. Ph 1 start dose will be the MTD for men with CRPC. AR(+) TNBC and ER(+)/HER2 BC cohorts will be expanded in Ph 2 using the MTD from Ph 1. Ph 2 will follow a Simon's two-stage design with pre-determined futility parameters. Eligible patients will have ER≥1% BC or AR≥1% (as determined by central IHC testing using the Dako antibody) TNBC. ER(+) patients must be postmenopausal and must have received at least 1 prior line of endocrine therapy. Additional eligibility criteria include: ≥ 18 years of age, ECOG PS ≤ 1, unresectable locally advanced or metastatic BC, available representative tumor specimen to enable correlative science. Treatment Plan: Eligible patients will receive VT-464 once-nightly with dinner in a continuous dosing schedule. Adverse events and concomitant medications will be collected from the time of signing of informed consent until 30 days after end of study visit (EOS). Safety labs will be monitored monthly through EOS. Dense PK will be collected after the first dose of study drug in Ph 1 and single morning samples collected approximately every two cycles thereafter in Ph 1 and Ph 2 until EOS. Blood samples for steroids, circulating tumor DNA and circulating tumor cells will be collected through Cycle 2 and then at EOS. Tumor biopsy will be collected at baseline and at disease progression. Radiographic response will be assessed every 8 weeks and EOS. Patient Accrual: Accrual is ongoing with 12-18 patients expected to be enrolled in Ph 1. Citation Format: Gucalp A, Hudis C, Norton L, Patil S, Kurman MR, Eisner JR, Moore WR, Traina TA. A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-03.

H29 - Correlation between circulating tumor biomarkers and positron-emission tomography in advanced non-small cell lung cancer

H29 - Correlation between circulating tumor biomarkers and positron-emission tomography in advanced non-small cell lung cancer

3123 Correlation between circulating tumor biomarkers and positronemission tomography in advanced non-small cell lung cancer

3123 Correlation between circulating tumor biomarkers and positronemission tomography in advanced non-small cell lung cancer

Circulating Tumor Markers in Patients with Neuroendocrine Tumors – a Clinical Perspective

Abstract: Neuroendocrine tumors (NETs) are uncommon malignancies with a very diverse presentation and prognosis. Patients with NETs frequently have circulating tumor biomarkers that may aid in the diagnosis and help with prognostication. The most commonly used and best studied marker is chromogranin A, which appears to reflect the tumor burden and is useful at the time of diagnosis, and to monitor for recurrence after resection as well as to assess response to systemic therapy. Despite being the best studied marker, chromogranin A has significant limitations. Multiple other biomarkers are in use, but most have not been studied well and need further validation before being recommended for clinical practice. We review both established and novel circulating biomarkers, and highlight some of the limitations of tumor marker use in patients with NETs.

Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients.

Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was ≥1 in 19 patients (70%) and ≥5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome.

Abstract 3826: Breast cancer metastasis suppressor-1 promoter methylation in cell free DNA provides prognostic information in non-small cell lung cancer

Abstract Background: Breast-cancer metastasis suppressor 1 (BRMS1) gene encodes for a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without blocking orthotopic tumor growth. The aim of the present study was to evaluate for the first time the prognostic significance of BRMS1 promoter methylation in cell free DNA (cfDNA) circulating in plasma of non-small cell lung cancer (NSCLC) patients. Towards this goal, we examined the methylation status of BRMS1 promoter in NSCLC tissues, matched adjacent non-cancerous tissues and corresponding cfDNA as well as in an independent cohort of patients with advanced NSCLC and healthy individuals. Methods: BRMS1 promoter methylation was examined in 57 NSCLC tumors and adjacent non-cancerous tissues, in cfDNA isolated from 48 corresponding plasma samples, in cfDNA isolated from plasma of 74 patients with advanced NSCLC and 24 healthy individuals. Results: BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and corresponding cfDNA (47.9%) but not in cfDNA from healthy individuals ( 0%), while it was also highly methylated in cfDNA from advanced NSCLC patients (63.5%). In operable NSCLC, Kaplan-Meier estimates were significantly different in favor of patients with non-methylated BRMS1 promoter in cfDNA, concerning both DFI (p=0.048) and OS (p=0.007). In advanced NSCLC, OS was significantly different in favour of patients with non-methylated BRMS1 promoter in their cfDNA (p=0.003). Multivariate analysis confirmed that BRMS1 promoter methylation has a statistical significant influence both on operable NSCLC patients' DFI time and OS and on advanced NSCLC patients' PFS and OS. Conclusions: BRMS1 promoter methylation in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumor biomarker. Citation Format: Ioanna Balkouranidou, Maria Chimonidou, Georgia Milaki, Emily Tsaroucha, Stelios Kakolyris, Danny Welch, Vasilis Georgoulias, Evi Lianidou. Breast cancer metastasis suppressor-1 promoter methylation in cell free DNA provides prognostic information in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3826. doi:10.1158/1538-7445.AM2014-3826

Abstract 4287: Novel method of liver tumor detection and characterization using ultrasound-induced biomarker release

Abstract Blood biomarkers can revolutionize early cancer detection by earlier detection of circulating tumor biomarkers. We have shown that cell membrane permeabilization by low frequency ultrasound can release biomarkers from tumor cells. We use this non-invasive method to increase the detectable blood biomarker level from orthotopic liver tumors in mice, allowing for tumor characterization. The ability to focus ultrasound enables localization of the biomarker-release site. This novel strategy could lead to the earlier characterization of unknown incidental lesions leading to earlier detection and localization of cancer. METHODS: The colon cancer cell line LS174T transfected with the firefly luciferase2 reporter gene was used to produce liver tumors in nude mice. This cell line produces the biomarkers carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA-19-9), which were detected using an enzyme-linked immunosorbant assay. The liver tumors were produced by either injecting 3 million cells in matrigel or transplantation of a piece of previously established subcutaneous tumor into the liver. The tumor growth was followed using bioluminescence and size was measured using ultrasound. The liver was exposed to low frequency (1MHz) ultrasound for 6 minutes, serum was collected and biomarkers measured. The increase in serum biomarker was determined by the difference in pre and post-ultrasound-treatment levels. Control samples were from tumor-bearing mice not ultrasound treated. Cells in culture were treated with the low frequency and biomarker release studied with an increase in time (0, 10, 30 min). RESULTS: Both the methods used to produce the liver tumors showed an 80% rate of tumor establishment within a week of implantation. The other 20% showed tumor growth at a slower rate. The transplantation of the previously established subcutaneous tumor piece showed a better control of the tumor size compared to the cells implanted. The tumors showed an exponential growth in three weeks (week-3 mean volume 0.815 cm3). The ultrasound treated tumors showed a significant increase in blood biomarkers released (CEA: p<0.007, n=10; CA19-9: p<0.002, n=6), when compared to controls. The cells in culture showed significant biomarker release (CEA and CA19-9 p<0.05) when treated with ultrasound. Previously studied cell death has been shown to be below 5 % under all conditions. CONCLUSIONS: Increase in biomarkers released from cells in culture and liver tumors was observed with ultrasound-treatment. This allows for characterization of tumors depending on the amplification of tumor specific blood biomarkers. This orthotopic liver model can be used to study tumor characterization as well as has implications in diagnostic monitoring of lesions and therapy. This novel method has a clear pathway for application of MR-guided focused ultrasound in characterization of incidental tumors, merging the fields of imaging and in vitro diagnostics. Citation Format: Aloma L. D'Souza, Xinrui Yan, Sanjiv S. Gambhir. Novel method of liver tumor detection and characterization using ultrasound-induced biomarker release. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4287. doi:10.1158/1538-7445.AM2014-4287

Circulating nucleosomes: a new addition to the personalized medicine toolkit.

Dr Stefan Holdenrieder is senior physician at the Institute of Clinical Chemistry and Clinical Pharmacology of the University Hospital Bonn, Germany. He is an expert in the field of circulating tumor biomarkers and particularly circulating nucleosomes. He has conducted numerous clinical studies concerning the biomarker-based detection and monitoring of cancer diseases and has published more than 90 papers in recognized international journals.

Noninvasive detection of colorectal cancer by nucleosomic markers

Dr Stefan Holdenrieder speaks with Caroline Telfer, Commissioning Editor: Stefan Holdenrieder is a senior physician at the Institute of Clinical Chemistry and Clinical Pharmacology of the University Hospital Bonn (Bonn, Germany). He is an expert in the field of circulating tumor biomarkers with particular focus on circulating nucleosomes. He has conducted numerous studies concerning biomarker-based detection and monitoring of cancer diseases and has published more than 90 papers in recognized international journals.

A critical review of the analytical approaches for circulating tumor biomarker kinetics during treatment

Changes in serum tumor biomarkers may indicate treatment efficacy. Traditional tumor markers may soon be replaced by novel serum biomarkers, such as circulating tumor cells (CTCs) or circulating tumor nucleic acids. Given their promising predictive values, studies of their kinetics are warranted. Many methodologies meant to assess kinetics of traditional marker kinetics during anticancer treatment have been reported. Here, we review the methodologies, the advantages and the limitations of the analytical approaches reported in the literature. Strategies based on a single time point were first used (baseline value, normalization, nadir, threshold at a time t), followed by approaches based on two or more time points [half-life (HL), percentage decrease, time-to-events…]. Heterogeneities in methodologies and lack of consideration of inter- and intra-individual variability may account for the inconsistencies and the poor utility in routine. More recently, strategies based on a population kinetics approach and mathematical modeling have been reported. The identification of equations describing individual kinetic profiles of biomarkers may be an alternative strategy despite its complexity and higher number of necessary measurements. Validation studies are required. Efforts should be made to standardize biomarker kinetic analysis methodologies to ensure the optimized development of novel serum biomarkers and avoid the pitfalls of traditional markers.

Surveillance and Monitoring in Breast Cancer Survivors: Maximizing Benefit and Minimizing Harm

Although the incidence of breast cancer has increased, breast cancer mortality has decreased, likely as a result of both breast cancer screening and improved treatment. There are well over two million breast cancer survivors in the United States for whom appropriate surveillance continues to be a subject of controversy. The guidelines from the American Society of Clinical Oncology (ASCO) and the American College of Physicians are clear: only performance of yearly screening mammography is supported by evidence. Although advanced imaging technologies and sophisticated circulating tumor biomarker studies are exquisitely sensitive for the detection of recurrent breast cancer, there is no proof that earlier detection of metastases will improve outcome. A lack of specificity may lead to more tests and patient anxiety. Many breast cancer survivors are not followed by oncologists, and their doctors may not be familiar with these recommendations. Oncologists also disregard the data. A plethora of both blood tests and nonmammographic imaging tests are frequently performed in asymptomatic women. The blood tests, marker studies, and advanced imaging techniques are expensive and, with limited health care funds, may prevent funding for more appropriate aspects of patient care. Abnormal marker studies lead to additional imaging procedures. Repeated CT scans and radionuclide imaging may induce a second cancer because of the radiation dose, and invasive procedures performed as a result of these examinations also add risk to patients without clear benefits. Improved adherence to the current guidelines can cut costs, reduce risks, and improve patient quality of life without adversely affecting outcome.

Surveillance and Monitoring in Breast Cancer Survivors: Maximizing Benefit and Minimizing Harm

Although the incidence of breast cancer has increased, breast cancer mortality has decreased, likely as a result of both breast cancer screening and improved treatment. There are well over two million breast cancer survivors in the United States for whom appropriate surveillance continues to be a subject of controversy. The guidelines from the American Society of Clinical Oncology (ASCO) and the American College of Physicians are clear: only performance of yearly screening mammography is supported by evidence. Although advanced imaging technologies and sophisticated circulating tumor biomarker studies are exquisitely sensitive for the detection of recurrent breast cancer, there is no proof that earlier detection of metastases will improve outcome. A lack of specificity may lead to more tests and patient anxiety. Many breast cancer survivors are not followed by oncologists, and their doctors may not be familiar with these recommendations. Oncologists also disregard the data. A plethora of both blood tests and nonmammographic imaging tests are frequently performed in asymptomatic women. The blood tests, marker studies, and advanced imaging techniques are expensive and, with limited health care funds, may prevent funding for more appropriate aspects of patient care. Abnormal marker studies lead to additional imaging procedures. Repeated CT scans and radionuclide imaging may induce a second cancer because of the radiation dose, and invasive procedures performed as a result of these examinations also add risk to patients without clear benefits. Improved adherence to the current guidelines can cut costs, reduce risks, and improve patient quality of life without adversely affecting outcome.

BACTERIAL INFECTION PROFILES AND TUMOR BIOMARKERS IN EGYPTIAN LUNG CANCER PATIENTS

A substantial number of bacterial pathogens have been putatively linked to cancer. In patients with lung cancer, pneumonia is the most important complication and has a high mortality. However, the common pathogens causing pneumonia are not clear. Also there is a need for identification of circulating tumor biomarkers by highly specific and accurate blood tests that can be performed at any medical facility. For these reasons the aim of the present study is identifying the major bacterial species present in sputum of lung cancer patients complaining from pneumonia and to measure the serum level of tumor markers with the assessment of their clinical significance. Methods: 60 patients diagnosed for lung cancer; 44 non small cell lung cancers (NSCLC) & 16 small cell lung cancers (SCLC); as well as 10 control normal healthy adults were included. The sputum of the patients & control were cultured on different culture media for identification of bacteria. Minimum Inhibitory Concentration (MIC) was determined by Microscan. The serums of the same candidates were analyzed for angiopoietin-2 (Ang-2), survivin, Carcinoembryonic antigen (CEA) and Neuron – specific enolase (NSE). Results: E. coli was isolated from 15 sputum samples, α or non hemolytic Streptococci were isolated from 43, Staphylococcus aureus was isolated from 3, K. pneumonia was isolated from 14, P. aeruginosa in 2, other bacteria in 9, Proteus mirabilis in 1, Acintobacter sp. in 2, Enterobacter cloacae in 2, Morganella morganii in 2, Serratia sp. in 1 and Candida in 3. The isolated bacteria showed multidrug resistance to the tested antibiotics. Serum Ang-2 was significantly higher in SCLC and NSCLC groups as compared to normal group. Mean value of serum survivin was significantly higher in SCLC group as compared to normal and NSCLC groups. While there was no significant increase of serum survivin level in NSCLC group as compared to normal group. Mean value of serum NSE was significantly higher in SCLC group and NSCLC as compared to normal group. Serum NSE was higher in SCLC than in NSCLC group but the difference was not statistically significant. Mean value of serum CEA was significantly higher in SCLC group and NSCLC as compared to normal group. Also the mean value of serum CEA in NSCLC was significantly higher than the mean value of SCLC group. Conclusion: The spectrum of pulmonary infection in patients with lung cancer is wide and depends on the underlying neoplasm and the immunologic deficit or deficits related to it, and to various treatment modalities. The development of drug resistance among common respiratory pathogens is of great concern and underscores the need for the appropriate use of antimicrobial agents and the importance of infection control. Serum survivin may be a useful marker in diagnosis of SCLC and also for differentiation between SCLC and NSCLC. Serum Ang-2 may be a good marker for lung cancer.

Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer

Studies have shown cell-free microRNA (miRNA) circulating in the serum and plasma with specific expression in cancer, indicating the potential of using miRNAs as biomarkers for cancer diagnosis and therapy. This study was to investigate whether plasma miRNA-21 (miR-21) can be used as a biomarker for the early detection of non–small cell lung cancer (NSCLC) and to explore its association with clinicopathologic features and sensitivity to platinum-based chemotherapy. We used real-time RT-PCR to investigate the expression of miR-21 in the plasma of 63 NSCLC patients and 30 healthy controls and correlated the findings with early diagnosis, pathologic parameters, and treatment. Thirty-five patients (stages NIB and IV) were evaluable for chemotherapeutic responses: 11 had partial response (PR); 24 had stable and progressive disease (SD+ PD). Plasma miR-21 was significantly higher in NSCLC patients than in age- and sex-matched controls (P < 0.001). miR-21 was related to TNM stage (P < 0.001), but not related to age, sex, smoking status, histological classification, lymph node status, and metastasis (all P > 0.05). This marker yielded a receiver operating characteristic (ROC) curve area of 0.775 (95% CI: 0.681 – 0.868) with 76.2% sensitivity and 70.0% specificity. Importantly, miR-21 plasma levels in PR samples were several folds lower than that in SD plus PD samples (P = 0.049), and were close to that in healthy controls (P = 0.130). Plasma miR-21 can serve as a circulating tumor biomarker for the early diagnosis of NSCLC and is related to the sensitivity to platinum-base chemotherapy.

Pseudomyxoma Peritonei

No standard treatment for advanced unresectable pseudomyxoma peritonei (PMP) has been defined so far. PMP is traditionally considered chemoresistant but nonrandomized series showed promising results with regimens for gastrointestinal tumors.We conducted a single-center prospective single-arm trial. Inclusion criteria were histologically confirmed PMP, unresectable or progressive to surgery/previous treatments. Patients received a continuous metronomic regimen with capecitabine (625 mg/m2 twice per day) with cyclophosphamide (50 mg/d) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was progression-free survival (PFS); secondary end points were disease control rate (DCR), overall survival (OS), and safety. Exploratory analyses were the variation of circulating tumor biomarkers and neutrophil to lymphocyte ratio (NLR).Twenty-three consecutive patients were enrolled from April 2015 to October 2017. At a median follow up of 22.4 months, median PFS was 9.5 months and 1-year OS rate was 73.7%. Overall, DCR was 87% and 6 (27%) patients achieved disease control ≥12 months. The safety profile was manageable: 26% of patients reported Grade 3 drug-related adverse events and none Grade 4/5. NLR baseline < 3 versus ≥ 3 was associated with prolonged PFS (12.6 vs. 3.4 months; P = .0001).Metronomic capecitabine with cyclophosphamide is a well tolerated regimen in unresectable/recurrent PMP, and its safety profile favorably compares with previously investigated regimens.