Trend For Better Survival Research Articles

Chidamide represses MYC expression and might improve survival for patients with double expressor lymphoma.

Double expressor lymphoma (DEL), characterized by high expressions of both MYC and BCL-2, displays poor prognosis after current therapies. The HDAC inhibitor chidamide has been approved for treatment of T cell lymphoma, but its efficacy on B cell lymphoma is unclear. Here, by combining inhibition screening and transcriptomic analyses, we found that the sensitivity of B lymphoma cells to chidamide was positively correlated with the expression levels of MYC. Chidamide treatment reduced MYC protein levels and repressed MYC pathway in B lymphoma cells with high MYC expressions. Ectopic expression of MYC in chidamide-insensitive B lymphoma cells increased their response to chidamide. Thus, we proposed that adding chidamide into R-CHOP (CR-CHOP) might be effective for DEL, and retrospectively analyzed 185 DEL patients treated in West China Hospital. 80% of patients showed response to CR-CHOP treatment. In the median follow-up of 42 months, CR-CHOP significantly improve the survival for DEL patients with R-IPI ≤2. Totally 35 patients underwent autologous stem cell transplantation (ASCT) in remission and demonstrated a trend for better survival. Combining CR-CHOP with ASCT resulted in the most superior PFS and OS above all. For response patients, CR-CHOP reduced relapse with better PFS than R-CHOP-like regimens with or without ASCT. Taken together, our data indicated that chidamide repressed the MYC pathway in B lymphoma and is potentially efficacious to treat DEL.

The differential response to immune checkpoint inhibitors (ICIs) according to mismatch repair alterations in gastrointestinal (GI) non-colorectal cancers (non-CRCs) and the impact of dual vs. monotherapy ICIs on survival in GI (CRC and non-CRC) cancers.

2620 Background: In patients with mismatch repair deficient (dMMR) colorectal cancers (CRCs), we previously reported that loss of expression of MSH2 and MSH6 (MutS co-loss) was associated with better response to ICIs and longer median overall survival (mOS) compared to loss of expression of MLH1 and PMS2 (MutL co-loss). Here, we expanded our analysis and included gastrointestinal (GI) non-CRCs and explored the impact of dual vs. monotherapy ICIs on mOS in GI (CRC and non-CRC) cancers. Methods: Specimens were profiled by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq) (Caris Life Sciences, Phoenix, AZ). MMR/microsatellite instability (MSI) status was determined by immunohistochemistry (IHC) of MMR protein. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first treatment with ICIs (Nivolumab, Nivo; Ipilumumab, ipi; or Pembrolizumab, pembro) to last contact. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: The GI non-CRC cohort (N= 19,767) included cancers of the esophagus, stomach, gastroesophageal junction, pancreas, bile duct and small bowel with 97 (0.49%) patients having MutS co-loss, and 494 (4.03%) patients having MutL co-loss. MutS co-loss was associated with increased KRAS (45.4% vs 25.2%, q<0.01), CDKN2A (29.2% vs 9.0%), GNAS (27.8% vs 7.8%) and SMAD4 (17.5% vs 5.9%) mutations compared to MutL co-loss. Independent of treatment, MutS co-loss (N=74) had improved mOS compared to MutL co-loss (N=332) (40.4 m vs. 26.2 m, HR = 0.66; (95% CI: 0.46-0.95), P=0.024). In patients treated with ICIs, the mOS in MutS co-loss (N=21) was better compared to MutL co-loss (N=76) (not reached (NR) vs. 25.4 m, HR= 0.23 (95% CI: 0.07-0.75), p=0.008). At 3 years, more than 80% of the patients with MutS co-loss were alive. Of particular importance, when looking at all GI (CRC and non-CRC) patients, the mOS of MutL co-loss treated with ipi/nivo (N=18) trended for better mOS compared to MutL co-loss treated with pembro (N=215) (NR vs. 28.2m (HR=0.39; (95% CI:0.14-1.07), p=0.057), while the mOS of MutS co-loss treated with ipi/nivo (N=6) was not different compared to MutS co-loss treated with pembro (N=44) (NR vs. NR, HR=0.75 (95% CI: 0.094-5.92), p=0.78). Conclusions: In ICI-treated GI non-CRCs, the mOS was longer in MutS co-loss compared to MutL co-loss. In ICI-treated GI (CRC and non-CRC) patients with MutL co-loss, there was a trend for better survival with ipi/nivo compared to pembro. Our data suggest that the MutS vs. MutL status may guide the choice of ICIs regimen (Dual vs. Monotherapy) but more data are needed.

Abstract 100: Multi-drug Cocktail Approach After Asphyxial Cardiac Arrest And Cardiopulmonary Bypass Resuscitation In Rats

Background: Cardiac arrest (CA) is a leading cause of death in the US. There are limited therapies that substantially improve survival with good neurologic outcomes. The lack of neuroprotective drugs has been cited as a major roadblock to improved outcomes. There have been many failed human trials of potentially neuroprotective drugs. However, most of the failed prior studies have focused on a single drug or single pathological pathway. By contrast, our metabolomic data suggests that after CA multiple pathways are severely dysregulated. Objective: The aim of this study was to develop and test the therapeutic effectiveness of a multi-drug cocktail targeting multiple dysfunctional pathways observed during brain ischemia-reperfusion. We sought to increase survival with good neurological outcomes in a highly lethal rat model of 20 min CA followed by cardiopulmonary bypass (CPB) resuscitation. Methods: A multi-drug cocktail formulation was developed comprised of ten drugs (Metformin, poloxamer 188, N- acetylcysteine, Sulbutiamine, Zoniporide, SS-31, Cyclosporin A, CoQ10, Vitamin C, and Edaravone) focusing on distinct metabolic pathways of ischemia-reperfusion injury. Male Sprague-Dawley rats (400-500 g) underwent 20 min of asphyxial-CA and 30 min of CPB resuscitation. After the resumption of spontaneous circulation (ROSC), rats received either cocktail or a vehicle (n=6) through a femoral vein for over a 20-minute. Animals were extubated after 4 h of mechanical ventilation. Body temperature was maintained at 37.0 ± 0.5°C. Outcomes assessed include a 4 h survival time and retention of corneal reflex. Results: Cocktail treatment resulted in 4/6 rats surpassing the 4 h survival window, while only 2/6 rats after vehicle treatment. The median survival time was 240.53 min vs 120.62 min for a cocktail vs vehicle, respectively (p=0.067). Furthermore, 4/6 rats treatment with a cocktail demonstrated retention of corneal reflex after 4 h compared with 2/6 rats after vehicle treatment. Conclusion: This pilot study is the first to use a multi-drug cocktail in a severe CA rodent model that demonstrates a trend for better survival and corneal reflex retention. Future studies of cocktails seem warranted if neuroprotective therapies are contemplated in the setting of CA.

Real-world evidence for immunotherapy in the first line setting in small cell lung cancer

ObjectiveDespite major progress over the past decade in the field of lung cancer care, only mild advances have occurred in Small Cell Lung Cancer (SCLC), with prognosis remaining poor. Based on two randomized clinical trials (RCTs), two checkpoint-inhibitors have recently been approved in extensive-SCLC with moderate improvements in median overall survival (OS). However, only limited data exist regarding the impact of immunotherapy in real-world SCLC patients. This study reports the efficacy of immunotherapy in the first-line treatment of extensive-stage SCLC patients in a real-world setting. Methodsa retrospective cohort study of all patients treated for extensive-SCLC with chemotherapy with or without immunotherapy, at a single center in Israel between October-2017 and July-2021. Patient characteristics, adverse-events and survival analyses were conducted. ResultsOf 102 patients identified, 54 patients (53%) received immunotherapy in addition to chemotherapy. 34.7% of patients had a performance status (PS) of 2–4. Patients that received only chemotherapy were older, had more liver metastasis and a poorer PS.In the whole cohort, patients receiving immunotherapy had a significantly longer median OS (353 days vs 194 days, HR = 0.40p < 0.0001). After stratification by PS groups, survival analysis remained significantly longer in the PS 0–1 group (HR 0.43, p = 0.0036), with a trend for better survival in the PS 2–3 group. Multivariate analysis validated an OS advantage with immunotherapy (HR = 0.46, p = 0.004). ConclusionWe present evidence for the efficacy of immunotherapy in SCLC in a real-world setting. Although treatment groups differ in their baseline characteristics, it appears that even some patients not included in RCTs, such as poor PS, may benefit from the addition of immunotherapy to their treatment protocol.

Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis.

Recently, we provided evidence that a single nucleotide polymorphism (SNP), rs41266431, on the gap junction protein alpha 4 (GJA4) gene, acts as a modifier for clinical disease severity in patients with cystic fibrosis (CF). These features are very similar to those of variants of the mannose-binding lectin (MBL). This study aimed to clarify whether the clinical disease phenotype associated with GJA4 variants is independent of MBL variants. One hundred and twelve patients with homozygous F508del (mean age, 27.6 years; m/f, 61/51) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. A sequence analysis was performed for GJA4 and MBL. The clinical phenotype was assessed over three years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, and inflammatory markers. A clinically relevant SNP of GJA4 was identified by sequence analysis. Pulmonary function (FVC% pred, mean 78/85; p < 0.055) and survival to end-stage lung disease were lower (p < 0.043) for this variant (rs41266431) in carriers homozygous for the G variant (n = 82/112; 73%) than in other carriers. Serum MBL (820/372 ng/mL, p < 0.001) was significantly higher in "MBL-sufficient" genotypes (n = 79/112; 71%) than in "MBL-insufficient" genotypes, and a trend for a significant difference in BMI percentiles (35.2/23.8; p < 0.059) was observed. For the MBL-sufficient genotype (median age at death, 38/26 years), there was a trend for better survival (p < 0.076). There was no augmentation by gene-gene interaction between MBL and GJA4 variants for any outcome parameter. The clinical disease phenotype associated with GJA4 variants is independent of MBL variants. MBL-sufficient variants were associated with superior BMI and a trend for better survival than MBL insufficient variants.

Serum Syndecan-1: A Novel Biomarker for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION:Syndecan-1 (SDC1) has multiple functions in tumorigenesis in general and specifically in pancreatic cancer. We aimed to evaluate SDC1 as a diagnostic and prognostic biomarker in patients with pancreatic ductal adenocarcinoma (PDAC).METHODS:In this case-control study, patients newly diagnosed with a biopsy-proven PDAC were enrolled alongside healthy individuals in a derivation-validation cohort design. Serum SDC1 was measured by enzyme-linked immunoassay. The diagnostic accuracy of SDC1 levels for diagnosing PDAC was computed. A unified cohort enriched with additional early-stage patients with PDAC was used to evaluate the association of SDC1 with survival outcomes and patient characteristics.RESULTS:In the derivation cohort, serum SDC1 levels were significantly higher in patients with PDAC (n = 39) compared with healthy controls (n = 20) (40.1 ng/mL, interquartile range 29.8–95.3 vs 25.6 ng/mL, interquartile range 17.1–29.8, respectively; P < 0.001). The receiver operating characteristic analysis area under the curve was 0.847 (95% confidence interval 0.747–0.947, P < 0.001). These results were replicated in a separate age-matched validation cohort (n = 38 PDAC, n = 38 controls; area under the curve 0.844, 95% confidence interval 0.757–0.932, P < 0.001). In the combined-enriched PDAC cohort (n = 110), using a cutoff of 35 ng/mL, the median overall 5-year survival between patients below and above this cutoff was not significantly different, although a trend for better survival after 1 year was found in the lower level group (P = 0.06). There were 12 of the 110 patients with PDAC (11%) who had normal CA 19-9 in the presence of elevated SDC1.DISCUSSION:These findings suggest serum SDC1 as a promising novel biomarker for early blood-based diagnosis of pancreatic cancer.

Composition of the Immune Environment at Baseline Correlates with Time to Response and Treatment Outcome in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (MM) Patients Randomized to Krd or Ktd Followed By Carfilzomib Maintenance or Observation (AGMT_MM 02 Study)

Composition of the Immune Environment at Baseline Correlates with Time to Response and Treatment Outcome in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (MM) Patients Randomized to Krd or Ktd Followed By Carfilzomib Maintenance or Observation (AGMT_MM 02 Study)

AKR1B1 and AKR1B10 as Prognostic Biomarkers of Endometrioid Endometrial Carcinomas.

The roles of aldo-keto reductase family 1 member B1 (AKR1B1) and B10 (AKR1B10) in the pathogenesis of many cancers have been widely reported but only briefly studied in endometrial cancer. To clarify the potential of AKR1B1 and AKR1B10 as tissue biomarkers of endometrial cancer, we evaluated the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 101 well-characterized patients with endometrioid endometrial cancer and 12 patients with serous endometrial cancer and compared them with the clinicopathological data. Significantly higher immunohistochemical levels of AKR1B1 and AKR1B10 were found in adjacent non-neoplastic endometrial tissue compared to endometrioid endometrial cancer. A trend for better survival was observed in patients with higher immunohistochemical AKR1B1 and AKR1B10 levels. However, no statistically significant differences in overall survival or disease-free survival were observed when AKR1B1 or AKR1B10 were examined individually in endometrioid endometrial cancer. However, analysis of AKR1B1 and AKR1B10 together revealed significantly better overall and disease-free survival in patients with both AKR1B1 and AKR1B10 staining above the median values compared to all other patients. Multivariant Cox analysis identified strong AKR1B1 and AKR1B10 staining as a statistically important survival prediction factor. Conversely, no significant differences were found in serous endometrial cancer. Our results suggest that AKR1B1 and AKR1B10 play protective roles in endometrioid endometrial cancer and show potential as prognostic biomarkers.

Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort.

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.

Predictive Role of Biopsy Based Biomarkers for Radiotherapy Treatment in Rectal Cancer.

Background and Purpose: Radiation therapy has long been contemplated as an important mode in the treatment of rectal cancer. However, there are few ideal tools available for clinicians to make a radiotherapy decision at the time of diagnosis for rectal cancer. The purpose of this study was to assess whether biomarkers expressed in the biopsy could help to choose the suitable therapy and provide predictive and/or prognostic information. Experimental Design: In total, 30 biomarkers were analyzed in 219 biopsy samples before treatment to discover the possibility of using them as an indicator for radiotherapy selection, diagnosis, survival and recurrence. Results: Twenty-two biomarkers (COX2-RT, COX2-NonRT, etc.; 36.67%) had diagnostic value. For survival, four biomarkers (NFKBP65, p130, PINCH and PPAR) were significant in regulating gene promoter activity and overall survival, while four had a trend (AEG1, LOX, SATB1 and SIRT6). Three biomarkers (COX2, PINCH and WRAP53) correlated with disease-free survival, while eight had a trend (AEG1, COX2, Ki67, LOX, NFKBP65, PPAR and SATB1). Four biomarkers (COX2-RT, NFKBP65cyto-RT, P130cyto-NonRT and PPARcyto-RT) were independent prognostic factors for recurrence. NFKBP65 and SIRT6 were significantly correlated with lymph node metastasis regardless of radiation. Patients with high AEG1, LOX, NFKBP65, PPAR and SATB1 had or showed a positive trend for better survival after radiotherapy, while those with positive PINCH and WRAP53 expression would not benefit from radiotherapy. Conclusions: AEG1, LOX, NFKBP65cyto, PPAR and SATB1 could be used as indicators for choosing radiotherapy. COX2-RT, COX2-NonRT and some other biomarkers may provide additional help for diagnosis.

COPD Comorbidities Predict High Mortality – Asthma-COPD-Overlap Has Better Prognosis

The purpose of this study was to investigate the characteristics and survival of patients with COPD and asthma-COPD overlap (ACO) and how these patient groups differ from each other. We examined the impact of different comorbidities, multimorbidity, lung function and other factors have on survival in COPD and ACO patients. We also examined the causes of death to determine how many patients die of other than respiratory diseases. This retrospective study includes 214 patients with an exacerbation of COPD requiring hospitalisation during the year of 2005. The patients were followed up until the end of year 2015. The survival of ACO patients was significantly higher than COPD patients (4.7 vs. 1.7 years, p = 0.001). Poor lung function predicted worse survival in both patient groups, but the prognosis was still better in ACO patients with both FEV1 over and under 50% of predicted (median survival 8.4 years vs. 5.8 years, p < 0.001) compared to COPD (4.9 and 3.1 years, respectively). In this study setting, the negative effect of having three or more comorbidities on survival was significant in both groups. We didn’t see major differences in the profiles of comorbidity patterns, in the underlying cause of deaths or in the pulmonary functions between ACO and COPD groups at the beginning of follow-up. Patients with a BMI over 25 seemed to have a trend for better survival (p = 0.055), but no differences were found between ACO and COPD groups.

Prognostic value of p16INK4a overexpression in penile cancer.

Penile cancer is rare, accounting for less than 1% of all male cancers in industrialized countries. It is most common in areas of high prevalence of HPV, being a third of cases attributed to the carcinogenic effect of HPV. Tumour cells infected with HPV overexpress p16INK4a, as such p16INK4a has been used as a surrogate of HPV infections. To evaluate the prognostic factor of p16INK4a overexpression in penile cancer. Retrospective analysis of patients diagnosed with penile cancer, submitted to surgery in a Portuguese Oncological Institution in the last 20 years (n = 35). Histological review of surgical pieces and immunohistochemical identification of p16INK4a. Relation between p16INK4a and the following factors were studied: age, histological subtype, tumour dimensions, grade, TNM stage, perineural invasion, perivascular invasion, disease free survival (DFS) and cancer specific survival (CSS). p16INK4a was positive in 8 patients (22.9%). Identification of p16INK4a did not correlate with none of the histopathological factors. In this work we identified a better DFS and CSS in patients positive for p16INK4a (DFS at 36 months was 100.0% vs. 66.7%; CSS at 36 months was 100.0% vs. 70.4%), although without statistical significance (p > 0.05). In multivariate analysis of histopathological factors studied, only N staging correlated with DFS and CSS (p = 0.017 and p = 0.014, respectively). the percentage of cases positive for p16INK4a is smaller than the one found in literature, which can suggest a less relevant part of HPV infection in the oncogenesis of penile cancer in the studied population. Identification of p16INK4a did not relate with other clinicopathological factors. Tendency for a more favourable prognosis in patients with p16INK4a agrees with results found in literature. The most relevant factor for prognosis is nodal staging. penile cancer positive for p16INK4a shows a trend for better survival, although the most relevant factor is nodal staging.

P1715Management and outcome in patients with non-ischemic cardiogenic shock and Impella CP use

Abstract Background and purpose From the various mechanical cardiac assist devices and indications available, use of the percutaneous intraventricular Impella CP pump is usually restricted to acute ischemic shock or prophylactic indications in high-risk interventions. In the present study, we investigated clinical usefulness of the Impella CP device in patients with non-ischemic cardiogenic shock as compared to acute ischemia. Methods In this retrospective single-center analysis, patients who received an Impella CP between 2013 and 2017 due to non-ischemic cardiogenic shock were age-matched 2:1 with patients receiving the device due to ischemic cardiogenic shock. Inclusion criteria were therapy refractory hemodynamic instability with severe left ventricular systolic dysfunction and serum lactate &gt;2.0 mmol/l at implantation. Basic clinical data, indications for mechanical ventricular support, and outcome were obtained in all patients with non-ischemic as well as ischemic shock and compared between both groups. Continuous variables are expressed as mean ± standard deviation or median (quartiles). Categorical variables are presented as count and percent. Results 25 patients had cardiogenic shock due to non-ischemic reasons, and were compared to 50 patients with cardiogenic shock due to acute myocardial infarction. Resuscitation rates before implantation of Impella CP were high (32 vs 42%; P=0.402). At implantation, patients with non-ischemic cardiogenic shock had lower levels of HsTNT (110.65 [57.87–322.1] vs 1610 [450.8–3861.5] pg/ml; P=0.001) and LDH (377 [279–608] vs 616 [371.3–1109] U/I; P=0.007), while age (59±16 vs 61.7±11; P=0.401), GFR (43.5 [33.2–59.7] vs 48 [35.75–69] ml/min; P=0.290), CRP (5.17 [3.27–10.26] vs 10.97 [3.23–17.2] mg/dl; P=0.195), catecholamine-index (30.6 [10.6–116.9] vs 47.6 [11.7–90] μg/kg/min; P=0.663), and serum lactate (2.6 [2.2–5.8] vs 2.9 [1.3–6.6] mg/dl; P=0.424) were comparable between both groups. There was a trend for longer duration of Impella support in the non-ischemic groups (5 [2–7.5] vs 3 [2–5.25] days, P=0.211). Rates of hemodialysis (52 vs 47%; P=0.680) and transition to ECMO (13.6 vs 22.2%; P=0.521) were comparable. No significant difference was found regarding both 30-days survival (48 vs 30%; P=0.126, Figure 1) as well in-hospital mortality (66.7 vs 74%; P=0.512) although there was a trend for better survival in the non-ischemic group. 30-days survival Conclusions The current results position short-time use of the Impella CP as an alternative in the treatment of patients with cardiogenic shock due to underlying non-ischemic cardiomyopathy and/or complicating additional factors. However, additional studies are needed to test whether these findings can be confirmed in larger patient populations and which subgroups might benefit most from Impella therapy.

Small Lymphocytic Lymphoma: Analysis of Two Cohorts Including Patients in Clinical Trials of the German Chronic Lymphocytic Leukemia Study Group (GCLLSG) or in "Real-Life" Outside of Clinical Trials.

Only few studies have focused exclusively on patients with small lymphocytic lymphoma (SLL). In the present report, 103 SLL patients were analyzed from both, clinical trials of the German Chronic Lymphocytic Leukemia Study Group and Greek centers, and emphasis was placed on the therapeutic strategy. The impact of lymph node characteristics, such as the presence of proliferation centers (PCs) on response and survival was also assessed. SLL patients included in clinical trials were treated mostly with fludarabine-based regimens while those in "real-life" were staged and treated mostly as patients with low-grade lymphomas. Our analysis showed a trend for better survival for patients with SLL without detectable PCs. Patients with SLL outside of clinical trials are usually treated as cases of lymphoma. In addition, this analysis supports published data regarding the adverse prognostic value of the presence of PCs in lymphoid nodes in SLL.

Abstract P2-08-20: Prognostic impact of SRC, CDKN1B and JAK2 expression in metastatic breast cancer patients treated with trastuzumab

Abstract Background-aim: SRC, CDKN1B and JAK2 play a crucial role in the coordination and facilitation of cell-signaling pathways controlling a wide range of cellular functions. In the present study, we investigated the prognostic significance and clinical utlity of these biomarkers in metastatic breast cancer (MBC) patients treated with trastuzumab (T). Methods: We assessed SRC, CDKN1B and JAK2 mRNA expression with qRT-PCR (Taqman-MGB assays) on 197 paraffin tumors. PIK3CA mutation status was previously assessed. Relapsed (RMBC) and de novo MBC (dnMBC) patients had received T for metastatic disease only. Tumors were centrally re-assessed for HER2 status. Results: Only 133/197 patients (67.5%) were found to be truly HER2(+). CDKN1B mRNA expression strongly correlated with SRC (rho = 0.71) and JAK2 (rho = 0.54); high CDKN1B was more frequent in RMBC compared to dnMBC (p = 0.001) and in PIK3CA wild-type tumors (p = 0.005). In HER2(+) patients, low CDKN1B conferred higher risk for progression (HR 1.58, 95% CI 1.08-2.32, p = 0.018). In HER2(-) patients, low SRC was associated with longer survival (HR 0.56, 95% CI 0.32-0.99, p = 0.045) and, as a trend, with increased progression-free survival (PFS) (p = 0.067). For PFS, in RMBC, we observed trends for unfavorable low CDKN1B (p = 0.068) and JAK2 (p = 0.086); similarly, in dnMBC for unfavorable low CDKN1B (p = 0.072). Low SRC showed a trend for better survival in RMBC (p = 0.087). Upon multivariable analyses, only PIK3CA mutations strongly predicted for unfavorable PFS in HER2(+) patients (HR 3.37, 95% CI 1.98-5.73, p &amp;lt; 0.001). Low CDKN1B and JAK2 mRNA expression remained unfavorable factors for PFS in dnMBC and RMBC patients (HR 2.36, 95% CI 1.01-5.48, p = 0.046 and HR 1.76, 95% CI 1.01-3.06, p = 0.047, respectively). Conclusions: Low CDKN1B and JAK2 mRNA expression were unfavorable prognosticators in a cohort of T-treated MBC patients previously unexposed to this agent, with distinct impact in de novo and RMBC. Our results highlight biological and clinical differences between de novo and RMBC and suggest that CDKN1B and JAK2, if validated, may serve as prognostic factors potentially implicated in T-resistance, which seems to be associated with distinct pathways in the two MBC settings. Citation Format: Economopoulou P, Kotoula V, Koliou G-A, Papadopoulou K, Christodoulou C, Pentheroudakis G, Koutras A, Bafaloukos D, Papakostas P, Pectasides D, Kotsakis A, Razis E, Samantas E, Kalogeras KT, Economopoulos T, Fountzilas G. Prognostic impact of SRC, CDKN1B and JAK2 expression in metastatic breast cancer patients treated with trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-20.

Patient reported abdominal pain as a surrogate of the clinical benefit of tipifarnib in pancreatic cancer patients.

275 Background: Tumor CXCL12 expression identifies patients who may benefit from tipifarnib therapy. In pancreatic cancer, CXCL12 is known to decrease abdominal pain by inducing the migration of pain suppressing Schwann cells to tumor lesions. Given the association between CXCL12 and pain suppression, we investigated whether the absence of patient reported abdominal pain could be a surrogate of clinical benefit from tipifarnib in pancreatic cancer patients. Methods: We conducted a retrospective analysis of a randomized placebo-controlled trial comparing gemcitabine plus tipifarnib (GT) versus gemcitabine plus placebo (GP) in pancreatic adenocarcinoma patients. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine at standard dosing. Primary study end point was overall survival. Results: 688 patients were enrolled of whom 155 (22.5%) reported no abdominal pain at study entry, 81 received GT and 74 GP. Baseline characteristics were balanced in the subset of patients with no reported abdominal pain (GT,GP): median age (63,59), female gender (35%,43%), ECOG 0-1 (89%,90%), metastatic disease (64%,70%), 6-month weight loss &gt;10% (48%,39%), 6-month jaundice history (51%,45%), and prior Whipple surgery (16%,13%). Subjects receiving GT who did not report abdominal pain at study entry had higher frequency of locally advanced disease (36% vs 24%) and 6-month jaundice (51% vs 38%), and lower frequency of lung (6% vs 14%) and peritoneum (4% vs 13%) metastases than those reporting pain. No differences in survival were observed in the overall study. Median overall survival for GT was 193 vs 182 days for GP. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 305 vs 176 days, HR=0.52, p&lt;0.0001, whereas no significant effect was observed in the control arm: 184 vs 182 days. A trend for better survival with GT was observed in subset of patients with no abdominal pain at study entry (GT,GP): 305 vs 184 days, p=0.058. Conclusions: Absence of abdominal pain may serve as a surrogate of clinical benefit from tipifarnib in pancreatic cancer. (Van Cutsem et al. JCO 2004;22:1430-8; NCT00005648; Trial Sponsor: J&amp;J PRD). Clinical trial information: NCT00005648.

Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors.

Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pretreatment. A nonsignificant association was observed between development of any autoantibodies and any irAEs [OR, 2.92; 95% confidence interval (CI) 0.85-10.01]. Patients with antithyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti-PD-1 therapy: 7/11 (54.6%) patients with antithyroid antibodies after ipilimumab developed thyroid dysfunction under anti-PD1 versus 7/49 (14.3%) patients without antibodies (OR, 9.96; 95% CI, 1.94-51.1). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66; 95% CI, 0.34-1.26) and therapy response (OR, 2.64; 95% CI, 0.85-8.16). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy.

Mid- and long-term prognosis of off- vs. on-pump coronary artery bypass graft in patients with multisite artery disease

Among patients with coronary artery disease (CAD), around 25% have multisite artery disease (MSAD). Patients with CAD and MSAD are at higher risk of peri-operative and long-term cardiovascular events. Whether off-pump coronary bypass grafting (CABG) can improve their prognosis is unknown. We aimed to assess the benefits of off- vs. on-pump cardiac surgery in patients undergoing CABG, according to coexistence of extra-cardiac artery disease. Between April 1998 and September 2008, 1221 patients undergoing CABG without any other intervention were enrolled. Overall death and major cardiovascular events were recorded at 1-month and during long-term follow-up. A propensity score (PS), derived from all relevant variables (P<0.25) associated with on-pump as compared to off-pump CABG, and representing the likelihood for each individual patient to receive off-pump CABG, was calculated. MSAD was observed in 279 patients (23%). Off-pump CABG was performed in 208 (17%) patients. The median follow-up was 7.6 years. The 10-year mortality was significantly lower in off- vs. on-pump CABG group (74±4% vs. 68±2%, P=0.024). In patients with MSAD, there was a trend for better survival for off- vs. on-pump CABG (63±8% vs. 50±4%, P=0.078). After adjustment for PS, we found no further difference between on- and off-pump CABG both in the whole cohort (HR=1.30, P=0.10), as well as in MSAD patients (HR=1.51, P=0.14). Patients with MSAD receiving CABG are at worst prognostic than those with isolated CAD. In these patients, we found no significant difference in the long-term mortality and cardiovascular events between on- and off-pump CABG.

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis.

In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (p=0.024), large splenomegaly (p=0.017), transfusion dependency (p=0.022), platelet count <200×109/l (p=0.028), and a time-interval between MF diagnosis and RUX start >2 years (p=0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.

Trastuzumab and survival of patients with metastatic breast cancer.

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer.