Os Values Research Articles

Neoadjuvant Folfiri+Bevacizumab in resectable liver metastases from CRC: results and comparison of PET/CT scan vs RECIST in predicting outcome

Background: Preoperative treatment of resectable liver metastases from CRC is an hot topic.The aims of this study were to test the feasibility and activity of Bevacizumab+FOLFIRI in this setting and to explore the role of PET/CT in predicting the efficacy of treatment and to compare it to the standard RECIST response. Methods: A single-arm phase 2 study design enrolling 39 patients was applied with 1-year PFS as primary end point. PET/CT was performed before and after 1 cycle of treatment. For each lesion a ≤ -50% change from baseline was used as threshold for significant metabolic response for maximum SUV.RECIST response was assessed with CT after 3 months of treatment.The association between metabolic and CT/RECIST and pathologic response(PR) was tested as well as the ability to predict PFS and OS. Results: Response rate was 66.7%. 37 patients (94.9%) were operated with a R0 rate of 84.6%. 5 patients had a complete PR(14%). At 1 year 24 patients were alive and free from disease(61.6%).Median PFS and OS were 14 and 38 months. Early metabolic PET/CT response had a stronger, independent and statistically significant predictive value for PFS and OS than both CT/RECIST and PR at multivariate analysis. Conclusion: Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible. PET/CT response was significantly predictive of long-term outcomes during preoperative treatment and its predictive ability was higher than that of CT/RECIST response after 3 months of treatment.

Prognostic Value of Radiomics Signature By Diagnostic 18F-FDG PET/CT Analysis in Aggressive Non-Hodgkin's Lymphoma

BACKGROUNDAlthough the overall prognosis of patients with aggressive non-Hodgkin's lymphoma (NHL) has improved, nearly a third of patients will have refractory disease or relapse. Identification of these high-risk patients using traditional prognostic factors is limited. PET is the recommended imaging modality for the staging of FDG-avid lymphoma but the value of a comprehensive new imaging biomarkers analysis applied to PET for the prediction of patients outcome has still not been deeply investigated.New metrics estimating the overall tumor burden such as metabolic tumor volume (MTV) and those that may capture intratumoral biological heterogeneity such as total lesion glycolysis (TLG) have been used to predict progression-free survival.AIMThe goal of the present work was to characterize Lymphoma lesions by extracting several metabolic volume and textural properties as radiomics features and evaluate their performance as surrogate indicators of the number of treatment cycles, and treatment response.Materials and methodsIn this retrospective, observational study, we included aggressive non-Hodgkin's lymphoma patients consecutively diagnosed according to the WHO 2016 between January of 2015 to December of 2017. A diagnostic PET/CT scan were essential. 1 patient without treatment was excluded. Clinical and biological data were extracted from medical records.PET/CT examinations were exported from the PACS and loaded into QUIBIM Precision 2.3 analysis platform (QUIBIM, Valencia, Spain) for the calculation of metabolic volumes and textural properties. The SUV values of the PET images were normalized to the average liver SUV, and the lesions were automatically segmented considering a threshold of 41% of the maximum SUV (SUVmax). Physiological uptakes in organs and tissues like bowel, bladder, brain, among others, were manually removed. In the lesions volumetry analysis, the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. For the extraction of texture features, first order histogram descriptors (SUV values distribution, skewness, kurtosis) as well as second order descriptors were extracted after computing the Gray-Level Co-Occurrence Matrix (GLCM).For the statistical analysis, the Z-score of all imaging features obtained was calculated and a multi-variate analysis was performed by first calculating the intra-class correlation (ICC) to reduce redundant variables. Second, data hierarchy clustering was applied to automatically obtain patient groups according to different imaging signatures. The prognostic performance of IPI with and without the imaging signature was evaluated by a Discriminant Analysis for the number of treatment cycles and treatment response. Prognostic value of OS was performed through Kaplan-Meier analysis.ResultsA total of 41 patients were included. The descriptive analysis of patients recruited with demographic and clinical data can be appreciated in Table 1. Radiomics features extracted allowed to clusterize patients in different groups that were later introduced in the classifier (Figure 1). The classifier based on discriminant model including the IPI factors predicted number of treatment cycles with a 65.9% of accuracy, being the age the factor with the highest weight (0.818). Adding information about imaging features from PET increased the accuracy to 86.5%. For the treatment response assessment, the IPI factors predicted response correctly in 71.4% of cases, being ECOG the parameter with the highest weight (0.974). Prediction was fully accurate when adding the imaging features, with a 100% of accuracy. The texture feature with the highest importance was ‘dissimilarity’ of the pixels (weight of 15.919).ConclusionThe addition of radiomics features to the conventional IPI evaluation of patients allows for a significant increase in predictive performance, both for determining which patients will have more than 1 treatment lines and those who will respond to treatment. The results of this study would have an impact in disease management with a combined IPI and radiomics-based prognostic evaluation of patients at diagnosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Effect of the Interaction between Salicylic Acid and Geographical Locations on Grapefruit Essential Oil

Essential oil of grapefruit used in various food and drug industries. Previous investigators indicted that salicylic acid and different locations had a significant role in essential oil production. Essential oil production is one way to utilize the reclaimed areas in Egypt. In this study, the effects of salicylic acid on grapefruit essential oil were evaluated in reclaimed and old areas of Egypt. Grapefruit trees were exposed to salicylic acid foliar spray at 0, 20 and 40 mg L-1 in Nubaria (reclaimed area) and Giza (old area). Data were statistically analyzed using 2-way analysis of variance (ANOVA-2). The highest amounts of essential oil extracted from young shoots or peels (0.3 % and 1.3 %) were recorded at 20 mg L-1 salicylic acid in Nubaria and Giza respectively. According to GC/MS analysis, sabinene (39.3 - 43.5 %), limonene (15.9 - 20.0 %) and terpinen- 4-ol (17.1 - 19.8 %) were detected as the major constituents of young shoot oil in both locations while limonene (73.1 - 78.9 %), β-myrcene (3.5 - 4.3 %) and octanal (2.9 - 5.3 %) were the major compounds in peel oil. The highest values of main components for young shoots (sabinene, 43.5 %; limonene; 20.0 %; terpinen-4-ol, 19.8 %) and peel oils (limonene, 78.9 %; octanal, 5.3 %) were recorded at 40 mg L-1 salicylic acid in the location of Nubaria except the component of β-myrcene (4.3 %) that recorded the highest value with Giza location x 40 mg L-1 salicylic acid. Salicylic acid x various locations produced highly significant changes (P < 0.001) in OM and SH and moderate significant (P < 0.01) in MH and insignificant in OS of essential oil extracted from young shoots. Regarding to the variations in the chemical classes of peel oil, it was found that the changes in MH, OM and SH were insignificant for the interactions between salicylic acid and both locations but the changes in OS were significant (P < 0.05). The highest amounts of chemical classes of young shoots oil such as MH (71.9 %) OM (27.1 %) and SH (3.9 %) were obtained from Nubaria location with salicylic acid at 40, 20 and 0.0 mg L- 1 respectively. The treatment of 20 mg L-1 (salicylic acid) x Nubaria location resulted in the greatest value of OS (0.7 %) of peel oil.

Effects of metformin treatment on radiotherapy efficacy in patients with cancer and diabetes: a systematic review and meta-analysis

PurposeMetformin is a key pharmaceutical for patients with diabetes mellitus (DM). Metformin also can enhance tumor radiosensitivity in vitro and in vivo. Some retrospective cohort studies have indicated that metformin can improve the efficacy of radiotherapy in patients with cancer and DM. The aim of this systematic review was to evaluate the radiotherapy efficacy of metformin in patients with cancer and DM.MethodsMultiple databases were queried for studies that address the efficacy of metformin in radiotherapy of patients with cancer and DM. Studies were included that involved comparisons of the short-term tumor responses and long-term survival outcomes of these patients who were managed with or without metformin as well as of nondiabetic patients without metformin. The OR and HR with accompanying 95% CI were assessed in a random effects model. The main endpoints were 2-year and 5-year overall survival (2y-OS and 5y-OS, respectively).ResultsThe database search yielded 17 cohort studies that met the inclusion criteria. The results indicated that the tumor response was higher in patients who also were treated with metformin than in those who were not (OR, 0.48; 95% CI, 0.22–1.07; P=0.07) and nondiabetic (OR, 0.27; 95% CI, 0.07–0.98; P=0.05). Moreover, patients who received metformin had survival benefits compared with patients not treated with metformin (2y-OS: OR, 0.48; 95% CI, 0.29–0.80; P=0.005; 5y-OS: OR, 0.38; 95% CI, 0.25–0.56; P<0.00001). The metformin-related HRs of OS values were not significantly different.ConclusionMetformin appears to improve the tumor response to radiotherapy in patients with cancer and DM and partly yield survival benefits. Despite the apparent advantages provided by metformin treatment on 2y-OS and 5y-OS, these retrospective data are at risk of bias and should be interpreted with caution.

The Impact of Chemotherapy on Survival of Patients with Extremity and Trunk Wall Soft Tissue Sarcoma: Revisiting the Results of the EORTC-STBSG 62931 Randomised Trial Using Sarculator, a Validated Nomogram-Based Risk Assessment Tool

BACKGROUND: To determine whether patients with high-risk soft tissue sarcoma (STS), as identified using the nomogram Sarculator, benefitted from adjuvant chemotherapy in the EORTC-STBSG 62931 randomised controlled trial (RCT) which failed to detect an impact for adjuvant doxorubicin plus ifosfamide (Adj) over observation (Obs). METHODS: A retrospective analysis of the EORTC-STBSG 62931 RCT was performed on individual patient data of study participants with extremity and trunk wall STS (N=290/351). 10-year predicted probability of overall survival (pr-OS) was calculated using the prognostic nomogram Sarculator. Patients were grouped in three categories of predicted pr-OS: high (pr-OS > 66%), intermediate (51< pr-OS ≤ 66), and low (pr-OS ≤ 51%). OS and disease-free survival (DFS) were calculated at the study median follow-up (8-year). FINDINGS: Nomogram pr-OS were dispersed (median 72%, IQR 57-83%) and had prognostic value for OS and DFS (Log-Rank test: P<0·001). 170 patients had high pr-OS (58·6%, 90 Obs/80 Adj), 68 intermediate (23·5%, 34 Obs/34 Adj) and 52 low (17·9%, 24 Obs/28 Adj). Adjuvant chemotherapy halved the risk of recurrence (HR=0·46, 95%CI 0·24-0·89) and death (HR=0·46, 95%CI 0·23-0·94) in the low pr-OS category, while no effect was detected in the intermediate and high pr-OS categories. In order to strengthen these findings, study participants with predicted pr-OS<60% were combined (N=80, 27·6%, 39 Obs/41 Adj) and a significant benefit in terms of DFS (HR=0·49, 95%CI 0·28-0·85) and OS (HR=0·50, 95%CI 0·30-0·90) was detected. INTERPRETATION: Patients of the EORTC-STBSG 62931 RCT with extremity and trunk wall STS and a low predicted pr-OS (i.e., high-risk patients) had a better outcome when treated with adjuvant chemotherapy. This may help reconcile the somewhat disparate results of published clinical studies on adjuvant/neoadjuvant chemotherapy in high/risk STS. Funding Statement: This was an academic non-funded study. The EORTC-STBSG 62931 trial was funded by European Organisation for Research and Treatment of Cancer (EORTC) and Rhone-Poulenc-Rorer. Declaration of Interests: The authors declare they have no conflicts of interest. Ethics Approval Statement: The protocol of the EORTC-STBSG 62931study was approved by the EORTC Protocol Review Committee and institutional review boards. The patients gave informed consent according to applicable laws in all participating countries. The current study was approved by EORTC through the ‘Request for data platform’.

Prognostic significance of neutrophil-lymphocyte ratio in multiple myeloma patients

Background: Increased neutrophil-to-lymphocyte ratio (NLR) has been proposed to predict poor prognosis in many cancer types. However, the prognostic value of NLR in multiple myeloma (MM) remains largely unknown. This study aimed to investigate whether NLR is an independent predictor of MM. Methods: Data were collected retrospectively from 136 patients who were diagnosed with MM and subjected to bortezomib-thalidomide-dexamethasone chemotherapy at the Nanjing Drum Tower Hospital from 2008 to 2016. The association between NLR and clinical characteristics was evaluated. The prognostic value of NLR was investigated by Kaplan-Meier and Cox proportional hazards method. All statistical tests were two-sided. Results: The cutoff value of NHL was set at 2. The OS and progression-free survival (PFS) of the patients with high NLR were shorter than those with low NLR (χ²=6.503, P=0.014 and χ²=6.087, P=0.011 respectively). Multivariate analysis further showed that increased NLR was an independent predictive value of poor OS [hazard ratio (HR)=0.098, 95% confidence interval (CI): 0.012–0.783, P=0.028] and PFS (HR=0.052, 95% CI=0.005–0.596, P=0.018). Conclusions: NLR can be used as an independent prognostic predictor of MM.

Coupled Re-Os and U-Pb geochronology of the Tonian Chuar Group, Grand Canyon

Well-preserved strata of the late Tonian Chuar Group exposed in the Grand Canyon host fossil evidence for the development of eukaryotic predation, the presence of unique biomarkers, and large changes in C, S, and Mo isotope chemostratigraphy. Despite the importance of this critical succession, few radioisotopic age constraints are available to place these records into a global context. Here, we couple high-precision U-Pb chemical abrasion−isotope dilution−thermal ionization mass spectrometry (CA-ID-TIMS) on zircon crystals with the rhenium-osmium (Re-Os) sedimentary and sulfide geochronometer to refine the temporal framework of this pivotal interval of Earth history. Zircons recovered from a tuff within the uppermost Walcott Member of the Kwagunt Formation yield a weighted mean 206Pb-238U age of 729.0 ± 0.9 Ma (mean square of weighted deviates [MSWD] = 0.86), differing significantly from the previous air-abrasion upper-intercept age of 742 ± 6 Ma on zircons from this same horizon. Organic-rich carbonates from the Carbon Canyon Member of the Galeros Formation yield a model 1 Re-Os age of 757.0 ± 6.8 Ma (MSWD = 0.47, n = 8), and an initial Os isotope (187Os/188Os [Osi]) composition of 1.13 ± 0.02. The radiogenic Osi value from this horizon suggests that the basin was restricted from the open ocean during deposition of the Carbon Canyon Member, in agreement with sedimentological and stratigraphic data. The Re-Os geochronology of marcasite (FeS2) nodules from the Awatubi Member of the Kwagunt Formation yield a model 1 age of 751.0 ± 7.6 Ma (MSWD = 0.37, n = 5), with an Osi of 0.44 ± 0.01. This Re-Os date is interpreted to constrain the growth of the marcasite nodules in the Awatubi Member during deposition. The formation of sulfides and the less radiogenic Osi value are consistent with an influx of sulfate-laden seawater to the basin during deposition of the Kwagunt Formation. Attempts to apply the Re-Os geochronometer to the Walcott and Tanner Members of the Chuar Group failed to yield meaningful ages, despite elevated Re enrichments (>20 ng/g). The Re-Os data from these units yielded negative Osi values, which suggest disturbance to the Re-Os system. The low Os abundances (typically <100 pg/g) relative to the amount expected based on the elevated Re abundances suggest leaching of Os due to oxidative weathering on geologically recent time scales. Finally, the Carbon Canyon Member provides a useful case study for quantifying how input uncertainties in the Re-Os geochronometer propagate into the resulting age uncertainty, and we discuss the protocols that will yield the best improvement in age precision for future studies. The U-Pb and Re-Os geochronology presented here illustrates the power of coupling these systems and the importance of recent improvements in both methods. Our analysis suggests that for our data, the most efficient way of reducing uncertainties in the presented Re-Os dates is through improved precision of measured Os values.

P3.17-001 The Prognostic Analysis of Postoperative Radiotherapy for Esophageal Squamous Cell Carcinoma with Different Status of Lymph Node Metastasis

Lymph node metastasis is a significant prognostic factor in patients with resected esophageal cancer. Although the role of postoperative radiotherapy has not been confirmed, a large number of studies have shown that postoperative radiotherapy can improve the local control and survival, especially for stage III and lymph node positive patients. This study retrospectively analyzed the prognostic factors of postoperative radiotherapy for locally advanced esophageal squamous cell carcinoma (ESCC), and evaluated the prognostic value of different status of lymph node metastasis. Data from 121 patients with locally advanced ESCC who underwent radical resection and received postoperative radiotherapy from 2006 to 2013 were reviewed retrospectively. OS and DFS were estimated using Kaplan-Meier. Univariate analysis and multivariate analysis were performed to investigate prognostic factors by the Log-rank test and the Cox regression model. The effects of different status of lymph node metastasis on OS and recurrence patterns were compared. The median DFS of all patients was 22.57 months, and median OS was 32.90 months. Multivariate analysis showed that Karnofsky Performance Status, length of tumor and positive lymph nodes ratio (LNR) were independent prognostic factors of DFS and OS. For patients with lymph nodes metastasis, LNR has better prognostic value for OS (AUC=0.673, P =0.04) compared with the number of positive lymph nodes (AUC=0.584 P=0.31). The median OS of patients with LNR≤ 15% and LNR>15% were 33.43 and 19.20 months, P =0.04. Patients without lymph node skip metastasis (NSM) had better OS than that with NSM, but the difference was not statistically significant. Among the patients with both LNR>15% and NSM, OS was significantly worse than other lymph node positive patients, with median OS of 14.33 vs. 32.50 months, P=0.02. The analysis of the treatment failure patterns showed that more distant metastases were observed in patients with LNR>15%, while more local and regional recurrences were observed with LNR≤15%. The status of lymph node metastasis was related to the prognosis of postoperative radiotherapy for locally advanced ESCC. LNR has better prognostic value for OS, treatment failure patterns varied in different LNR. The patients with both high LNR and NSM have significantly poorer prognosis.

Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab. We analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R-CHOP-like regimen. There was a significant association between a low LMR (≤ 2.6) and shorter overall survival (OS; P<.001) and progression-free survival (PFS; P< .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P< .001) and PFS (P< .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse. The LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups.

Nomogram for predicting overall survival (OS) in patients (pts) treated with nab-paclitaxel (nab-P) plus gemcitabine (Gem) or Gem alone for metastatic pancreatic cancer (MPC).

4109 Background: Prognostic nomograms have been developed in various cancers, including ovarian, breast, and gastrointestinal; however, there is limited information on nomograms in MPC. The large, phase 3 MPACT study of nab-P + Gem vs Gem alone for the treatment of MPC provides a robust database for the development of a nomogram to predict OS using baseline patient variables. Methods: A multivariable Cox model was created from MPACT data using factors that were significantly predictive of OS in univariable analysis or considered clinically important (stepwise selection to remain in model). From the Cox model, a nomogram was derived that assigned points equal to the weighted sum of relative significance of each variable. The nomogram was internally validated using bootstrapping, a concordance index (c-index), and calibration plots. Results: Data from all 861 pts were used. Seven of the 34 considered variables were retained in the multivariable analysis (Table; all factors significant at the P &lt; 0.01 level, except for analgesic use [ P = 0.07]). The resulting nomogram was able to distinguish low (n = 216), medium (n = 430), and high (n = 215) risk groups (c-index: 0.69; CI: 0.67-0.71) with median OS values of 12.9, 8.2, and 3.7 months, respectively. Calibration curves showed that the nomogram’s predicted probabilities were mostly consistent with observed probabilities for 6-, 9-, and 12-month OS. Conclusions: Treatment arm, Karnofsky performance status (KPS), neutrophil-to-lymphocyte ratio (NLR), albumin level, sum of longest tumor diameters (SLD), and presence of liver metastasis were the key predictors of OS. This nomogram, which will be presented in visual format in the final presentation, may help physicians and pts make informed treatment decisions. Clinical trial information: NCT00844649. [Table: see text]

Measurements of Lα, Lβ, Lγ and M X-ray production cross sections of Os, Ir and Pt by low-energy electron impact: Comparisons of experiment with theory

Experimental determinations of Lα, Lβ, Lγ and M X-ray production cross sections and their ratios for Os (Z=76), Ir (Z=77) and Pt (Z=78) by electron impact at incident energies of 6–30keV are presented. Thin films of the studied elements deposited on thick carbon substrates were employed as targets in the experiments. Enhancements in L- and M-shell characteristic X-ray production due to electron-scattering effects in the double-layer structure target were corrected by means of Monte Carlo simulations. Comparisons were made between the measured Lα, Lβ, Lγ and M X-ray production cross sections and their ratios with the DWBA and PWBA-C-Ex theories and with other experimental data in the literature. In the case of L-subshells, the measured data of Os and Pt agree well with the theoretical values within the experimental uncertainties, but appreciable discrepancies between the experiment and theory exist for Ir; in the case of the M-shell, measured data for Ir show good agreement with theoretical values within the experimental uncertainties, but the measured results are somewhat lower than the theoretical values for Os and Pt. Finally, possible factors that could affect the comparisons between experiment and theory on cross-section ratios are discussed.

Ceritinib in anaplastic lymphoma kinase-positive nonsmall cell lung cancer among patients who were previously exposed to crizotinib: Experience from the Indian subcontinent.

Ceritinib is a novel ALK inhibitor approved for advanced stage NSCLC with ALK gene rearrangement, progressed and/or intolerant to crizotinib. 13 patients were included in our study who received ceritinib. Majority of them were women and never smokers with a median age of 47 yrs. Nearly half of them had a compromised performance status and received ceritinib in third line and beyond. Ceritinib showed nearly 50% response rates. With a median follow up of 9 months for the entire cohort, median PFS and OS were not reached. However, the mean values for PFS and OS were 10.9 and 14.8 months,with an estimated 1 year PFS and OS being 56% and 78% respectively.1/3 of the patients had gastrointestinal and liver toxicities. Metabolic abnormalities were seen in 1/4 th of them. ceritinib was permanently discontinued in one patient due to pneumonitis. In conclusion, ceritinib has a favorable efficacy and side effect profile in our patient population., similar to that reported in large clinical trials. It has shown promising efficacy even in patients with compromised performance status; presence of brain metastases and heavily pre-treated disease.

The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer.

The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in KRAS-wild-type (KRAS -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells, as already confirmed in KRAS-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models. Kaplan-Meier and Cox regression analysis indicated that DDX3, KRAS, and YAP1 expression had prognostic value for OS and RFS in KRAS-WT and KRAS-mutated tumors, but SIX2 and YAP1/SIX2 were prognostic value only in KRAS-WT patients. The observation from patients seemed to support the mechanistic action of cell and animal models. We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3-mediated tumor aggressiveness and enhance CTX sensitivity in KRAS-WT colorectal cancer.

Comprehensive definition of oxidation state (IUPAC Recommendations 2016)

Abstract Oxidation state (OS) is defined using ionic approximation of bonds. Two principal algorithms are outlined for OS determination in a chemical compound described by a Lewis formula or bond graph. Typical origins of ambiguous OS values are pointed out, and the relationship between OS and the d n electron configuration of transition metals is commented on.

Abstract 1414: Treatment outcome under cetuximab-based therapy and individual ADCC capability in head and neck cancer

Abstract Introduction Cetuximab is a IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) used for head and neck squamous cell carcinoma (HNSCC) treatment. In addition to EGFR targeting, cetuximab is able to develop an antibody-dependent cell-mediated cytotoxicity (ADCC), triggered by Fc receptors (Fcγ-R) on Natural Killer cells, macrophages and polymorphonucleated leukocytes. This prospective study examined the possible prognostic value of cetuximab-mediated ADCC response in a cohort of HNSCC patients. Patients and Methods There were 63 patients treated with curative intent with chemo-radiotherapy (CT-RT), associated (N = 39) or not (N = 24) with cetuximab. Peripheral blood samples were collected at start of therapy. Intrinsic ADCC was evaluated from ex vivo NK-dependent activity measuring LDH release through the Cytotox 96® non radioactive cytotoxicity assay, previously standardized in our laboratory (Crit Rev Oncol Hematol, 2015). EGFR tumoral expression was analyzed by immunohistochemistry. Results Median ADCC response at treatment start for all patients was 56.1% (range 5-99%). Analysing the whole population, patients with ADCC above the median value (high) showed a better OS as compared to patients with ADCC below the median (low), HR = 0.3827 (95% CI, 0.1464 to 1.000), p = 0.05 (Long-rank Mantel-Cox Test). A sub-group analysis confirmed a possible link between high ADCC and a better OS (CT-RT group, p = 0.223 and CT-RT+cetuximab group, p = 0.244). Importantly, considering CT-RT+cetuximab treatment and EGFR tumoral expression (N = 21), patients with EGFR 3+ status and high ADCC showed an improved OS as compared to patients with ADCC below median value, HR = 0.09031 (95% CI, 0.009983 to 0.8170), p = 0.032 (Long-rank Mantel-Cox Test). Median OS values for patients with high EGFR expression were 34.8 months (range 9.1-53.7) and 13.1 months (range 2.1-39.5) for patients with respectively high ADCC and low ADCC. Conclusion ADCC is shown to be a strong driver of cetuximab-based therapy outcome in HNSCC. High tumoral EGFR expression and high ADCC confer a particularly long overall survival. These data suggest an ADCC-based and EGFR expression-based precision therapy under cetuximab in HNSCC and open perspectives for NK boosting. Citation Format: Cristiana Lo Nigro, Laura Lattanzio, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Giuliana Strola, Marco Merlano, Gerard Milano. Treatment outcome under cetuximab-based therapy and individual ADCC capability in head and neck cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1414.

Gemcitabine–oxaliplatin (GEMOX) for epithelial ovarian cancer patients resistant to platinum-based chemotherapy

BackgroundPatients with platinum-resistant epithelial ovarian cancer (EOC) experience poor outcome. Currently, no clearly superior management strategy exists for platinum-resistant EOC patients. PurposeAnalyze the efficacy and safety of gemcitabine–oxaliplatin (GEMOX) in platinum resistant EOC patients. Patients and methodsThirty-two patients with platinum-based resistant EOC were included. Studied patients had received GEM at the dose of 1000mg/m2 on days 1 and 8 and OX 100mg/m2 on day 1, administered over 2h 30min after GEM infusion of 3week treatment cycle. ResultsIn the evaluation of tumor response, none of patients had achieved CR while PR, SD, were observed in 7 (21.9%), 9 (28.1%) respectively, clinical benefit (CR+PR+SD) was recorded in 50% of patients while PD was observed in 16 (50%) patients. In regard to survival, the median value of OS was 10.5months (range, 2.2–17.5months). The median value of PFS was 6.37months (range, 1–17.5months). The one-year OS rate was 34.4% and the one-year PFS rate was 12.5%. Concerning hematological toxicity grade 3 neutropenia was recorded in 4 (12.5%) patients while grade 4 febrile neutropenia was recorded in 2 (6.3%) patients and grade 4 anemia was represented by 3.1%. Grade 1–2 fatigue was the most common non-hematological toxicity and represented by 65.6% of patients. Grade 3 non hematological toxicity was recorded with nausea/vomiting and hepatic toxicity represented by 3.1% for both. ConclusionThe GEMOX combination is a regimen with a moderate therapeutic efficacy and tolerable toxic side effects in patients with platinum-resistant EOC.

Biomarker quantification by multiplexed quantum dot technology for predicting lymph node metastasis and prognosis in head and neck cancer.

PurposeTo predict lymph node metastasis and prognosis in head and neck squamous cell carcinoma (HNSCC).ResultsThe combination of membranous E-cadherin and membranous epidermal growth factor receptor (EGFR) quantified by QD technology with age, gender, and grade had greater predictive power than any of the single biomarkers or the two combined biomarkers quantified by conventional immunohistochemistry (IHC). The predictive power of this model was validated in another independent sample set; the predictive sensitivity of this model for LNM was 87.5%, with specificity up to 97.4%, and accuracy 92.9%. Furthermore, a higher membranous E-cadherin level was significantly correlated with better overall and disease-free survival (OS, DFS; P = 0.002, 0.033, respectively), while lower cytoplasmic vimentin and membranous EGFR levels were significantly correlated with better OS (P = 0.016 and 0.021, respectively). The combined biomarkers showed a stronger prognostic value for OS and DFS than any of the single biomarkers.MethodsMultiplexed quantum dots (QDs) were used to simultaneously label E-cadherin, vimentin, and EGFR with β-actin as an internal control. Primary tissue samples from 97 HNSCC patients, 49 with and 48 without LNM were included in the training set. Levels of membranous E-cadherin, cytoplasmic vimentin, and membranous EGFR were quantified by InForm software and correlated with clinical characteristics.ConclusionsMultiplexed subcellular QD quantification of EGFR and E-cadherin is a potential strategy for the prediction of LNM, DFS, and OS of HNSCC patients.

Validation of the prognostic impact of lymphocyte infiltration (LI) in patients (pts) with stage III colon cancer (CC) treated with adjuvant FOLFOX+/- cetuximab: A PETACC8 translational study.

553 Background: The prognostic value of LI of CC has been demonstrated by several groups. However no validated test is available for clinical practice. We previously described an automated and reproducible method for testing LI (Allard MA et al 2012) and aimed to validate it for clinical use. Methods: According to NIH criteria, we designed a prospective analysis of this biomarker in pts included in the PETACC8 phase III study. Primary objective was to compare % of pts without recurrence at 2 years in pts with high versus low LI (#NCT02364024). Secondary objectives were comparison of disease free (DFS) and overall (OS) survivals, and prognostic value of LI on these endpoints. Automated testing of LI was performed on virtual slides without access to clinical data. Results: Among the 1,220 CC pts enrolled, LI was high, low and not evaluable in 241 (20%), 790 (65%) and 189 (15%), respectively. High and low LI groups did not differ except for treatment arm (p=0.04) and microsatellite status (MSI/MSS) status (p=0.04). Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in pts with high and low LI respectively (p=0.02). Pts with high LI also had better DFS and OS (table). Stage, grade, KRAS status and LI were the only prognostic markers in multivariate analysis. Sub-group analyses revealed that high LI had better DFS and OS in MSS pts, and in pts without KRAS codon 12-13 mutation, but not in MSI neither in KRAS mutated pts. Conclusions: This is the first prospective validation of a LI testing in pts with stage III CC treated with FOLFOX adjuvant. Automated testing of LI also had a prognostic value for DFS and OS. Funding: Merck-Serono, Sanofi, Région Ile de France. Clinical trial information: NCT02364024. [Table: see text]

Re-Os pyrite geochronology of Zn-Pb mineralization in the giant Caixiashan deposit, NW China

The newly discovered Caixiashan Irish-type Zn-Pb deposit (∼131 Mt at 3.95 % Zn + Pb), located in the Eastern Tianshan of Xinjiang, is one of the largest Zn-Pb deposits in NW China. Massive colloform/framboidal textured syn-sedimentary pyrite yielded a Re-Os isochron age of 1019 ± 70 Ma (MSWD = 3.5), which is interpreted to be the depositional age of the Kawabulake group that hosts the ore. The age of the main mineralization stage is constrained by two types of pyrite: the layered pyrite coexists with recrystallized calcite and dolomite and is locally replaced by sphalerite, whereas the euhedral pyrite occurs with galena that crosscuts the massive sphalerite. The layered pyrite yielded a Re-Os age of 859 ± 79 Ma (MSWD = 6.7; initial 187Os/188Os ratio [IOs] = 0.19 ± 0.25) and the euhedral pyrite 837 ± 39 Ma (MSWD = 6.5; [IOs] = 0.16 ± 0.09), which are interpreted to be the Zn and Pb mineralization ages, respectively. The low radiogenic initial Os values of the Zn-Pb mineralization suggest interaction between a hydrothermal fluid and a mafic or ultramafic source rock with a mantle Os signature with some contamination with Mesoproterozoic Kawabulake group. Based on our new Re-Os ages, we conclude that the giant Caixiashan Zn-Pb deposit formed in the early Neoproterozoic and it represents a newly identified mineralization epoch in the Eastern Tianshan of the Central Asia Orogenic Belt.