Pretherapeutic Levels Research Articles

Elevated Pre-Therapeutic Serum Levels of Soluble Programmed Death 1 Protein (sPD-1) Identify DLBCL Patients with Adverse Prognostic Features

* Contributed equally to this workBackgroundCheckpoint proteins regulate the immune system and their down-regulation of effector mechanisms is exploited by malignant cells to evade antitumor response. Membrane bound programmed death 1 protein (PD-1) and its ligand (PD-L1) are checkpoint proteins whose over-expression has been reported as an adverse prognostic factor in lymphoid malignancies. Monoclonal antibodies targeting these checkpoint proteins are therefore a rational therapy trying to re-establish an effective antitumor immunity.Soluble forms of PD-1 and PD-L1 (sPD-1 and sPD-L1) exist, but their biological and clinical significance is yet to be clarified. High pre-therapeutic levels of sPD-L1 have been reported to impact overall survival in diffuse large B cell lymphomas (DLBCL). However, the role and significance of soluble levels of the receptor protein sPD-1 are still largely unknown.AimsThe aims of the present study were to measure pre-therapeutic sPD-1 levels in selected lymphoid malignancies and, for de novo DLBCL, investigate the potential correlation with outcome-related parameters.MethodsWe established and validated a Time Resolved Immunoflourometric assay (TRIFMA) to determine levels of sPD-1. In total, 106 archival serum samples were analysed in duplicate. This single-institution study population consisted of patients with chronic lymphocytic leukemia (CLL; n=42), DLBCL (n=30), Hodgkin lymphoma (HL; n=12), and healthy controls (n=22).Information on clinical parameters was obtained from medical records. sPD-1 levels were compared between patient subgroups and controls using a non-parametric test (Mann-Whitney). Correlation with clinical parameters were analysed using a linear regression model and Spearman's rank correlation. P-values below 0.05 were considered statistically significant.ResultsIn general, sPD-1 levels were higher in patients, taken as one group, compared to controls (p=0.002, see table 1). When analysed according to individual diagnostic subgroups, patients with DLBCL and CLL still had, despite of their limited cohort size, significantly elevated sPD-1 levels compared to controls (p=0.009 and p=0.002, respectively), while patients with HL did not. Although not significantly different, DLBCL patients showed consistently higher mean values of sPD-1 compared to CLL and HL (see table 1).A separate analysis of patients with DLBCL revealed a positive correlation between pre-therapeutic sPD-1 and IPI-score (β1=0.579 (95% CI 0.169;0.990), p=0.007)(see figure 1). The correlation was confirmed with Spearman's test of no association (p=0.0043). More specifically, higher sPD-1 levels correlated with higher IPI score and with the presence of known adverse prognostic factors such as age >60 years, disseminated clinical stage, elevated p-LDH, ECOG performance score ≥2, presence of >1 extranodal site.DLBCL patents were also analysed according to whether their tumor cell population was of GCB (n=14) or non-GCB (n=16) origin (assessed by the immunohistochemistry-based Hans algorithm). Non-GCB cases (mean 671 pg/ml (95% CI 268; 1680)) had higher sPD-1 levels than GCB cases (mean 323 pg/ml (95% CI 174; 560)), however not statistically significant (p=0.1575).ConclusionPre-therapeutic serum levels of sPD-1 were found to be higher in selected lymphoid malignancies (DLBCL, CLL) than in healthy controls. Highest mean values were detected in DLBCL patients, where higher sPD-1 levels also significantly correlated to the presence of classical clinical prognosticators for adverse outcome and, possibly, also to a non-GCB phenotype. Correlation analyses between pre-therapeutic levels of sPD-1, sPD-L1 and clinico-pathological features as well as clinical behaviour and outcome are ongoing. [Display omitted] DisclosuresClausen:Takeda: Research Funding. d'Amore:Nordic Nanovector: Other: Advisory Board; Les Laboratoires Servier: Honoraria, Other: Advisory Board; Takeda Pharma: Honoraria, Other: Advisory Board, Research Funding; Sanofi: Research Funding.

The Impact of Pre-Therapeutic Haemoglobin Levels on the Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with Anthracycline Containing Chemotherapy before and after the Introduction of Rituximab: A Nation-Wide Cohort Study

▪Introduction: In diffuse large B-cell lymphoma (DLBCL), hemoglobin (Hb) at diagnosis is often low. In other cancers, pre-therapeutic anemia has been identified as an independent predictor of poor outcome and incorporated in well-established prognostic indices. The aim of our study was to investigate whether this also could apply to DLBCL.Methods:Clinical and laboratory data from DLBCL patients diagnosed between 2000 and 2012 were retrieved from nation-wide registries. Inclusion criteria were: a confirmed diagnosis of de novo DLBCL, treatment with anthracycline-containing chemotherapy with or without rituximab and no primary CNS-lymphoma. Four subgroups of pre-treatment Hb values (g/L) were defined for men/women: (i) >149/>133, (ii) 134-149/118-133, (iii) 98-133/98-117 and (iv) <98. While subgroup i and ii represented normal Hb levels either over or under the mean value for healthy individuals, subgroups iii and iv defined increasing grades of anemia. Correlation analyses between Hb subgroups and the clinical parameters contained in the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), sex, comorbidity and rituximab treatment were performed. Five-year overall (OS) and progression free survival (PFS) were estimated according to the method of Kaplan and Meier. A uni- and multivariable Cox regression model was used to calculate 5-year hazard rate ratios (HRR) for death or disease progression depending on Hb subgroup (where subgroup i was used as reference), NCCN-IPI, sex, comorbidity, and rituximab treatment with mutual adjustment. Finally, restricted cubic splines, stratified on sex, were used to illustrate the relative risk for death as a function of Hb at diagnosis.Results:In total, 3,531 patients fulfilled the inclusion criteria. Hb levels below normal (subgroup iii and iv), were found in 1,612 patients (46%). Notably, pre-therapeutic anemia was more frequent in men (53%) than in women (38%). Anemia was correlated with elevated lactate dehydrogenase, disseminated disease and involvement of extranodal sites such as bone marrow, gastrointestinal tract, lung or liver. Patients with a normal Hb, but below the median value for healthy individuals had inferior outcome with a HRR for death of 1.55 (95% confidence interval [95%CI] 1.29-1.88). In subgroups iii and iv the HRR was 2.79 (95%CI 2.34-3.31) and 4.56 (95% CI 3.70-5.61). After adjusting for NCCN-IPI, sex, comorbidity and rituximab treatment, the HRR remained significantly increased for Hb subgroups ii, iii and iv, compared with subgroup i (reference). Patients treated with rituximab had a significantly better OS in all Hb subgroups and an adjusted HRR of 0.62 (0.55-0.70). When progression free survival was used as end point similar results were obtained. The restricted cubic splines illustrated the inverse correlation between Hb at diagnosis and the risk of death over a subsequent five-year period (Figure 1).Conclusion:In this nationwide cohort study, anemia at diagnosis was a strong and independent predictor of both overall and progression free survival. This finding persisted after adjusting for NCCN-IPI score, sex, treatment with rituximab and comorbidity. The importance of Hb for prognosis was further evidenced by the fact that even a lowering of Hb within the range of normal (subgroup ii), resulted in an increased risk of death. [Display omitted] DisclosuresClausen:Takeda: Research Funding. Nørgaard:Program for Clinical Research Infrastructure (PROCRIN): Research Funding. d'Amore:Les Laboratoires Servier: Honoraria, Other: Advisory Board; Nordic Nanovector: Other: Advisory Board; Sanofi: Research Funding; Takeda Pharma: Honoraria, Other: Advisory Board, Research Funding.

Evaluation of Choroidal Melanoma Vascularization by Color Doppler Flow Imaging: An Option for Follow-Up Tumor Control Assessment after CyberKnife®?

Background and Objectives: Thus far, tumor control for choroidal melanoma after teletherapeutic radiation is clinically difficult. In contrast to brachytherapy, the tumor height does not necessarily have to shrink as a result of teletherapy. Therefore, the objective of this study was to evaluate tumor vascularization determined by color Doppler flow imaging (CDFI) as a possible approach for monitoring the therapy response after teletherapy of choroidal melanoma. Materials and Methods: A single-center retrospective pilot study of 24 patients was conducted, all of whom had been diagnosed with choroidal neoplasm, treated and followed up. Besides tumor vascularization, the following parameters were collected: age, gender, tumor entity, location, radiation dose, knowledge of relapse, tumor height, radiation-related complications, occurrence of metastases, visual acuity in logMAR. Results: The level of choroidal melanoma vascularization markedly decreased in all included subjects after treatment with the CyberKnife® technology. Initially, the level of vascularization was 2.1 (SD: 0.76 for n = 10); post-therapeutically, it averaged 0.14 (SD: 0.4). Regarding the tumor apex, CDFI sonography also demonstrated a significant tumor regression (mean value pre-therapeutically: 8.35 mm—SD: 3.92 for n = 10; mean value post-therapeutically: 4.86 mm—SD: 3.21). The level of choroidal melanoma vascularization declined in the patient collective treated with ruthenium-106 brachytherapy. The pre-therapeutic level of vascularization of 2 (SD: 0 for n = 2) decreased significantly to a level of 0 (mean: 0—SD: 0). The tumor height determined by CDFI did not allow any valid statement regarding local tumor control. In contrast to these findings, the patient population of the control group without any radiation therapy did not show any alterations in vascularization. Conclusions: Our data suggest that the determination of the tumor vascularization level using CDFI might be a useful and supplementary course parameter in the follow-up care of choroidal melanoma to monitor the success of treatment. This especially applies to robot-assisted radiotherapy using CyberKnife®. Further studies are necessary to validate the first results of this assessment.

Soluble High Mobility Group Box 1 (HMGB1) Is a Promising Biomarker for Prediction of Therapy Response and Prognosis in Advanced Lung Cancer Patients.

Background: High mobility group box 1 protein (HMGB1) is known for its significant elevation in a multitude of tumors and benign diseases. In this study, we investigated the relevance of soluble HMGB1 for the prediction and monitoring of therapy response as well as the estimation of prognosis in advanced lung cancer. Materials and Methods: In a retrospective study, HMGB1 levels were assessed by an enzyme-linked immunosorbent assay (ELISA) in the sera of 96 patients with advanced lung cancer (79 non-small-cell lung carcinoma (NSCLC); 14 small cell lung carcinoma (SCLC), 3 Mesothelioma) prior to cycles 1, 2, and 3 of chemotherapy and correlated with radiological therapy response after 2 and 4 cycles as well as with overall survival. In addition, HMGB1 was compared with established tumor markers cytokeratin 19-fragments (CYFRA 21-1), carcinoembryonic antigen (CEA) and neuron specific enolase (NSE). Results: While pretherapeutic HMGB1 levels were not predictive or prognostically relevant in NSCLC patients, HMGB1 values prior to cycles 2 and 3 as well as kinetics from cycle 1 to 2 discriminated significantly between patients with good (remission and stable disease) and poor response (progression). Performance of HMGB1 in receiver operating characteristic (ROC) analyses of NSCLC patients, with areas under the curve (AUCs) of 0.690 at cycle 2 and 0.794 at cycle 3 as well as sensitivities of 34.4% and 37.5%, respectively, for progression at 90% specificity, was comparable with the best tumor-associated antigen CYFRA 21-1 (AUCs 0.719 and 0.799; sensitivities of 37.5% and 41.7%, respectively). Furthermore, high concentrations of HMGB1 at cycles 2 and 3 were associated with shorter overall survival in NSCLC patients. Conclusion: Soluble HMGB1 is a promising biomarker for prediction of therapy response and prognosis in advanced NSCLC patients.

Primary metastatic prostate cancer between prognosis or adequate/proper medical therapy

PurposeTo define the efficacy of standard androgen deprivation therapy (ADT) in the treatment of metastatic prostate cancer (PCa).Materials and methodsFifty patients with mean age of 70.48 ± 9.95 years old (range 52–87) who had metastatic PCa and received ADT between 2014 and 2019 were retrospectively evaluated. Median values of pre-therapeutic PSA and Gleason scores were 50 ng/ml (range 8–1201) and 8 (range 6–9), respectively. All patients received luteinizing hormone-releasing hormone (LHRH) analogue and anti-androgen. The patients were evaluated in terms of age, pre-therapeutic PSA serum levels, Gleason scores, presence of metastasis, number and percentage of cores involved, nadir PSA, time to nadir PSA, duration of ADT, and PSA at last follow-up. Multivariate analysis was used to define the factors which have impact on ADT response. The mean follow-up period was 13.87 ± 7.78 months, (range 2–32).ResultsAll patients showed reduction in serum PSA level after initiation of ADT, and the median value of nadir PSA was 1.12 ng/ml (range 0.02–50). The mean value of time to nadir PSA was 3.85 ± 1.57 months (range 2–7). The median value of PSA at last follow-up was 2 ng/ml (range 0.02–50.21). Multi-variant analysis showed that nadir PSA have a significant correlation with pre-therapeutic PSA, PSA at last follow-up, age, and Gleason scores (p < .05).ConclusionStandard ADT is a feasible option in the treatment of metastatic PCa. Gleason scores, age, pre-therapeutic PSA, and PSA at last follow-up have significant impact on outcomes of ADT. Further studies of high number of patients with long-term follow-up including other chemo-hormonal therapy and androgen receptor blockers should be carried out to confirm and improve efficacy of ADT.

Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials

Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials

Biomarkers of Haemostasis and Occurrence of Venous Thromboembolism Are Associated with Disease Progression and Poor Prognosis in Patients with Pancreatic Cancer

Background: Patients with pancreatic cancer have a high risk for venous thromboembolism (VTE). Activation of haemostasis has been suggested to contribute to the progression of cancer and its metastatic spread. However, clinical data to support the contribution of activation of haemostasis to disease progression are scarce. Our aim was to evaluate the association biomarkers indicating activation of haemostasis and/or hypercoagulability and of VTE occurrence with survival and therapy response in patients with pancreatic cancer. Methods: Within a prospective, observational cohort study (Vienna Cancer and Thrombosis Study, CATS), we evaluated the subgroup of patients with pancreatic cancer (n=145). Levels of a comprehensive panel of haemostatic biomarkers (D-dimer, prothrombin fragment 1+2, fibrinogen, factor VIII, plasminogen activator inhibitor 1 (PAI-1), soluble (s)P-selectin, peak thrombin generation, endogenous thrombin potential) were measured at baseline. Differences in levels of haemostatic biomarkers between disease stages were tested for statistical significance by Kruskal-Wallis-test. The association of biomarker levels with overall survival (OS) and therapy response (progression-free survival (PFS) and radiological disease control rate; sub-cohort of patient initiating palliative chemotherapy, n=95) was analysed by multivariable Cox regression, adjusting for disease stage, grade, sex, age, ECOG, VTE (as time-dependent covariable) and vascular infiltration or compression by the primary tumour. Cumulative incidence of VTE was estimated in competing risk analysis, considering death as competing outcome event. The impact of VTE on OS and PFS was evaluated by multi-state modelling, adjusting for stage, grade, sex, age, ECOG and vascular involvement. Results: We observed higher baseline levels of biomarkers according to increasing stage of disease for D-dimer (stage I/II: median 1.25 µg/ml [interquartile range (IQR): 0.65-2.10]; stage III: 1.41 µg/ml [IQR: 0.65-2.24]; stage IV: 1.68 µg/ml [IQR: 0.98-3.82], p=0.035), and sP-selectin (stage I/II: median 34.2 ng/ml [IQR: 26.8-43.1]; stage III: 37.6 ng/ml [IQR: 31.4-49.1]; stage IV: 38.8 ng/ml [IQR:32.9-51.5], p=0.033). Higher levels of D-dimer, PAI-1 and sP-selectin were associated with shorter OS in multivariable analysis (hazard ratio (HR) for death per doubling: 1.33 [95% confidence interval (CI): 1.08-1.66], 1.25 [95% CI: 1.08-1.45, and 1.42 [95% CI: 1.00-2.01] (Figure 1). In the subgroup of patients initiating palliative chemotherapy, pre-therapeutic levels of D-dimer predicted for shorter PFS (HR for disease progression per double: 1.29 [95% CI: 1.03-1.61]) and a decreased probability for radiological therapy response (odds ratio to achieve radiological disease control per double: 0.61 [95% CI: 0.38-0.99]). Cumulative incidence estimates of VTE in competing risk analysis at 3, 6, 12, and 24 months were 9.0% [95% CI: 5.0-14.3], 13.1% [95% CI: 8.2-19.1], 16.6% [95% CI: 11.1-23.1], and 19.5% [95% CI: 13.4-26.2], respectively. The occurrence of VTE was associated with an immediate increase in risk of death (transition hazard ratio, (THR): 2.37 [95% CI: 1.47-3.84]) and early disease progression (THR: 2.34 [95% CI: 1.50-3.66]), which prevailed upon multivariable adjustment. In landmark analyses, median OS and PFS after VTE were 5.5 months [95% CI: 2.2-6.5] and 3.0 months [95% CI: 1.5-3.9] compared to 13.4 months [95% CI: 9.7-16.6] and 7.5 months [95% CI: 5.9-9.8] in those without VTE (Mantel-Byar: both p&amp;lt;0.001). Figure 2 displays landmark analyses of OS and PFS according to occurrence of VTE within the first 3 months of observation. Conclusion: Occurrence of VTE, activation of haemostasis and hypercoagulability, as indicated by elevated levels of D-dimer, PAI-1 and sP-selectin are associated with poor prognosis and D-dimer predicts for unfavourable response to palliative chemotherapy in patients with pancreatic cancer. Disclosures No relevant conflicts of interest to declare.

C-Reactive Protein is a Poor Marker of Baseline Inflammation in Prostate Cancer and Response to Radiotherapy or Androgen Ablation

C-Reactive Protein (CRP) is an acute phase reactant used as a general marker for inflammation. There is some evidence that elevated levels are associated with increased risk of prostate cancer development, PSA, Gleason score, and decreased response to chemotherapy and radiotherapy (RT). Available literature largely focuses on pre-therapeutic levels as a prognostic marker. We seek to establish whether CRP levels reflect inflammation caused by prostate cancer before and in response to RT with or without prior androgen ablation (AA). This study included 209 patients who had a CBC, PSA, and CRP taken at up to four different time points. Labs were performed prior to AA via leuprolide injection (pre-AA), up to one week prior to RT (pre-RT), during the final week of RT (post-RT), and 3 months following RT completion (FU). Prior to RT, 33% of patients had received prior prostatectomy and 50.7% had received AA. Radiation fields included pelvic lymph nodes in 82% of patients. For comparisons at each time point, CRP had a significant relationship with WBCs pre-AA (p-value = 0.0050), pre-RT (p-value = 0.0170), and post-RT (p-value = 0.0113), but not at FU (p = .096). CRP had no significant relationship with PSA at any time points. For those who did or did not receive AA, pre-RT mean PSA was significantly lower (2.3 vs 5.4, p-value = 0.0072) while CRP was not. Pre-AA, pre-RT, and post-RT CRP levels were not significantly related to FU-PSA. No CRP levels were associated with risk groups. Only PSA significantly changed from pre-AA to pre-RT (p-value<0.0001). PSA, WBCs, and lymphocytes significantly decreased from pre-RT to post-RT, with significant recovery from post-RT to FU (p-value<0.0001 for all six comparisons), though still with overall significant change from pre-RT to FU (p-value = 0.0054, p-value<0.0001, p-value<0.0001, respectively). CRP did not significantly change during any period, nor significantly relate to changes in WBCs or PSA. There was a significant difference between the treated vs. untreated lymph node groups in post-RT lymphocytes (p-value<0.0001), FU-lymphocytes (p-value<0.0001), post-RT-WBCs (p-value = 0.0004), and FU-WBCs (p-value = 0.0141). CRP was not significantly different between these groups. Our results demonstrate a lack of clinical utility for CRP as a marker of the inflammatory effects of prostate cancer. It has no correlation with PSA levels or trends, before or after radiation therapy, with or without androgen ablation. It does not change with significant PSA decrease after androgen ablation and corresponding decrease in cancer activity. It does not change at the end of radiation therapy despite significant changes in lymphocytes and WBCs. It does not change with 3-month follow-up to correspond with either significant recovery of lymphocytes and WBCs or a decrease of radiation-induced inflammation.

SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis.

Background and aimThis investigation was aimed at disclosing whether SRPX2 affected pancreatic cancer (PC) chemoresistance by regulating PI3K/Akt/mTOR signaling.MethodsTotally 243 PC patients were recruited, and they were incorporated into partial remission (PR) group, stable disease (SD) group and progressive disease (PD) group in accordance with their chemotherapeutic response. PC cell lines (i.e. AsPC1, Capan2, VFPAC-1, HPAC, PANC-1, BxPC-3 and SW1990) and human pancreatic ductal epithelial cell lines (hTERT-HPNE) were also collected.ResultsPC patients of SD + PD group were associated with higher post-chemotherapeutic SRPX2 level than PR group, and their post-chemotherapeutic SRPX2 level was above the pretherapeutic SRPX2 level (P < 0.05). PR population showed lower SRPX2 level after chemotherapy than before chemotherapy (P < 0.05). Besides high serum SRPX2 level and SRPX2 level change before and after chemotherapy were independent predictors of poor PC prognosis. Additionally, si-SRPX2 enhanced chemosensitivity of PC cell lines, and expressions of p-PI3K, p-AKT and p-mTOR were suppressed by si-SRPX2 (P < 0.05). IGF-1 treatment could changeover the impact of si-SRPX2 on proliferation, migration, invasion and chemoresistance of PC cells (P < 0.05).ConclusionThe SRPX2-PI3K/AKT/mTOR axis could play a role in modifying progression and chemoresistance of PC cells, which might help to improve PC prognosis.

Gamma Knife radiosurgery for acromegaly: Evaluating the role of the biological effective dose associated with endocrine remission in a series of 42 consecutive cases.

Stereotactic radiosurgery (SRS) is a valuable treatment option for persistent and/or recurrent acromegaly secondary to growth hormone (GH) secreting pituitary adenoma (PA). Here, we assess the role of biological effective dose (BED) received by PA treated with SRS in relation with endocrine remission. Forty-two patients (minimum 6months follow-up) were included. Mean marginal dose was 27.7 (median 28, 20-35), and mean BED received by tumour was 193.1Gy2.47 (median 199.7, 64.1-237.1). Based on the median values, we divided the patients in high tumour BED group (H-BEDtm, 199.7-237.1Gy2.47, n=12) and low BED one (L- BEDtm, 64.1-199.7Gy2.47 , n=10). The two groups did not differ by pretherapeutic IGF-1 levels (p=.1) or by the prescribed dose (p=.6). Mean follow-up period was 62.5months (median 60.5, 9-127). Probability of IGF-1 normalization was 65% at 3years and 72.4% at 4years, remaining stable until last follow-up. Twenty-two (52.4%) patients had complete endocrine remission in absence of any Somatostatin analogues. Actuarial rates were 33% at 3years and 57.4% at 7years, further remaining stable during follow-up course. In univariate analysis, only statistically significant parameter was pretherapeutic serum IGF-1 and IGF-1 index (p=.01). Five patients (5/26, 19.3%) without previous hypopituitarism developed new pituitary insufficiency. H-BEDtm was associated with higher rates of endocrine remission compared with L-BEDtm, with actuarial probability of 70.2% versus 48.2% at 9years, although this did not reach statistical significance (p>.05). Our study confirms that SRS by Gamma Knife is safe and effective for GH-secreting PA. Pretherapeutic serum levels of IGF-1 were only statistically significant parameter for endocrine remission.

Clinical Significance of Pretherapeutic Serum Squamous Cell Carcinoma Antigen Level in Patients with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

Although squamous cell carcinoma antigen (SCC-Ag) is a tumor marker widely used to estimate the progression of esophageal SCC (ESCC), only a few studies have focused on the relationship between serum SCC-Ag levels and the therapeutic effect of neoadjuvant chemotherapy (NAC). This study aimed to elucidate the clinical significance of pretherapeutic serum SCC-Ag levels in patients who underwent NAC followed by esophagectomy. Data of 453 patients who underwent NAC followed by esophagectomy were collected from the esophageal cancer database of two high-volume Japanese centers. Serum SCC-Ag levels were measured prior to NAC, and the pathological therapeutic effect of NAC and patient survival were evaluated. Patients were classified according to the tertiles of the serum SCC-Ag value (low, middle, and high groups), and the outcomes among the groups were compared. The levels of serum SCC-Ag were significantly associated with tumor stage (p<0.01). With regard to the pathological therapeutic effect, the levels of serum SCC-Ag were negatively correlated with the therapeutic effect (p=0.02). Moreover, increased levels of serum SCC-Ag negatively influenced relapse-free survival (p<0.01). Multivariate analyses revealed the 'high' group as the independent factor for both the unfavorable therapeutic effect (p=0.01) and the increased risk of disease recurrence (p<0.01) when compared with the 'low' group. Elevated levels of pretherapeutic serum SCC-Ag are significantly associated with advanced tumor stage, poor response to NAC, and increased risk of disease recurrence.

Work Loss in Relation to Pharmacological and Surgical Treatment for Crohn's Disease: A Population-Based Cohort Study.

PurposePatients with Crohn’s disease have increased work loss. We aimed to describe changes in work ability in relation to pharmacological and surgical treatments.Patients and MethodsWe linked data from the Swedish National Patient Register, The Swedish Quality Register for Inflammatory Bowel Disease SWIBREG, The Prescribed Drug Register, The Longitudinal Integrated Database for Health Insurance and Labour Market Studies, and the Social Insurance Database. We identified working-age (19–59 years) patients with incident Crohn’s disease 2006–2013 and population comparator subjects matched by sex, birth year, region, and education level. We assessed the number of lost workdays due to sick leave and disability pension before and after treatments.ResultsOf 3956 patients (median age 34 years, 51% women), 39% were treated with aminosalicylates, 52% with immunomodulators, 22% with TNF inhibitors, and 18% with intestinal surgery during a median follow-up of 5.3 years. Most patients had no work loss during the study period (median=0 days). For all treatments, the mean number of lost workdays increased during the months before treatment initiation, peaked during the first month of treatment and decreased thereafter, and was heavily influenced by sociodemographic factors and amount of work loss before first Crohn’s disease diagnosis. The mean increase in work loss days compared to pre-therapeutic level was ~3 days during the first month of treatment for all pharmacological therapies and 11 days for intestinal surgery. Three months after treatment initiation, 88% of patients treated surgically and 90–92% of patients treated pharmacologically had the same amount of work loss as before treatment start. Median time to return to work was 2 months for all treatments.ConclusionIn this regular clinical setting, patients treated surgically had more lost workdays than patients treated pharmacologically, but return to work was similar between all treatments.

Radioligand therapy using [177Lu]Lu-PSMA-617 in mCRPC: a pre-VISION single-center analysis

BackgroundRadioligand therapy with [177Lu]Lu-PSMA-617 is efficacious for the treatment of patients with metastasized castration-resistant prostate cancer (mCRPC). Various studies have evaluated the efficacy and safety of [177Lu]Lu-PSMA-617 using a dose of 6.0 GBq and an 8-week therapy interval. However, the first prospective phase III trial (VISION) plans to use an elevated cumulative dose by applying 7.5 GBq in a 6-week interval. The aim of the present study was to compare safety and efficacy of the two aforementioned [177Lu]Lu-PSMA-617 therapy regimes (7.5 GBq every 6 weeks vs. 6.0 GBq every 8 weeks).MethodsA total number of 78 consecutive patients with mCRPC and a history of first-line chemotherapy were included in this retrospective analysis. The outcome of patients treated with 6.0 GBq [177Lu]Lu-PSMA-617 per cycle (n = 37) were compared with those treated with 7.5 GBq (n = 41) per cycle. The median therapy intervals were 8.4 weeks (6.0 GBq group) vs. 6.5 (7.5 GBq group). PSA response, PSA progression-free survival (PSA-PFS), overall survival, and adverse events were evaluated and compared between both groups. Chi-squared test, Kaplan Meier estimates, Cox regression, and log-rank test were used. The highest decline from pretherapeutic PSA levels was measured as percentage (best PSA response) and compared between groups by Wilcoxon test.ResultsThere was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and − 40.2% vs. − 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258). There was no significant difference regarding the change of kidney, liver, and blood cell parameters under therapy between the treatment groups.ConclusionHigher cumulated doses of [177Lu]Lu-PSMA-617 were well tolerated and caused no significantly increased rate of adverse reactions. Moreover, 7.5 GBq of [177Lu]Lu-PSMA-617 every 6 weeks causes slightly higher, though not statistically significant, response rates and seems therefore to be the preferable treatment regime. However, future studies are needed to elucidate the dose-related efficacy of [177Lu]Lu-PSMA-617 as a way to personalized medicine.

The pathological complete response and secreted protein acidic and rich in cysteine expression in patients with breast cancer receiving neoadjuvant nab-paclitaxel chemotherapy.

Biomarkers that can accurately predict treatment response are required for indicating optimal neoadjuvant treatments. The current study assessed the predictive value of secreted protein acidic and rich in cysteine (SPARC) mRNA expression for the response to neoadjuvant nab-paclitaxel (nab-PTX) therapy in patients with breast cancer. It was hypothesized that SPARC expression can affect the response to albumin-bound taxanes, including nab-PTX since SPARC binds albumin with a high affinity. Pre-therapeutic specimens of core needle biopsies were analyzed from 50 patients in a phase II trial of neoadjuvant nab-PTX and the factors that were associated with a pathological complete response (pCR) were assessed. The pre-therapeutic tumor mRNA levels of chemotherapy-related proteins were quantified, including SPARC, and the correlations with post-therapeutic clinicopathological factors were assessed, including with pCR. The results demonstrated that pre-therapeutic SPARC mRNA expression was significantly higher in non-pCR patients compared with patients with pCR (92.37±55.33 vs. 56.53±30.19; P=0.027). A cutoff point of 48.5 was determined using receiver operating characteristic (ROC) curve analysis (sensitivity, 83.3%; specificity, 50.0%), and patients were classified into low and high SPARC expression groups. High SPARC expression was associated with histological grade (P=0.035), estrogen receptor expression (P=0.037), and progesterone receptor expression (P=0.002) but not with HER2 (P=0.895), and Ki-67 LI (P=0.743) expression. The results of the current study indicated that a high SPARC mRNA expression was a negative predictor of pCR following neoadjuvant nab-PTX therapy regardless of breast cancer subtype. The phase II study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the National Hospital Organization Takasaki General Medical Center (Registration nos. H23-9 and H23-33).

The Predictive Value of Pre-therapeutic Serum Gamma-glutamyl transferase in Efficacy and Adverse Reactions to Neoadjuvant Chemotherapy among Breast Cancer Patients.

PurposeGamma-glutamyl transferase (GGT) has been reported as being involved in tumor progression. Previous studies documented a potential relationship between serum GGT level and survival outcome in several types of human malignancies. However, the association between serum GGT levels and response to neoadjuvant chemotherapy (NAC) has not yet been reported. The present study aimed to evaluate the association between pre-therapeutic serum GGT level and the efficacy, long-term survival, and adverse reactions of NAC and to investigate its role in predicting NAC sensitivity in patients with breast cancer.MethodsA total of 129 patients were recruited and stratified into 2 groups according to serum GGT level (< 29 U/L and ≥ 29 U/L). The association between pre-therapeutic serum GGT levels and clinicopathological parameters was examined. The correlation between pre-therapeutic serum GGT levels and pathological complete response (pCR) was analyzed using univariate and multivariate logistic regression. Survival analyses of relapse-free survival (RFS) and disease-free survival (DFS) were performed. Pearson's χ2 test and multivariate logistic regression model were used to analyze the correlation between pre-therapeutic serum GGT levels and adverse reactions.ResultsPre-therapeutic serum GGT levels were associated with pCR among breast cancer patients treated with NAC. Multivariate analysis showed that low-level GGT significantly increased pCR rate. Patients in the high-level GGT group had poorer survival than those in the low-level GGT group. Subgroup analysis demonstrated that serum GGT level was potentially related to RFS and DFS in the hormone receptor-positive group. Low levels of GGT are significantly associated with a higher incidence of neutropenia.ConclusionPre-therapeutic serum GGT level is an independent and novel biomarker for predicting the efficiency, prognosis, and adverse reactions to NAC in breast cancer patients. Patients with low pre-therapeutic serum GGT levels are more likely to have higher pCR rates, better RFS and DFS, and higher hematologic toxicity.Trial RegistrationClinicalTrials.gov Identifier: NCT02199418, NCT02221999

Circulating lncRNA H19 may be a useful marker of response to neoadjuvant chemotherapy in breast cancer.

Novel biomarkers are needed to predict the effectiveness of the treatment of presurgical neoadjuvant chemotherapy (NAC) in breast cancer (BC). This is an exploratory study to assess the impact of 3 cancer-related long non-coding RNAs (lncRNAs) (H19, MALAT1 and GA5) in blood plasma of patients with BC in predicting the response to NAC. The plasma levels of RNAs were relatively measured by quantitative PCR at baseline, and at the end of the fourth cycle of NAC in patients with locally advanced BC. Only H19 was associated with patients' characteristics, and with the response to NAC. Higher plasma expression of H19 was associated with younger age at diagnosis, triple negative tumors, and Ki-67 index. Patients with a pathological complete response (20%) had lower pre-therapeutic levels of H19 compared with the non-complete responders (relative levels 0.1 vs 0.2, respectively, P: 0.04). In addition, the patients with higher degree of downstaging of initial tumors had lower baseline levels of H19 among non-complete responders. Our study reveals that H19, but not MALAT1 and GAS5, may be a useful marker of response to NAC in BC.

144P - Severe hypovitaminosis D in metastatic gastric cancer patients from the Northern and Southern hemispheres: Data from the EXPAND phase III trial

BackgroundOur primary goal was to evaluate the association between vitamin D (25-OHD) plasma levels and overall survival (OS) in metastatic gastric cancer patients receiving first-line chemotherapy in the international phase III EXPAND study (EudraCT 2007-004219-75). Here we report on 25-OHD plasma levels and OS according to geographic hemisphere of residence. Methods25-OHD pre-therapeutic plasma levels were measured in 630 patients using chemiluminescent immunoassay (Abbott Laboratories, Illinois). All patients were treated with chemotherapy based on capecitabine and cisplatin ± cetuximab. The Cox proportional hazard regression model was used to analyse the association between 25-OHD and survival in both treatment arms. Results549 and 73 patients were recruited in the Northern and Southern hemispheres, respectively. The majority had severe hypovitaminosis D at baseline prior to start of treatment. Only 9.2% of patients had a normal 25-OHD plasma levels (applying accepted criteria of 25-OHD insufficiency with plasma levels < 75 nmol/l; deficiency defined as < 50 nmol/l). Median 25-OHD plasma level was 38.2 nmol/l (IQR 25.8; 58.9) and mean was 43.5 nmol/l. Patients from the Southern versus Northern hemisphere had slightly higher 25-OHD levels (median 45.6 vs. 37.4 nmol/l; p = 0.0172; mean 48.92 vs. 42.74; p = 0.03 ). This difference persists when adjusting for season in a linear regression model. As expected, we observed the highest levels of 25-OHD in samples drawn during the summer season and the lowest values in winter. No proof for a negative impact of hypovitaminosis D on survival or treatment response was detected and no difference in OS was seen between patients from the Southern vs. Northern hemisphere (median 8.3 months [95%CI 7.4-10.6] vs. 10.5 [95%CI 9.4-11.3]; Hazard Ratio = 1.195; p = 0.2001). ConclusionsNo prognostic value of vitamin D deficiency was found in the EXPAND cohort. However, the majority of patients with metastatic gastric cancer have a severe vitamin D deficiency with only minor differences comparing Southern versus Northern hemisphere of residency. Legal entity responsible for the studyMasaryk Memorial Cancer Institute. FundingMasaryk Memorial Cancer Institute, University Leipzig. DisclosureR. Obermannova: Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly. F. Lordick: Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen, AstraZeneca, Astellas, Biontech, BMS, Eli Lilly, Elsevier, Excerpta Medica, Imedex, Infomedica, Iomedico AG, Medscape, MedUpdate GmbH, Merck Sharp Dohme, Merck Serono, Oncovis Gmbh, Promedicis, Springer Nature Group, StreamedUp!, Zymeworks; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

Prognostic value of serum creatine level in patients with vulvar cancer

Vulvar cancer is a rare malignancy with poor prognosis that generally occurs in elderly patients. The individual prognosis is difficult to assess. Serum creatinine levels are frequently elevated in elderly patients. Recent evidence have shown shown that - besides indicating kidney impairment - serum creatinine levels may be used to predict the survival in cancer patients. Several studies observed an association between elevated serum creatinine levels and poor prognosis in patients with solid tumors. In this retrospective cohort study, serum creatinine levels were evaluated in 170 patients with invasive vulvar cancer. Serum creatinine levels were correlated to established clinicopathologic factors. Univariate and multivariate survival analysis were performed. Elevated serum creatinine levels (>1.2 mg/dl) were significantly associated with both poor disease specific and overall survival. Three year overall survival rates were 74.8% and 32.5% for patients with serum creatinine levels of ≤ and >1.2 mg/dl, respectively. In a multivariate survival model, serum creatinine levels were significantly associated with overall survival independent of tumor stage and patients’ age. In conclusion, pretherapeutic serum creatinine levels may be useful as an independent prognostic parameter in patients with vulvar cancer.

High prevalence of severe hypovitaminosis D in patients with advanced gastric cancer treated with first-line chemotherapy with or without anti-EGFR–directed monoclonal antibody (EXPAND trial) showing no prognostic impact

PurposeThe goal of our analysis was to study pretherapeutic circulating 25-OHD plasma levels in patients with previously untreated advanced gastric cancer treated in the randomised controlled phase III Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) trial (NCT00678535) and to explore whether low 25-OHD plasma levels are associated with worse prognosis and may compromise the clinical efficacy of cetuximab. MethodsSix hundred thirty patients with available pretherapeutic 25-OHD plasma levels and treated with chemotherapy based on capecitabine and cisplatin, or chemotherapy and cetuximab, were included. The Cox proportional hazard regression model was used to analyse the association between low 25-OHD and survival in both treatment arms. ResultsMajority of study patients were found to have severe vitamin D deficiency. No prognostic impact of 25-OHD plasma levels could be found in our patient cohort, and there was no indication of an interference of 25-OHD plasma levels and the efficacy of treatment with the anti–epidermal growth factor receptor monoclonal antibody cetuximab. ConclusionsAlthough majority of patients with advanced gastric cancer show hypovitaminosis D deficiency, there is no proof for a negative impact on survival or reduced treatment response. A prospective study is needed to investigate the potential benefit of vitamin D supplementation in this patient cohort during first-line chemotherapy.

The role of mSEPT9 in screening, diagnosis, and recurrence monitoring of colorectal cancer

BackgroundThe application of circulating, cell-free, methylated Septin9 (mSEPT9) DNA in screening and recurrence monitoring is highly promising. CpG island methylator phenotype (CIMP) is associated with microsatellite instability (MSI). The present study was performed to determine the diagnostic accuracy of mSEPT9 for colorectal cancer (CRC) and to evaluate its utility in CRC screening and recurrence monitoring.MethodsFor screening and diagnosis of CRC, peripheral mSEPT9 detection and fecal occult blood test (FOBT) were performed in 650 subjects, then the level of CEA, CA19–9 and CA724 was quantified in 173 subjects. Clinicopathological parameters and mismatch repair protein were detected among subjects with CRC. For recurrence monitoring of CRC, the sensitivity of mSEPT9 of 70 subjects was compared with tumor markers and contrast enhanced computed tomography (CECT).ResultsSeventy-three percent of CRC patients were mSEPT9-positive at 94.5% specificity, and 17.1% of patients with intestinal polyps and adenoma were mSEPT9-positive at 94.5% specificity, which were higher than FOBT for the screening of CRC. The sensitivity and specificity of mSEPT9 for diagnosis and recurrence monitoring were higher than that of CEA, CA19–9 and CA724. The combined detection of mSEPT9 and CECT enhanced the sensitivity for recurrence monitoring. Pre-therapeutic levels of mSEPT9 were strongly associated with TNM stage, Dukes stages and mismatch repair deficiency (dMMR).ConclusionsmSEPT9 analysis might be popularized as a routine biomarker for CRC screening. The combined detection of mSEPT9 and CECT can play an important role for recurrence monitoring. CIMP was highly associated with the pathological stage of CRC and dMMR.