Predictor Of Poor Progression-free Survival Research Articles

Pretreatment Tumor 18F-FDG Uptake Improves Risk Stratification Beyond RECIST 1.1 in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer: FDG Uptake and Risk Stratification.

This study investigated the prognostic role of tumor F-FDG uptake on pretreatment scans as an independent indicator and whether its addition improves risk prediction from Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). We measured the SUVmax of the most F-FDG-avid tumor lesions on pretreatment scans from 222 patients (age, 60.5 ± 9.5 years; males, 55.2%) with advanced nonsquamous non-small-cell lung cancer who were enrolled in a prospective phase II clinical trial. We then examined the prognostic value of SUVmax compared with other clinical factors, including chemotherapy response according to RECIST 1.1 criteria. A multivariable Cox proportional hazards model revealed that an SUVmax greater than 16.3 was an independent predictor of poor progression-free survival (hazards ratio, 3.50; 95% confidence interval, 1.89-6.51; P < 0.000) and overall survival (hazards ratio, 6.87; 95% confidence interval, 2.51-18.76; P < 0.000), whereas RECIST 1.1 did not show a significant association with any survival outcome. Furthermore, improvement was achieved by adding SUVmax to RECIST 1.1, which increased the net reclassification index (27.4%; P = 0.046) and integrated discrimination improvement (integrated discrimination improvement, 10.6%; P = 0.026). Similarly, adding RECIST 1.1 to SUVmax also improved net reclassification index (68.9%, P = 0.006) and integrated discrimination improvement (25.4%, P = 0.006) for prognosis prediction. High tumor F-FDG uptake on a pretreatment scan is an independent prognostic indicator that can significantly improve risk stratification when added to RECIST 1.1 for patients with advanced nonsquamous non-small-cell lung cancer.

Prognostic Characterization of Higher-Grade Meningiomas: A Histopathological Score to Predict Progression and Outcome.

Higher-grade meningiomas (WHO grade II and III) represent a diagnostic and prognostic challenge. We assessed the pathological and molecular characteristics of 94 higher-grade meningiomas (85 grade II, 9 grade III) to identify novel prognostic parameters. Higher mitotic count (p = 0.018), diffuse (≥50%) prominent nucleoli (p < 0.001), and sheeting (p < 0.001) were associated with recurrence. Lower SSTR2a-positive cells median rate (p = 0.048) and TERT promoter mutations (p = 0.014) were associated with recurrence and patient death, respectively; further analyses did not identify other outcome associations. Presence of Ki67 hot spots was associated with a shorter progression-free survival (PFS), independently of WHO grade at multivariate analysis (HR = 3.35, p = 0.008). Necrosis was related to a poorer overall survival (OS) at univariate (focal: HR = 4.55, p = 0.041 and diffuse: HR = 7.38, p = 0.020) and Kaplan-Meier analyses. A prognostic score was designed based on previous results: Presence of diffuse (≥50%) prominent nucleoli (0/1 point), diffuse (≥50%) sheeting (0/1 point), focal (<50%) or diffuse (≥50%) necrosis (0/1/2 points), and Ki67 hot spots (0/1 point). A total score ≥4 predicted poorer PFS and OS by Kaplan-Meier (PFS: 1.7 vs 6.4 years, p < 0.001 and OS: 5.2 vs 10.8 years, p = 0.001) and multivariate (PFS: HR = 5.98, p < 0.001 and OS: HR = 2.99, p = 0.048) analyses. These results were confirmed in an independent series of 58 grade II meningiomas (PFS: HR = 7.22, p = 0.002 and OS: HR = 9.69, p = 0.003). These associations and the integrated score could complement WHO grading.

Analysis of Clinical Outcomes of Pseudomyxoma Peritonei from Appendicular Origin Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy-A Retrospective Study from INDEPSO.

To evaluate the clinical outcomes of patients of pseudomyxoma peritonei of appendiceal origin undergoing cytoreductive surgery and HIPEC. Data collected from members, an independent collaborative group of Indian surgeons specializing in the management of peritoneal surface malignancy (INDEPSO), was analyzed retrospectively. Clinicopathological and perioperative outcomes of patients treated for pseudomyxoma peritonei (PMP) of appendicular origin were evaluated. Ninety-one patients were diagnosed with pseudomyxoma peritonei of appendicular origin between March 2013 and December 2017. The median age was 53years and 60% were females. The median PCI was 27 [range 3-39] and a CC-0/1 resection was achieved in 83.5% patients. The most common histological grade was low-grade PMP, seen in 71.4% cases. The overall rate of grades 3-4 morbidity was 33% (30/91) and the 90-day mortality rate reported was 6.5%. Pulmonary complications and systemic sepsis emerged as the most significant factors affecting morbidity, mortality, and failure to rescue. At a median follow-up of 24months, the median OS was not reached and the median PFS was 53months. On univariate and multivariate analysis, high-grade histology, prior chemotherapy, debulking surgery alone without HIPEC, and high PCI > 10 were predictors of poor progression-free survival. The survival and morbidity results of pseudomyxoma peritonei from appendicular origin following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are encouraging. With further awareness and understanding of the disease, and improvement in surgical expertise and learning curve, there is scope for further reduction in morbidity and better improvement in survival.

Clinical and positron emission tomography responses to long-term high-dose interferon-\u03b1 treatment among patients with Erdheim\u2013Chester disease

BackgroundErdheim–Chester disease (ECD) is a rare multi-systemic form of histiocytosis. Treatment with BRAF inhibitors has markedly improved outcomes of ECD; however, this targeted therapy is expensive (estimated annual cost is $50,000). Since estimated annual cost of interferon-α (IFN-α) is only approximately $1600 in China, we retrospectively evaluated the long-term therapeutic efficacy of IFN-α and the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as an assessment method among 32 ECD patients who received high dose IFN-α therapy at Peking Union Medical College Hospital.ResultsThe median age at diagnosis was 48 years (range, 6–66 years). The median duration of treatment was 18.5 months (range, 1–51 months). The overall clinical response rates were 80.0%, including 33.3% complete response, 36.7% partial response and 10.0% stable disease. Thirty-one patients underwent a total of 81 scans by FDG-PET. Seventeen patients had serial FDG-PET results, nine patients had experienced a partial metabolic response at the last follow-up. The median reduction of ratios between the most active target lesion standardized uptake value (SUV) and liver SUV from baseline to last FDG-PET scan was 61.4% (range, 8.8–86.6%). Eight of thirteen patients who experienced continuous clinical improvement during follow-up had at least one target lesion SUV increased by FDG-PET which decreased in subsequent scans without changing treatment strategy. The estimated 3-year progression-free survival (PFS) and overall survival (OS) were 64.1 and 84.5%, respectively. Central nervous system (CNS) involvement was the only predictor for poor PFS and OS.ConclusionsHigh-dose IFN-α treatment is a cost-effective option, especially for patients without CNS involvement. Single target lesion SUV elevation according to FDG-PET do not accurately demonstrate disease progression, but serial FDG-PET imaging effectively discriminate treatment response.

Abstract 2599: Circulating nucleic acids as biomarkers of prognosis and chemorefractory status in metastatic pancreatic cancer

Abstract Background: Prognostic and therapeutic stratification of pancreatic ductal adenocarcinoma (PDAC) patients remains elusive due to a lack of effective biomarkers, and a predilection towards metastatic disease. Peripheral blood-based liquid biopsies for tumor markers has emerged as a potential minimally invasive strategy for tumor monitoring. We have implemented a liquid biopsy assay utilizing DNA derived from vesicles known as exosomes (exoDNA) and circulating tumor DNA (ctDNA) in the metastatic setting to determine the potential utility of these liquid biopsy compartments in tumor management. Methods: A total of 318 plasma samples from 123 metastatic pancreatic patients were prospectively collected. ExoDNA and ctDNA were then extracted from matched plasma samples. Digital PCR, was used to identify codon 12/13 KRAS gene mutations. We assessed clinical endpoints in relation to progression free survival (PFS) and overall survival (OS) using univariate and multivariate analyses. In a metastatic PDAC patient, six serial liquid biopsies and seven tissue biopsies taken throughout disease progression underwent whole genome sequencing for detection of copy number events. Results: Detection rates of KRAS mutations in exoDNA and ctDNA at baseline treatment naïve staus were 61.0% and 52.9%, respectively. On multivariate COX regression analysis, exoDNA KRAS mutant allelic fraction (MAF) ≥ 5% was a significant predictor of poorer PFS (HR 2.28, 95% CI 1.18-4.40, P=0.014) and OS (HR 3.46, 95% CI 1.40-8.50, P=0.007) in metastatic patients. Among 34 patients, liquid biopsy tumor monitoring was performed across 127 serial blood draws during a median followup time of 11.1 months. The presence of an exoDNA MAF peak ≥ 1% during tumor monitoring was significantly correlated to radiological progression (p=0.0003). Specifically, detection of an exoDNA MAF peak ≥ 1% preceded radiological progression by a median of 50 days compared to a median of 0 days for CA19-9 (p=0.03). CtDNA did not emerge as a significant predictor of survival outcomes in our cohort. In a patient with multiple longitudinal liquid biopsies, comprehensive genomic profiling of exoDNA further demonstrated our ability to capture additional mutational events as they emerged during therapy and correlated to progression including amplifications in ERBB2 and MYC and deletions in CDKN2A and SMAD4. Conclusions: Liquid biopsies in PDAC provide direct evidence of those patients likely to experience poorer outcomes allowing for more effective therapeutic stratification. Liquid biopsies also demonstrate utility in characterization of putative emerging driver events during disease progression. Citation Format: Vincent Bernard, Dong U. Kim, F. Anthony San Lucas, Jonathan Castillo, Kelvin Allenson, Feven C. Mulu, Bret M. Stephens, Jonathan Huang, Eugene Koay, Cullen M. Taniguchi, Milind Javle, Robert A. Wolff, Matthew H. Katz, Gauri R. Varadhachary, Hector A. Alvarez, Anirban Maitra. Circulating nucleic acids as biomarkers of prognosis and chemorefractory status in metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2599.

A high neutrophil to lymphocyte ratio prior to BRAF inhibitor treatment is a predictor of poor progression-free survival in patients with metastatic melanoma.

Some studies have shown that a high neutrophil/lymphocyte ratio (NLR) ≥4 before initiating ipilimumab treatment is an independent prognostic indicator of poor survival in patients with metastatic melanoma (MM). To determine whether the NLR before starting BRAF inhibitor (BRAFi) treatment in patients with (MM) is associated with progression-free survival (PFS). This retrospective study included 49 patients consecutively receiving BRAFi for MM between July 2012 and December 2014. Cox proportional hazards regression was used to analyse the relationship between NLR and other factors, such as lactate dehydrogenase (LDH), performance status, BRAFi as first- or second-line therapy, and corticosteroid intake with PFS. The NLR before starting BRAFi was significantly associated with PFS based on univariate analysis and multivariate analysis adjusted for potential confounding factors, such as LDH activity, ulceration, performance status, first-line therapy, and corticosteroid intake. A high NLR (continuous variable) was associated with short PFS (HR: 1.35; 95%CI: 1.07-1.70; p=0.01), and NLR ≥4 was associated with shorter PFS (HR: 3.24; 95%CI: 1.30-8.12; p=0.01). Corticosteroid intake was not associated with short PFS based on multivariate analysis. An NLR >4, before starting BRAFi treatment, is an independent prognostic indicator of poor progression-free survival.

Prognostic Value of Baseline 18F-Fluorodeoxyglucose PET/CT in Patients with Multiple Myeloma: A Multicenter Cohort Study.

ObjectiveWe investigated the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with multiple myeloma (MM).Materials and MethodsSubjects were 76 patients with newly diagnosed myeloma and pretreatment with 18F-FDG PET/CT from four hospitals. The PET/CT features were evaluated and the clinical characteristics were reviewed. Prognostic factors related to poor progression-free survival (PFS) and overall survival (OS) were identified using a Cox proportional hazards regression model and a prediction scale was developed based on the identified factors.ResultsMultivariate analysis showed that the presence of 18F-FDG-avid focal bone lesions (≥ 3) was a significant and independent predictor of PFS (hazard ratio [HR] = 3.28, p = 0.007) and OS (HR = 11.78, p = 0.001). The presence of extramedullary disease on PET/CT scan was also a significant predictor of poor PFS (HR = 2.79, p = 0.006) and OS (HR = 3.89, p = 0.003). A prognostic scale was developed using these two predictors. An increase in score on the scale corresponded to a significantly increased risk of poor OS (p = 0.005). In addition, Kaplan-Meier analysis demonstrated that patient survival varied significantly according to the scale (p < 0.001 for OS and p = 0.001 for PFS).Conclusion18F-FDG-avid focal lesions and the presence of extramedullary disease on PET/CT scan are significantly associated with poor OS in MM patients. The scale developed according to these predictors represents a potential prognostic tool for evaluation of patients with MM.

Delayed recovery of serum immunoglobulin G is a poor prognostic marker in patients with follicular lymphoma treated with rituximab maintenance.

Clinical trials involving various treatment schedules for rituximab maintenance have been conducted for patients with follicular lymphoma (FL) and have not confirmed their impact on serum immunoglobulin (sIg) levels until the completion of maintenance. However, the long-term use of rituximab is a concern because of circulating plasma cell-depletion risk, suggesting that the mechanism of change in sIg levels after RM has not been determined. Additionally, the relationship between host humoral immunity and the prognosis of patients with B cell malignancies has not been determined. We retrospectively investigated data from 213 patients with FL from a single institute who achieved at least a partial response with rituximab, cyclophosphamide, vincristine, and prednisolone with or without doxorubicin. Of these, 166 patients underwent RM with a median period of 1.6years. A significantly delayed recovery of sIgG levels was observed in the maintenance group until 3years after RM in comparison to the observation group. A multivariate analysis showed that a sIgG level of < 718mg/dl 1year after RM was an independent predictor for poor progression-free survival (PFS) (hazard ratio, 2.3; P = 0.04). Therefore, the sIgG levels scarcely recovered and were significantly delayed after RM, leading to shorter PFS in patients with FL.

Loss of beclin 1 expression in ovarian cancer: A potential biomarker for predicting unfavorable outcomes.

The clinicopathological significance and prognostic value of the expression of proteins associated with autophagy, beclin 1 (BECN1), 1A/1B-light chain 3 (LC3) and high mobility group box-1 protein (HMGB-1), were investigated in patients with ovarian carcinoma, receiving combination chemotherapy with a platinum agent and a taxane. Immunohistochemical staining was performed for autophagy-associated proteins in tumor tissues from 141 patients with ovarian carcinoma. Clinical data were collected retrospectively by reviewing medical charts, and the association between protein expression, clinicopathological features and survival was investigated. Amongst 141 ovarian carcinoma samples, the loss of BECN1, LC3, and HMGB-1 expression was identified in 59 (41.8%), 35 (24.8%), and 66 (46.8%) samples, respectively. Clinicopathological factors were not significantly associated with the loss of BECN1 expression. However, significant associations were demonstrated between the expression of BECN1, LC3, and HMGB-1. In addition, loss of BECN1 expression demonstrated a significant association with poor progression-free and poor overall survival. Multivariate analysis demonstrated that loss of BECN1 expression and postoperative residual tumor were significant independent predictors of poor progression-free survival and poor overall survival. These results indicated that loss of BECN1 expression in ovarian carcinoma is a negative prognosticator in patients receiving platinum-based chemotherapy. Assessment of BECN1 expression may be useful for predicting an unfavorable response to platinum-based chemotherapy in ovarian carcinoma.

The predictive and prognostic values of serum amino acid levels for clear cell renal cell carcinoma

ObjectivesTo investigate the predictive and prognostic values of the logistic regression model based on the serum amino acid levels. Materials and methodsThe study enrolled 42 patients with clear cell renal cell carcinoma (ccRCC) and 66 matched healthy people admitted to PLA General Hospital from April 2015 to June 2015. Serum samples from the 2 groups were analyzed by isobaric tags for relative and absolute quantitation-liquid chromatography-tandem mass spectrometry (iTRAQ-LC-MS/MS) method. Variables of the 2 groups were compared by Student’s t-test or chi-square test. The prediction model was constructed by logistic regression analysis. Oncological outcomes were evaluated by Kaplan-Meier survival analysis and Cox regression analysis. ResultsPathological diagnosis confirmed that all patients had ccRCC. No significant differences were found in the distribution of age, sex, or body mass index between patients with ccRCC and matched healthy people. A total of 32 amino acids were quantitatively analyzed, and serum levels of 23 amino acids were significantly different between the 2 groups. A predictive logistic regression model containing histidine, glutamine, 1-methyl histidine, and norvaline was constructed. Receiver operating characteristic (ROC) curves for all patients with ccRCC and controls, patients with T1 ccRCC and controls, patients with Fuhrman grade 1 to 2 ccRCC and controls, patients with T2 ccRCC and controls, and patients with Fuhrman grade 3 ccRCC and controls were drawn based on the model. The area under the curve values of the 5 receiver operating characteristic curves were 0.878, 0.885, 0.890, 0.830, and 0.788, respectively. Patients with higher model scores (>2) had significantly poorer progression-free survival (PFS) than patients with lower model scores (≤2). Multivariable Cox regression analysis showed that logistic regression model score was an independent predictor of PFS. ConclusionSerum amino acid levels are a potential predictive biomarker for distinguishing patients with ccRCC, especially early T-stage and low Fuhrman grade patients, from healthy people. Serum amino acid levels can also be used in the prognostic evaluation of patients with ccRCC.

Clonal B-Cell Lymphocytosis with Marginal Zone Features and Splenic Marginal Zone Lymphoma Share a Similar Cytogenetic and Mutational Profile

Introduction: Clonal B-cell lymphocytosis with marginal zone features (CBL-MZ) is a non-CLL type B-cell monoclonal lymphocytosis that has been recently recognized in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Whether CBL-MZ corresponds to the early stage of splenic marginal zone lymphoma (SMZL) is not clearly defined. The aim of the study was to compare CBL-MZ and SMZL in patients diagnosed during the same period in two French university hospitals.Methods: We performed a retrospective study including all consecutive patients with a diagnosis of CBL-MZ or SMZL between 2010 and 2014. For the purpose of the present study, all CBL-MZ and SMZL were reclassified according to the 2016 WHO classification. Patient and disease characteristics comprised clinical data, immunophenotyping of lymphocytes by flow cytometry, cytogenetic studies (G-banding and TP53 FISH) and targeted gene sequencing (TP53, NOTCH2 and MYD88). We assessed progression-free survival (PFS), lymphoma-specific survival (LSS), overall survival (OS) and cumulative incidence of histologic transformation.Results: Forty-one patients were diagnosed with CBL-MZ (n=15) or SMZL (n=26) on consensus review. None had HCV infection. Median age was 74 years (range 43-93). At diagnosis, B symptoms (7% vs 46%, p=0.009), elevated lactate dehydrogenase (13% vs 50%, p=0.023) and elevated β2-microglobulin (50% vs 93%, p=0.039) were significantly more frequent in SMZL patients. HPLL score A was more frequent in patient with CBL-MZ (93% vs 58%, p=0.003). On lymphocyte immunophenotyping, CD23 was expressed only in SMZL (0% vs 38%, p=0.015).Aberrant karyotype was displayed in 5/7 CBL-MZ and 15/18 of SMZL (p=0.591). Fourteen patients (56%; 2 CBL-MZ and 12 SMZL, p=0.177) had at least 3 chromosomal abnormalities and were considered to have a complex karyotype. There was no significant difference between CBL-MZ and SMZL for the frequency of detection of +3, +12, +18, del(7q) or 14q alterations. A chromosome 17p abnormality or monosomy 17 was seen in 12/25 patients (48%) without significant difference between CBL-MZ and SMZL, and was confirmed in 11/11 cases by TP53 FISH analysis (one patient had an isochromosome 17q and TP53 FISH was not done). In 11 other patients, no TP53 deletion was detected by FISH. In the 2 remaining patients (one normal karyotype and one abnormal karyotype without abnormal 17p) there was no more material for FISH analysis.TP53 mutation was present in 1/15 (7%) CBL-MZ and 6/22 (27%) SMZL (p=0.161), NOTCH2 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0,632) and MYD88 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0.632).After a median follow-up of 47 months (CBL-MZ, 52 months; SMZL, 46 months, p=0.771), no CBL-MZ patients had event (progression, histologic transformation or death) or started treatment, whereas 24/26 (92%) SMZL patients started a first-line treatment (chemotherapy in 62%, rituximab in 42% and/or splenectomy in 39%). Twelve SMZL patients (50% of treated patients) relapsed or progressed after the first-line treatment. Among them, 6 had histologic transformation, either in diffuse large B-cell lymphoma (DLBCL, n=5) or Hodgkin lymphoma (HL, n=1). Finally, 5 SMZL patients died (3 of DLBCL, 1 of HL, 1 of SMZL).Overall, 4-year PFS was 100% and 31% (95% CI, 13% to 49%) for CBL-MZ and SMZL, respectively (p=0.002); 4-year LSS was 100% and 77% (95% CI, 61% to 93%) for CBL-MZ and SMZL, respectively (p=0.26); and 4-year OS was 100% and 71% (95% CI, 54% to 88%) for CBL-MZ and SMZL, respectively (p=0.25).Clinical, laboratory, cytogenetic and molecular features were subjected to univariate analyses to evaluate their impact on PFS, LSS, OS and histologic transformation in SMZL patients. In univariate analysis for PFS, only NOTCH2 mutations and TP53 inactivation (i.e. del(17p) or TP53 mutations) predicted poorer PFS, but in multivariate analysis NOTCH2 mutations were the sole factor significantly affecting PFS rates (p=0.041). For LSS, OS and histologic transformation, no prognostic factor was identified in univariate analysis.Conclusions: Our data suggest that CBL-MZ and SMZL share a similar cytogenetic and mutational profile. These findings suggest the possible involvement of a common oncogenic mechanism in the development of these lymphoid neoplasms. DisclosuresHermine:Novartis: Research Funding; Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Research Funding.

Aneuploidy of chromosome 8 in circulating tumor cells correlates with prognosis in patients with advanced gastric cancer.

ObjectivePrevious work indicated that aneuploidy of chromosome 8 in circulating tumor cells (CTCs) correlated with therapeutic efficacy for advanced gastric cancer (AGC) patients. In this follow-up study performed on the same population of AGC patients, we investigated whether and how aneuploidy of chromosome 8 in CTCs correlates with patients’ clinical prognosis.MethodsThe prospective study was performed on 31 patients with newly diagnosed AGC. Previously established integrated subtraction enrichment (SE) and immunostaining-fluorescence in situ hybridization (iFISH) platform was applied to identify, enumerate and characterize CTCs. Quantification of CTCs and analysis of their aneuploidy of chromosome 8 were performed on patients before and after therapy. ResultsCTCs were measured in 93.5% of AGC patients, and two CTC subtypes with diverse threshold values were identified, multiploid CTCs with the threshold of ≥2 per 7.5 mL and multiploid plus triploid CTCs with the threshold of ≥4, which were found to significantly correlate with poor progression-free survival (PFS) and overall survival (OS). In particular, patients with ≥10% increased multiploid CTCs after an initial 6 weeks of therapy had poor PFS and OS, whereas improved PFS and OS were observed on those who had ≥10% decreased multiploid CTCs. After adjusting for clinically significant factors, ≥10% increased post-therapy multiploid CTCs was the only independent predictor of PFS and OS.ConclusionsAneuploidy of CTCs correlates with prognosis of AGC patients. Quantitative comparison monitoring multiploid CTCs before and after therapy may help predict improved or inferior prognosis and chemoresistance.

FDG PET/CT metabolic tumor volume and total lesion glycolysis predict prognosis in patients with advanced lung adenocarcinoma

We investigated fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT)-assessed metabolic tumor volume (MTV) and total lesion glycolysis (TLG) as prognostic factors in lung adenocarcinoma patients. This retrospective study included 106 patients (19 stage I/II and 87 stage III/IV lung adenocarcinoma) who underwent FDG PET/CT before treatment. Standardized uptake value (SUV), MTV, and TLG (MTV×mean SUV) of each malignant lesion were measured. Whole MTV and whole TLG were the summation of all the MTV and TLG values in each patient. Survival analysis and FDG PET/CT parameters regarding epidermal growth factor receptor (EGFR) gene mutation status were evaluated. Univariate survival analysis of stage III/IV patients identified high whole MTV (≥90), high whole TLG (≥600), and stage IV as significant predictors of poor progression-free survival. For overall survival, high whole MTV (≥90), high whole TLG (≥600), EGFR mutation-negative, and stage IV were significant poor prognostic predictors. After multivariate survival analysis, high whole MTV (P=0.001), high whole TLG (P=0.027), and stage IV (P=0.006) were independent predictors of poor progression-free survival. High whole MTV (P<0.001), high whole TLG (P=0.001), and EGFR mutation-negative (P=0.001) were independent prognostic predictors for poor overall survival. In a survival analysis of stage I/II patients, none was an independent prognostic predictor. No significant differences were found in FDG PET/CT parameters for EGFR mutation-negative and EGFR mutation-positive patients. Assessment of MTV and TLG by FDG PET/CT in advanced lung adenocarcinoma patients provides useful information regarding prognosis.

Up-regulation of miR-9 expression as a poor prognostic biomarker in patients with non-small cell lung cancer

Emerging evidences indicate that dysregulated microRNAs are implicated in cancer tumorigenesis and progression. MicroRNA-9 (miR-9) has various expression patterns in diverse human cancers. However, its clinical significance in human non-small cell lung cancer has not yet been elucidated. In the present study, we detected the expression of miR-9 in non-small cell lung cancer and adjacent noncancerous tissues and explored its relationships with clinicopathological characteristics and prognosis. Expression levels of miR-9 in 116 pairs of non-small cell lung cancer and adjacent normal tissues were detected by real-time quantitative RT-PCR assay. To determine its prognostic value, overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. MiR-9 expression in non-small cell lung cancer tissues was significantly higher than that in adjacent normal tissues (p = 0.001), and its up-regulation was significantly correlated to advanced tumor-node-metastasis (TNM) stage (p < 0.001), tumor size (p = 0.013), and lymph node metastasis (p = 0.001). Furthermore, Kaplan-Meier analysis demonstrated that high miR-9 expression clearly predicted poorer PFS (p < 0.001) and OS (p < 0.001). In the multivariate analysis, increased miR-9 expression was an independent prognostic factor for both PFS (p = 0.002) and OS (p = 0.013). MiR-9 was up-regulated in non-small cell lung cancer tissues and correlated with adverse clinical features and unfavorable survival, indicating that miR-9 might be involved in non-small lung cancer progression and could serve as a promising biomarker for further risk stratification in the treatment of this cancer.

Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPO-I, TOPO-iia, TOPO-iib, and c-MYC genes in patients with small cell lung cancer (SCLC) who received first-line therapy with cisplatin and etoposide.

7594 Background: to evaluate the predictive value of genes correlated with cisplatin-etoposide (EP) metabolism or mode of function in patients with SCLC. Methods: Tumor samples from 184 patients, with SCLC were analyzed for ERCCI, BRCA1, ATP7B, TOPOI, TOPOIIA, TOPOIIB PKM2 and C-MYC mRNA expression by quantitative real-time PCR, from microdissected cells derived from patients’ primary tumors. All patients were treated with EP (plus radiotherapy for patients with limited disease-LS) in the department of Medical Oncology of the University Hospital of Heraklion. Results: The median age of the patients was 63 years (min-max: 33-78). One hundred-twenty (65%) patients presented with extended stage (ES), LDH was above the UNL in 75 (41%), while ECOG performance status was 0-1 in 131 (71%) of them. Shorter progression free survival (PFS) was observed in patients with LS-SCLC whose tumors expressed high ERCC1 (p=0.028), PKM2 (p=0.046), TOPO-I (p=0.008), TOPO-IIA (p=0.002) and TOPO-IIB (p&lt;0.001) expression. High expression of ERCC1 (p=0.014), PKM2 (p=0.026), TOPO-IIA (p=0.021) and TOPO-IIB (p=0.019) was correlated with shortened median overall survival (OS) in LS-SCLC patients. In patients with ES-SCLC, only high TOPO-IIB expression was associated with decreased OS (p=0.035). The favorable genotype (low expression of ERCC1, PKM2, TOPO-IIA and TOPO-IIB) was correlated with significantly improved PFS in both LS-SCLC (p&lt;0.001) and ES-SCLC (p=0.007) patients as well as with improved OS in the LS-SCLC (p=0.007) and ES-SCLC (p=0.011) group. Unfavorable genotype was independent predictor of poor PFS (HR: 3.18; p=0.002) and OS (HR: 4.35; p=0.001) in LS-SCLC as well as for both PFS (HR: 3.14; p=0.021) and OS (HR: 3.32; p=0.019) in ES-SCLC. Conclusions: Single gene’s expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPO-IIA and TOPO-IIB may predict treatment outcome in patients with SCLC. The results of our study, if validated prospectively, may help in selecting patients for personalized therapeutic strategies.

AIB1 predicts bladder cancer outcome and promotes bladder cancer cell proliferation through AKT and E2F1

Background:We previously demonstrated that AIB1 overexpression is an independent molecular marker for shortened survival of bladder cancer (BC) patients. In this study, we characterised the role and molecular mechanisms of AIB1 in BC tumorigenicity.Methods:AIB1 expression was measured by immunohistochemistry in non-muscle-invasive BC tissue and adjacent normal bladder tissue. In addition, the tumorigenicity of AIB1 was assessed with in vitro and in vivo functional assays.Results:Overexpression of AIB1 was observed in tissues from 46 out of 146 patients with non-muscle-invasive BC and was an independent predictor for poor progression-free survival. Lentivirus-mediated AIB1 knockdown inhibited cell proliferation both in vitro and in vivo, whereas AIB1 overexpression promoted cell proliferation in vitro. The growth-inhibitory effect induced by AIB1 knockdown was mediated by G1 arrest, which was caused by reduced expression of key cell-cycle regulatory proteins through the AKT pathway and E2F1.Conclusion:Our results suggest that AIB1 promotes BC cell proliferation through the AKT pathway and E2F1. Furthermore, AIB1 overexpression predicts tumour progression in patients with non-muscle-invasive BC.

Decreased expression of microRNA-31 associates with aggressive tumor progression and poor prognosis in patients with bladder cancer

MicroRNA-31 (miR-31) has different expression patterns in various human cancers. Especially in urothelial carcinoma of the bladder, it has been demonstrated to be decreased expression in the invasive tumors and homozygously deleted. However, its clinical significance in human bladder cancer has not yet been elucidated. Thus, the purpose of this study was to investigate the diagnostic and prognostic values of miR-31 in this disease. Expression levels of miR-31 in 126 pairs of bladder cancer and adjacent normal tissues were detected by real-time quantitative RT-PCR assay. To determine its prognostic value, overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. MiR-31 expression in bladder cancer tissues was significantly lower than those in adjacent normal tissues (mean expression level: 2.1 ± 0.9 vs. 3.8 ± 1.2, P < 0.001). When categorized into low vs. high expression, low miR-31 expression was negatively associated with the tumor stage (P = 0.02), the status of recurrence (P = 0.01), progression (P = 0.01), and death (P = 0.006) of patients with bladder cancer. Moreover, low miR-31 expression clearly predicted poorer PFS (P = 0.001) and OS (P < 0.001). In the multivariate analysis, low miR-31 expression was an independent prognostic factor for both PFS (P = 0.01) and OS (P = 0.008). These findings show that miR-31 may contribute to the progression of bladder cancer and its downregulation may be independently associated with unfavorable PFS and OS, suggesting that miR-31 might be a promising marker for further risk stratification in the treatment of this cancer.

Reduced expression of microRNA-100 confers unfavorable prognosis in patients with bladder cancer

ObjectiveMicroRNA-100 (miR-100) has been demonstrated to be downregulated in bladder cancer tissues, and enforced expression of this miRNA may inhibit cell growth and colony formation of human bladder cancer 5637 cells in vitro. However, the clinical significance of miR-100 in human bladder cancer has not yet been elucidated. Thus, the aim of this study was to investigate the diagnostic and prognostic values of miR-100 in this disease.MethodsExpression levels of miR-100 in 126 pairs of bladder cancer and adjacent normal tissues were detected by TaqMan real-time quantitative RT-PCR assay. In order to determine its prognostic value, overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis.ResultsExpression levels of miR-100 in bladder cancer tissues were significantly lower than those in adjacent normal tissues (mean expression level: 2.6 ± 1.2 vs. 3.9 ± 1.5, P < 0.001). When categorized into low vs. high expression, low miR-100 expression was negatively associated with the stage (P = 0.01), the recurrence (P = 0.008), the progression (P = 0.01), and the death (P < 0.001) of patients with bladder cancer. Moreover, low miR-100 expression clearly predicted poorer PFS (P = 0.001) and OS (P < 0.001). In the multivariate analysis, low miR-100 expression was an independent prognostic factor for both PFS (P = 0.01) and OS (P = 0.008).ConclusionOur data offer the convincing evidence that miR-100 may play an important role in the progression of bladder cancer and that the reduced expression of this miRNA may be independently associated with shorter PFS and OS of patients, suggesting that miR-100 might be a potential marker for further risk stratification in the treatment of this cancer.Virtual slidesThe virtual slides’ for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1105483419841671

Circulating tumor cells in metastatic breast cancer: Are they a strong and independent predictor of poor progression-free and overall survival?

1090 Background: Circulating tumor cells (CTCs) are detected in 30–60% of patients with metastatic breast cancer (MBC). The aim of this prospective multi-center study was to evaluate the impact of CTCs on progression free survival (PFS) and overall survival (OS) in a large cohort of 486 patients with progressive metastatic disease. Methods: CTC levels were determined for 486 patients at nine German University Breast Cancer Centers between 12/2007 and 06/2011. Samples of 7.5 ml blood were taken before initiation of a new line of therapy and CTCs were enumerated using the CellSearch System (Veridex LLC, Raritan, NJ, USA). CTC status (≥ 5 CTCs vs. &lt; 5 CTCs per 7.5 ml blood) was assessed as a prognostic factor for PFS and OS using univariate (log-rank test) and multivariate (Cox regression model) statistical methods. Results: CTCs were detected in 205/486 (42%) patients. The median CTC count was 2 (range 0–6380) per 7.5 ml blood. The presence of ≥ 5 CTCs/7.5 ml blood did not correlate with any of the established clinicopathological factors except estrogen receptor status (p = 0.038). PFS and OS were both significantly shorter in patients with ≥ 5 CTCs/7.5 ml than in those with &lt; 5 CTCs/7.5 ml blood. PFS was 5.0 [95% CI 4.1–5.8] months vs.7.6 [95% CI 5.9–9.3] months, p &lt; 0.001; and OS was 15.0 [95% CI 13.5–16.5] months vs. 18.3 [95% CI 17.4–19.2] months, p &lt; 0.001. In the multivariate analysis considering all clinicopathological factors and the CTC status, independent predictors of reduced OS and PFS were site of metastasis (visceral vs. bone), number of metastatic sites (multiple sites vs. one site), and CTC status. Conclusions: The presence of ≥ 5 CTCs/7.5 ml blood is a strong and independent predictor of poor PFS and OS in patients with MBC.

Abstract 2460: Extracellular matrix protein expression is associated with chemotherapy resistance in breast cancer

Abstract Extracellular matrix protein expression is associated with chemotherapy resistance in breast cancer Purpose: Biomarkers to predict sensitivity and resistance to chemotherapy are still lacking. A recent study reported that stromal gene signatures in breast cancer may predict chemoresistance. We aim to determine the changes of 5 extracellular matrix (ECM) proteins in response to neoadjuvant chemotherapy in breast cancer. Experimental design: 100 female patients with locally advanced or metastatic breast cancer were treated with 6 cycles of pre-operative alternating sequential doxorubicin and docetaxel. Immunohistochemistry staining for thrombospondin 1 (THBS1), tenascin C (TNC), fibronectin (FN), smooth muscle actin-α (α-SMA) and secreted protein acidic and rich in cysteine (SPARC) was performed on pre- and post-treatment core biopsies, and correlated with estrogen receptor status, intrinsic chemotherapy response, pathological lymph node involvement and survival. Changes in THBS1 and TNC in relation to chemoresponse was additionally evaluated with mass spectrometry, and further validated with immunohistochemistry in an independent cohort of 31 breast cancer patients. Results: High baseline THBS1 and SPARC and high post-treatment α-SMA expression were associated with poor overall survival (p&amp;lt;0.05 for each marker). High expression of combined baseline ECM proteins was an independent predictor for poor progression-free survival (HR 2.22, 95% CI 1.06-4.64, p=0.034) and overall survival (HR 5.94, 95% CI 2.25-15.71, p&amp;lt;0.001). After 1-2 cycles of chemotherapy, increased expression of THBS1 and TNC compared to baseline was seen in intrinsically resistant tumors (p&amp;lt;0.05 for both), and in patients with pathological lymph node involvement (p&amp;lt;0.05 for both), but not in sensitive ones. Mass spectrometric analyses revealed &amp;gt;2 fold increase in THBS1 and TNC expression compared to baseline in tumors that were intrinsically resistant to doxorubicin relative to sensitive ones. The association between THBS1 and TNC immunohistochemistry changes and chemotherapy resistance was confirmed in the validation cohort. Conclusions: Up-regulation in ECM proteins after chemotherapy was associated with clinical and pathological response to doxorubicin- and docetaxel-based neoadjuvant chemotherapy in breast cancer. Assessment of these proteins may uncover strategies to overcome drug resistance. Key words: ECM proteins, neoadjuvant chemotherapy, breast cancer, drug resistance Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2460. doi:1538-7445.AM2012-2460