Independent Predictors Of Complete Response Research Articles

High serum miR-223-3p expression level predicts complete response and prolonged overall survival in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.

AHSCT is the treatment of choice for newly diagnosed patients with transplant-eligible multiple myeloma (MM). However, considerable variability in response to autologous hematopoietic stem cell transplantation (AHSCT) results in only 50% of patients achieving complete response (CR) after AHSCT, which is directly associated with improved progression-free and overall survival (OS). In this study, we aimed to investigate the potential predictive role of selected serum miRNAs in MM patients who underwent AHSCT. Serum expression level of 6 miRNAs: miR-221-3p, miR-15b-5p, miR-223-3p, miR-320c, miR-361-3p, and miR-150-5p was evaluated in 51 patients who underwent AHSCT. Blood samples were collected at two time points: before conditioning chemotherapy (T1) and fourteen days after transplant (+14) (T2). All selected miRNAs significantly changed their expression level across the procedure- two were up-regulated after AHSCT: hsa-miR-320c (FC 1.42, p<0.0001) and hsa-miR-361-3p (FC 1.35, p=0.0168); four were down-regulated: hsa-miR-15b-5p (FC 0.53, p<0.0001), hsa-miR-221-3p (FC 0.78, p=0.0004), hsa-miR-223-3p (FC 0.74, p=0.0015) and hsa-miR-150-5p (FC 0.75, p=0.0080). Notably, before AHSCT, hsa-miR-223-3p was down-regulated in International Staging System (ISS) III patients (FC=0.76, p=0.0155), and hsa-miR-320c was up-regulated (FC=1.27, p=0.0470). These differences became non-significant after AHSCT. Eight (15.69%) patients achieved CR before AHSCT and 17 patients (33.33%) at +100 days after AHSCT. In multivariate logistic regression analysis, achievement of CR after induction and hsa-miR-223-3p at T1 were independent predictors of CR after AHSCT. In multivariate Cox regression analysis, hsa-miR-223-3p at T1 expression level was associated with prolonged OS (HR 0.06, 95%CI: 0.00 - 0.99, p=0.0488). Serum expression of has-miR-223-3p is a predictor of CR and prolonged OS in MM patients undergoing AHSCT.

Impact of Programmed Death-ligand 1 Expression on Oncological Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Radiation-based Therapy

BackgroundNo biomarkers are recommended for patients undergoing radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC). ObjectiveWe aim to evaluate the predictive role of programmed death-ligand 1 (PD-L1) expression on the oncological outcomes of patients treated with RT for MIBC. Design, setting, and participantsA single-center retrospective analysis of tumor specimens collected through transurethral resection (TURBT) from 104 MIBC patients, implemented in a tissue microarray and stained with the SP263 PD-L1 clone (Ventana Medical Systems, Tucson, AZ, USA), was conducted. Two reviewers measured the PD-L1 H-score for tumor and immune cells. InterventionRT (maximal TURBT followed by radiation and concurrent chemotherapy when eligible). Outcome measurements and statistical analysisLogistic and Cox regression models were used to predict 3-mo complete response (CR) and overall survival (OS) after RT, respectively. Results and limitationsA total of 88 (85%) patients had cT2 disease and 39 (37.5%) had high immune cell PD-L1 expression. A CR was achieved in 68 (65%) patients. On the multivariable analysis (MVA), a higher clinical stage (p = 0.02) and a low immune cell PD-L1 H-score (p = 0.02) were associated with a decreased CR after RT. The median time to death was 43 mo (95% confidence interval 20–66). On Cox MVA, a high immune cell PD-L1 H-score (p = 0.0017) was associated with better OS, independently of performance status (p = 0.0005) or tumor stage (p = 0.0013). A high tumor cell PD-L1 H-score was not an independent predictor of CR or OS. Limitations of the study include the retrospective design. ConclusionsMIBC patients with high PD-L1 expression on immune cells appear to have better oncological outcomes following RT. Our results may aid in patient stratification for future clinical trial design. Patient summaryIn this report, we evaluated the role of programmed death-ligand 1 (PD-L1) expressed on tumor and immune cells in the tumor microenvironment for patients treated with a bladder-sparing regimen. We found that PD-L1 overexpression on immune cells is able to predict a better response to radiation-based therapy.

Clinical Study on the Treatment of Pediatric Primary Nocturnal Enuresis by Integrated Traditional Chinese and Western Medicine

To investigate the curative effect of integrated traditional Chinese and Western medicine in the treatment of children with primary nocturnal enuresis is the objective of the study. 160 children with primary nocturnal enuresis were randomly divided into four groups and received suoquan capsules, solifenacin combined with suoquan capsules, solifenacin or behavioral intervention for 2 mo. The response rates of each group were evaluated and logistic regression analysis was used to analyze the influencing factors of curative effect. In addition, the patients were followed up after 3 mo to investigate the recurrence rate. The complete remission (complete response) rate in solifenacin combined with suoquan capsules group was higher than that in behavioral intervention group (37.5 % vs. 7.5 %, p=0.007). The complete response rate and non-response rate in the solifenacin group were lower than those in the solifenacin combined with suoquan capsules group (all p<0.05). The recurrence rate in the solifenacin group was significantly higher than that in the solifenacin combined with suoquan capsules group (72.5 % vs. 30.0 %, p=0.027). Multivariate analysis showed that treatment group, enuresis frequency and age were independent predictors of complete response at 2 mo. Integrative traditional Chinese and Western medicine has good effect in the treatment of children with primary nocturnal enuresis and the recurrence rate is low. Enuresis frequency, treatment method and age were important predictors of complete remission after treatment

Evaluating Clinical Outcomes and Potential Prognostic Factors Among 308 Children and Adolescents with Immune Thrombocytopenia (ITP): An 11-Year Retrospective Cohort Study

Background:Immune thrombocytopenia (ITP) usually is a mild and self-limited disease; however, 25-30% of children develop chronic ITP. Nordic score is a validated clinical prediction tool, yet its use in children is limited and evidence for other prognostic factors is unclear.Purpose:To evaluate clinical outcomes among pediatric ITP patients, and examine their relationship to patient characteristics, including Nordic score. We hypothesized that Nordic score and patient characteristics will be predictive of ITP resolution or development of chronic ITP.Methods:We conducted a retrospective chart review of all children diagnosed with ITP at our institution between May 2008 to May 2019. Data extraction included patients' age, sex, presenting signs and symptoms, laboratory values, treatment decisions, and clinical outcomes. Nordic score calculated with 6 clinical features from diagnosis: abrupt onset <14 days, age < 10 years, preceding infection <1 month, platelet count < 5x10 9/L, wet purpura, and male sex. High scores (10-14) predict a brief disease course (<3 months), whereas low scores (0-4) predict a more prolonged course.Primary outcomes included complete response (CR) (platelets 100 x10 9/L on 2 occasions >7 days apart), recurrence (platelets < 100 after achieving CR), development of chronic ITP, and resolution (long term normal platelet count). Secondary outcomes included early response (platelets 30 x10 9/L in <1 week), time to CR, duration of CR (months between CR and recurrence), and time to resolution. Data presented as odds ratio (OR) with 95% confidence intervals. OR for Nordic score presented per 5-unit increase correlating with Nordic score categories (low 0-4, moderate 5-9, high 10-14).Results:A total of 308 patients were included (median age 5 years, IQR 2.0-10.8; 54.5% male) (Table 1). About 56% presented with platelets < 10 x10 9/L and 42% had bleeding at diagnosis (bleeding score 3 or higher), only 3% were severe. Median Nordic score was 10 (IQR 6-11). Overall, 64% of patients were treated upfront, majority (98%) receiving intravenous immunoglobulin (IVIG).Treatment at diagnosis was more likely for patients with platelets < 10 x10 9/L (OR 21, 10.4-42.5), bleeding score 3 or higher (OR 2.0, 1-4), and higher Nordic score (OR 6.2, 5.6-6.9) (Table 2). Treatment was predictive only of early response in multivariate analysis, not of CR, recurrence, development of chronic ITP, or disease resolution. Additionally, treatment at diagnosis was not associated with reduction in ITP-related complications, such as major bleeding episodes, need for platelet or red cell transfusions, or iron deficiency anemia.Overall rate of CR was 90% over a median of 1 month (IQR 0.3-4 months), while 13% had recurrence after median 19 months (IQR 8.3-26.0 months) and 32% developed chronic ITP. Overall, 80% of all study patients had resolution of ITP after median 1 month (IQR 0.3-5), with 86% achieving this before 12 months. About 36% of patients with chronic ITP had disease resolution over median 25 months (IQR 16.3-46.5 months).Univariate analysis showed significant variation across subgroups for age, viral symptoms, abrupt onset, Nordic score, hospital admission at diagnosis, platelet count, and treatment. Using multivariate regression analysis adjusted for the above variables, Nordic score was the only independent predictor of all primary outcomes. Higher Nordic score group had increased likelihood of CR (OR 6.2, 5.6-6.8) and disease resolution (OR 6.8, 5.1-8.9). Lower Nordic score group was associated with increased likelihood of recurrence (OR 6.5, 5.3-6.9) and development of chronic ITP (OR 8.6, 6.5-11.4). Additionally, higher Nordic score group was associated with increased time to recurrence and duration of response, decreased time to CR and resolution.Conclusions:In our cohort, low platelet count and bleeding symptoms were drivers of upfront treatment in pediatric ITP. Treatment initiation, associated with Nordic score, was predictive of faster increase in platelet count; however, it had no impact on overall disease trajectory or likelihood of complications. Our analysis demonstrate that Nordic score is an independent predictor of CR, resolution, recurrence, and development chronic ITP. Nordic score is a useful, simple prognostic tool that has the potential to help predict clinical course of pediatric ITP and identifying patients who may benefit from closer monitoring. [Display omitted] DisclosuresBadawy: Bluebird Bio Inc: Consultancy; Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy.

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation.

Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described. The study population consisted of children (n=83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array. Patients with R/D lesions receiving CSI (n=32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P=.0493), IL-6 (P=.0111), and IL-10 (P=.0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P < .0001, P=.018, P < .0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively. CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.

Predictors of Complete Response in Patients with Hepatocellular Carcinoma Treated with Trans-Arterial Radioembolization.

Background: Trans-arterial radioembolization (TARE) has shown promising results in treating hepatocellular carcinoma (HCC). We identified independent predictors of radiological complete response (CR) in patients with intrahepatic HCC who were treated with TARE. Methods: Patients with intrahepatic HCC treated with TARE between 2011 and 2017 were recruited. CR was defined according to the modified Response Evaluation Criteria in Solid Tumors. Cox regression analysis was used to determine independent predictors of CR. Results: The median age of study participants (83 men and 19 women) was 64.3 years. The mean survival after TARE was 55.5 months, and 21 (20.6%) patients died during the study period. Patients who achieved CR (14 patients, 13.7%) had significantly higher serum albumin level (median 4.1 vs. 3.9 g/dL), lower total bilirubin level (median 0.6 vs. 0.7 mg/dL), lower aspartate aminotransferase level (median 30.0 vs. 43.0 IU/L), lower alkaline phosphatase level (median 79.0 vs. 103.0 IU/L), lower alpha-fetoprotein level (median 12.7 vs. 39.9 ng/mL), lower des-gamma-carboxyprothrombin level (median 575.5 vs. 2772.0 mAU/mL), lower model for end-stage liver disease (MELD) score (median 6.0 vs. 7.0), and smaller maximal tumor diameter (median 6.3 vs. 9.0 cm) compared to those who did not achieve CR (all p < 0.005). Multivariate Cox regression analysis showed that lower MELD score (hazard ratio (HR) = 0.436, p = 0.015) and maximal tumor size < 9 cm (HR = 11.180, p = 0.020) were independent predictors of an increased probability of radiological CR after TARE. Conclusions: Low MELD score and small maximal tumor size were independently associated with an increased probability of CR after TARE in patients with intrahepatic HCC.

Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: prediction of pathological response and postoperative recurrence

BackgroundThe “watch-and-wait” approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC). However, the diagnostic sensitivity of clinical modalities, such as colonoscopy and magnetic resonance imaging to determine pathological response, is not high. We analysed the clinical utility of circulating tumour DNA (ctDNA) of patients with LARC to predict response to preoperative therapy and postoperative recurrence.MethodsA serial ctDNA analysis of 222 plasma samples from 85 patients with LARC was performed using amplicon-based deep sequencing on a cell-free DNA panel covering 14 genes with over 240 hotspots.ResultsctDNA was detected in 57.6% and 22.3% of samples at baseline and after preoperative treatment, respectively, which was significantly different (P = 0.0003). Change in ctDNA was an independent predictor of complete response to preoperative therapy (P = 0.0276). In addition, postoperative ctDNA and carcinoembryonic antigen (CEA) were independent prognostic markers for risk of recurrence after surgery (ctDNA, P = 0.0127 and CEA, P = 0.0105), with a combined analysis having cumulative effects on recurrence-free survival (P = 1.0 × 10–16).ConclusionsSerial ctDNA analysis may offer clinically useful predictive and prognostic markers for response to preoperative therapy and postoperative recurrence in patients with LARC.

Baseline serum miR-125b levels predict virologic response to nucleos(t)ide analogue treatment in patients with HBeAg-positive chronic hepatitis B.

The aim of the present study was to investigate the predictive value of baseline serum microRNA (miRNA)-125b for nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). A total of 66 patients with Be antigen (HBeAg)-positive CHB received NAs therapy for 144 weeks. Serum miRNA-125b levels were measured at the baseline, while hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg) and alanine aminotransferase (ALT) levels were measured throughout treatment. Stepwise logistic regression analysis was performed to identify predictors of treatment response. The results indicated that baseline serum miR-125b (OR=4.377; P=0.006), HBsAg (OR=0.120; P=0.010), ALT >5× upper limit of normal (ULN; OR=11.726; P=0.018) and undetectable HBV DNA at week 24 (OR=7.828; P=0.021) were independent predictors of complete response (CR) at 144 weeks (CR is defined as HBV DNA <500 IU/ml and HBeAg seroconversion). The baseline serum miRNA-125b combined with baseline HBsAg level yielded an area under the receiver-operating curve of 0.852 in discriminating CR and non-CR at 144 week. The combination of baseline miRNA-125b ≥1.7 and ALT >5× ULN had a positive predictive value 80% for CR at 144 weeks. The combination of baseline miRNA-125b ≥1.7 and HbsAg ≤4.4 (log10 IU/ml) had a negative predictive value of CR at 144 weeks of 100%. Together, these results suggest that baseline miRNA-125b is a reliable predictor of HBeAg seroconversion following NAs treatment. The present study may be used as a basis for the use of baseline miRNA-125b to optimize treatment prior to NAs therapy.

Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: Randomized controlled trial.

Nocturnal enuresis (NE) is a common pediatric developmental disorder. Desmopressin is frequently used for NE and is an evidence-based therapy. Suoquan capsule is a Chinese medicine commonly used for treating NE in children but is poorly understood by most scholars. A total of 369 children with NE were randomized to receive either suoquan, desmopressin plus suoquan, desmopressin, or behavioral intervention for 2months, and the response rates evaluated. Subsequently, the viable demographic factors that could lead to success were investigated on logistic regression analysis. Moreover, after 3months of follow up, the relapse rate was investigated. The complete response (CR) rate in the desmopressin plus suoquan group (37.5%) was higher than that in the behavioral intervention group (6.3%, P<0.007). The desmopressin group had a lower CR rate (22.5%) and a higher non-response rate (25.0%) than the desmopressin plus suoquan group (non-response rate, 21.9%; P>0.007). The relapse rate in the desmopressin group was significantly higher than that in the desmopressin plus suoquan group (72.2% vs. 30.6%, P<0.007). On Multivariate analysis, treatment group, NE frequency, and age were independent predictors of CR at 2months (P<0.05). Combined traditional Chinese and Western treatment in children with NE is effective and has a low relapse rate. NE frequency, treatment method, and age are important predictive factors for CR after treatment.

Outcomes Comparing Initial Short vs Long Course Echinocandin Therapy in Patients with Candidemia Caused by Fluconazole Susceptible Strains

Background Guidelines for candidemia (CAND) treatment recommend initial echinocandin (ECHINO) therapy with transition to fluconazole (FLUC) after 5–7 days in patients with clinical stability, FLUC-susceptibility, and negative cultures; however, optimal timing for transition is unknown. In the era of rapid diagnostics and antimicrobial stewardship programs (ASP), studies are needed to evaluate the impact of earlier transition in CAND due to routinely FLUC-susceptible species.Methods Retrospective study of adult patients at NewYork-Presbyterian Hospital from 2012 to 2014. Inclusion criteria included ≥1 blood culture with C. albicans, C. tropicalis or C. parapsilosis, ≥1 dose ECHINO initial therapy, ≥3 days total treatment, and no prior episode of CAND within 30 days. Patients with polymicrobial bloodstream infection excluded. Patients de-escalated from ECHINO at ≤3 days (short-course; SC-ECH) were compared with those who received ≥4 days of ECHINO (long course; LC-ECH). The primary outcome was 14-day complete response (CR), defined as survival with clinical improvement and sterilization of blood cultures. Secondary outcomes included day 7 microbiological success (MicroS) and 28-day survival (SURV).Results76 patients included: 21 in SC-ECH, 55 in LC-ECH groups. C. albicans (58%) most common species. Majority were male (59%) with median age 64 years (IQR 49–74), 62% were in ICU at time of CAND, 50% had recent surgery. No significant baseline differences between SC-ECH and LC-ECH groups, including in PITT bacteremia score ≥4 (43% vs. 42%; P = 0.4) or median APACHE (20 vs. 20; P = 0.684). There was no difference between SC-ECH vs. LC-ECH in CR (52% vs. 49%; P = 1.0), early MicroS (81% vs. 87%; P = 0.484), or SURV (62% vs. 73%; P = 0.523). On multivariable analysis with duration of ECHINO therapy forced into the model, only PITT bacteremia score <4 remained an independent predictor of CR (OR 6.1, 95% CI 2.1, 17.9; P = 0.001).Conclusion In adult patients with CAND due to routinely FLUC-susceptible species, early de-escalation from ECHINO was associated with similar outcomes, including day 7 MicroS. Early de-escalation based on early species identification has the potential to be a target for ASPs to optimize antifungal therapy without compromising clinical outcomes.Disclosures All authors: No reported disclosures.

Measurement of Phosphorylated ERK As a Prognostic and Predictive Marker for MEK Inhibition in Pediatric B-Lymphoblastic Leukemia: A Pilot Study

Abstract Background: Outcomes for patients with relapsed B- acute lymphoblastic leukemia (B-ALL) remain suboptimal. We and others have identified the Mitogen activated protein kinase/ Extracellular signal regulated kinase (MAPK/ERK) pathway as a primary driver of drug resistance in pediatric B-ALL. Constitutive activation of ERK has been found to be an independent predictor of complete response and is associated with other poor prognostic factors in adults with B-ALL. Mutations that affect activation of the Ras/Raf/MEK/ERK pathway have been found in up to 40% of children with newly diagnosed and relapsed ALL and these mutations correlate with early relapse and poor overall survival. However, we have demonstrated MAPK activation in the absence of Ras pathway mutations, suggesting alternative mechanisms of activation. Hypothesis: We hypothesize that activation of the MAPK pathway drives drug resistance in pediatric B-ALL. Activation of this pathway at diagnosis may portend a high likelihood of relapse and inhibition of the MAPK pathway may restore chemosensitivity to conventional agents. Methods: For our initial pilot study, a total of 24 patient samples from initial diagnosis obtained from Children's Oncology Group cell bank and from NYU, were thawed and placed either in serum-free media or media containing Trametinib (MEK1/2 inhibitor) at 1µM for 4 hours. Samples were then stimulated with Phorbol 12-myristate 13-acetate (PMA), a specific activator of Protein Kinase C, which activates MEK via Ras. Samples were then fixed with 4% paraformaldehyde, permeabilized with 95% methanol, and stained for Caspase 3, CD10, phosphorylated ERK (p-ERK), and p-AKT. All samples were simultaneously processed on the BD LSRII HTS and analyzed on FlowJo software (Treestar, V.10). Viable leukemic blasts were identified as CD10 positive and Caspase 3 negative cells, which were gated on for further analysis. Median fluorescence intensity (MFI) for phosphorylated proteins was measured, expressed as a ratio to isotype controls and compared between samples. MAPK activation was defined by maximal p-ERK levels upon stimulation with PMA. Inhibition was quantified as percentage decrease in maximal p-ERK levels (upon PMA stimulation) after treatment with Trametinib. Targeted Sanger sequencing of commonly mutated exons of Ras pathway genes (NRAS, KRAS, FLT3 and PTPN11) was performed on 14 samples based on availability of DNA. Results: Of our 24 samples, 4 samples were excluded from analysis due to poor viability (&lt;40% live cells), giving an assay success rate of 83.3%. We were able to successfully measure p-ERK in all 20 viable patient samples and also measure levels of baseline p-AKT in 16 samples. A wide range of p-ERK levels and MAPK activation was observed within patient samples (median activation ratio 12.3, range 4.4-44.7) and 7 samples showed markedly higher levels of activation with ratios between 21.9 - 44.78. Levels of inhibition by Trametinib ranged from 0-82.2%, with a median of 43%. Greater degree of MAPK activation was found to correlate strongly with higher levels of inhibition by Trametinib (overall correlation coefficient 0.72). In 2 samples, the levels of inhibition by Trametinib seemed lower than anticipated for levels of MAPK activation, but both of these samples showed higher than average levels of p-AKT (p-AKT to isotype ratio of 12.3-12.9, median of 2.4 in rest of the samples), suggesting a possible alternative mechanism of activation via the PI3K/AKT signaling pathway. DNA was obtained for Sanger sequencing in 14 of the 20 viable patient samples. Three of the 14 samples had point mutations in Ras pathway genes of which two had mutations in exon 2 of NRAS while one had a mutation in exon 14 of FLT3. Two of the seven patient samples with the highest MAPK activation had Ras mutations, which is consistent with our prior data showing that additional mechanisms of pathway activation are operative. Conclusion: We have successfully established a phospho-flow protocol that enables the measurement of MAPK activation in real time in patient samples. Based on our pilot data, we also conclude that MAPK activation in itself serves as a better predictive marker for susceptibility to MAPK inhibition, as opposed to Ras pathway mutation status alone. Ongoing investigation will allow correlation with outcome and the assay could serve in the future to identify those patients who might benefit from MEK inhibition or other nodes in the pathway. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

Impact of Hyperglycemia on Outcomes among Patients Receiving Neoadjuvant Chemotherapy for Bulky Early Stage Cervical Cancer.

BackgroundThe impact of hyperglycemia on survival of patients undergoing neoadjuvant chemotherapy (NACT) for bulky early stage cervical cancer (BESCC) has not been explored.MethodRecords of patients who received NACT and radical hysterectomy in our institution between January 2005 and June 2010 were reviewed.ResultsIn total, 347 patients were included. The median follow-up time was 37 months (range: 4–65). Patients with hyperglycemia (fasting blood glucose ≥ 100 mg/dl) had shorter recurrence-free survival (RFS) (univariate hazard ratio [HR] = 1.95, 95% confidence interval [CI] [1.16, 3.28], P = 0.010) and cancer-specific survival (CSS) (univariate HR = 2.24, 95% CI [1.33, 3.78], P = 0.002) compared with those with euglycemia (fasting blood glucose <100 mg/dl). In multivariate analysis, positive surgical margins, parametrium invasion, node metastasis, hyperglycemia and complete response to NACT independently predicted recurrence and cancer-specific death. To further validate the prognostic value of hyperglycemia, we conducted a subgroup analysis based on patient baseline characteristics and prognostic effect of hyperglycemia remained significant in all subgroups. On multivariable logistic regression analysis, euglycemia before NACT, squamous cell tumor and pre-treatment squamous cell carcinoma antigen levels < 3.5 ng/ml were identified as independent predictors of complete response after NACT.ConclusionsFBG ≥100 mg/dl is a negative prognostic predictor for cervical cancer patients receiving NACT for BESCC. Patients with hyperglycemia are less likely to achieve complete response after NACT. Our findings underscore the clinical utility of hyperglycemia screening of for cervical cancer patients.

Pretreatment serum lactate dehydrogenase is an independent prognostic factor for patients receiving neoadjuvant chemotherapy for locally advanced cervical cancer.

For locally advanced cervical cancer (LACC), hypoxia is a characteristic property. This study aimed to investigate whether baseline lactic dehydrogenase (LDH) level, which is a marker of hypoxia, had clinical value in determining neoadjuvant chemotherapy (NACT) response and prognosis for LACC patients. The study cohort included 418 patients with a median follow‐up of 37.5 months. Cox proportional hazards models were used to assess the prognostic value of baseline LDH levels. Multivariate logistic regression analysis was performed to identify independent predictors of complete response after NACT. Backward stepwise selection with the Akaike information criterion was used to identify factors that could be entered into the multivariate regression model. Compared with patients with LDH levels <252.0 μ/L, patients with LDH levels ≥252.0 μ/L were more likely to have an elevated level of squamous cell carcinoma antigen, lymphatic vascular space involvement, lymph node metastasis, and positive parametrium and achieved lower complete remission rates. Baseline LDH levels ≥252.0 μ/L was an independent prognosticator for recurrence‐free survival (adjusted hazard ratio [HR], 3.56; 95% confidence interval [CI] 2.22–5.69; P < 0.0001) and cancer‐specific survival (adjusted HR, 3.08; 95% CI, 1.89–5.01; P < 0.0001). The predictive value of baseline LDH value remained significant in the subgroup analysis. LDH level ≥252.0 μ/L was identified as an independent predictor of complete remission after NACT (adjusted odds ratio [OR], 0.29; 95% CI, 0.15–0.58; P < 0.0001). Baseline LDH ≥252.0 μ/L is an independent prognostic predictor for patients receiving neoadjuvant chemotherapy for LACC. It helps distinguish patients with different prognosis and select patients who are more likely to benefit from NACT.

A real-world study focused on the long-term efficacy of mycophenolate mofetil as first-line treatment of autoimmune hepatitis.

Front-line therapy with mycophenolate mofetil (MMF) in autoimmune hepatitis (AIH) has shown high on-treatment remission rates. To study prospectively in a real-world fashion the long-term outcome of a large group of consecutive treatment-naïve AIH patients. Between 2000 and 2014, 158 patients were recruited but only 131 were eligible for treatment (109 MMF/prednisolone; 22 prednisolone ± azathioprine). Long-term data on outcome after drug withdrawal were evaluated. Patients stopped treatment after having achieved complete response (normal transaminases and IgG) for at least the last 2 years. At diagnosis, 31.6% of patients had cirrhosis and 72.8% insidious presentation. A total of 102 of 109 (93.6%) responded initially to MMF within 2 (1-18) months. A total of 78 of 109 (71.6%) had complete response on treatment and 61 of 78 (78.2%) maintained remission off prednisolone. MMF-treated patients had increased probability of complete response compared to those receiving azathioprine (P = 0.03). Independent predictors of complete response were lower ALT at 6 months (P = 0.001) and acute presentation (P = 0.03). So far, treatment withdrawal was feasible in 40/109 patients and 30 (75%) are still in remission after 24 (2-129) months. Remission maintenance was associated with longer MMF treatment (P = 0.005), higher baseline ALT (P < 0.02), lower IgG on 6 months (P = 0.004) and histological improvement. Mycophenolate mofetil proved to be an efficient first-line treatment for AIH, achieving so far the highest rates of remission maintenance off treatment (75%) ever published for at least a median of 2 years, although the remission criteria used were strict. However, the risk of potential bias and overestimation of intervention benefits from MMF cannot be completely excluded as this is a real world and not a randomised controlled trial.

Predictors of Complete Response and Disease Recurrence Following Chemoradiation for Rectal Cancer.

Approximately 10-40% of rectal patients have a complete response (CR) to neoadjuvant chemoradiation (CRT), and these patients have improved survival. Thus, non-operative management ("watch-and-wait" approach) may be an option for select patients. We aimed to identify clinical predictors of CR following CRT. Patients treated with definitive CRT for T3-T4, locally unresectable T1-T2, low-lying T2, and/or node-positive rectal cancer from August 2004 to February 2015 were retrospectively reviewed. Most patients were treated with 50.4 Gy radiation and concurrent 5-fluoruracil or capecitabine. Patients were considered to have a CR if surgical pathology revealed ypT0N0M0 (operative management), or if they had no evidence of residual disease on clinical and radiographic assessment (non-operative management). Statistical analysis was carried out to determine predictors of CR and long-term outcomes. Complete records were available on 138 patients. The median follow-up was 24.5 months. Thirty-six patients (26.3%) achieved a CR; 30/123 operatively managed patients (24.5%) and 6/15 (40%) non-operatively managed patients. None of the 10 patients with mucinous adenocarcinoma achieved a CR. Carcinoembryonic antigen (CEA) ≥5 μg/L at diagnosis (OR 0.190, 95% CI 0.037-0.971, p = 0.046), tumor size ≥3 cm (OR 0.123, 95% CI 0.020-0.745, p = 0.023), distance of tumor from the anal verge ≥3 cm (OR 0.091, 95% CI 0.013-0.613, p = 0.014), clinically node-positive disease at diagnosis (OR 0.201, 95% CI 0.045-0.895, p = 0.035), and interval from CRT to surgery ≥8 weeks (OR 5.267, 95% CI 1.068-25.961, p = 0.041) were independent predictors of CR. The CR group had longer 3-year distant metastasis-free survival (DMFS) (93.7 vs. 63.7%, p = 0.016) and 3-year disease-free survival (DFS) (91.1 vs. 67.8%, p = 0.038). Three-year locoregional control (LRC) (96.6 vs. 81.3%, p = 0.103) and overall survival (97.2 vs. 87.5%, p = 0.125) were higher in the CR group but this did not achieve statistical significance. CR was not an independent predictor of LRC, DMFS, or DFS. CEA at diagnosis, tumor size, tumor distance from the anal verge, node positivity at diagnosis, and interval from CRT to surgery were predictors of CR. These clinical variables may offer insight into patient selection and timing of treatment response evaluation in the watch-and-wait approach.

Reasons for Initiation of First-Line Therapy and Early Outcomes for Patients (Pts) with Rai 0/1 Chronic Lymphocytic Leukemia (CLL): An Analysis of the Connect CLL® Cohort Study

Reasons for Initiation of First-Line Therapy and Early Outcomes for Patients (Pts) with Rai 0/1 Chronic Lymphocytic Leukemia (CLL): An Analysis of the Connect CLL® Cohort Study

Pattern of Retained Contrast on Immediate Postprocedure Computed tomography (CT) After Particle Embolization of Liver Tumors Predicts Subsequent Treatment Response

To determine if the pattern of retained contrast on immediate postprocedure computed tomography (CT) after particle embolization of hepatic tumors predicts modified Response Evaluation Criteria in Solid Tumors (mRECIST) response. This study was approved by the Institutional Review Board with a waiver of authorization. One hundred four liver tumors were embolized with spherical embolic agents (Embospheres, Bead Block, LC Bead) and polyvinyl alcohol. Noncontrast CT was performed immediately after embolization to assess contrast retention in the targeted tumors, and treatment response was assessed by mRECIST criteria on follow-up CT (average time 9.0 ± 7.7 weeks after embolization). Tumor contrast retention (TCR) was determined based on change in Hounsfield units (HUs) of the index tumors between the preprocedure and immediate postprocedure scans; vascular contrast retention (VCR) was rated; and defects in contrast retention (DCR) were also documented. The morphology of residual enhancing tumor on follow-up CT was described as partial, circumferential, or total. Association between TCR variables and tumor response were assessed using multivariate logistic regression. Of 104 hepatic tumors, 51 (49%) tumors had complete response (CR) by mRECIST criteria; 23 (22.1%) had partial response (PR); 21 (20.2%) had stable disease (SD); and 9 (8.7%) had progressive disease (PD). By multivariate analysis, TCR, VCR, and tumor size are independent predictors of CR (p = 0.02, 0.05, and 0.005 respectively). In 75 tumors, DCR was found to be an independent predictor of failure to achieve complete response (p < 0.0001) by imaging criteria. TCR, VCR, and DCR on immediate posttreatment CT are independent predictors of CR by mRECIST criteria.

Prognostic Factors for Complete Obliteration of Arteriovenous Malformations Treated with LINAC-Based Stereotactic Radiosurgery

Few series analyzing prognostic fac tors predicting for obliteration of arteriovenous malformations (AVMs) following linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) have been reported. We analyzed prognostic variables, outcomes, and toxicities in 88 patients undergoing LINAC-based SRS for AVMs. Following IRB approval, patient records were retrospectively analyzed to identify independent predictors of complete response (obliteration) (CR) and time-to-CR. The majority of AVMs were treated using multiple isocenters and non-coplanar arcs. The median AVM volume was 2.67 cm3 (0.05 - 33.51). Median marginal and maximal doses were 17 (12-24) and 26.1 Gy (15-40), with a median prescription isodose surface of 65%. Spetzler-Martin (SM) grade was determined for 86 patients and was: I-3 pts (3%); II-23 pts (27%); III-45 pts (52%); IV-13 pts (15%); V-2 pts (2%).Of 80 patients with follow-up imaging, 44 (55%) had documented complete responses (CR). Kaplan-Meier estimate probability for CR at 4 years was 62% (95% CI: 0.50, 0.74). Median time to CR was 3 years (95% CI: 2.08, 3.17). Multivariate analysis demonstrated the Spetzler-Martin grade (OR=0.14 for grade III vs. grade I-II; p=0.004 and OR 0.07 for grade IV-V vs. grade I-II; p=0.002) and dichotomized marginal dose > 17 Gy (OR=4.19; p=0.01) to be significantly associated with CR. This report demonstrates that for LINAC-based SRS of AVM, marginal dose and Spetzler-Martin grade are strong predictors of complete AVM obliteration.

Accelerated superfractionated radiotherapy with concomitant boost for invasive bladder cancer

Purpose To determine the toxicity and clinical effectiveness of accelerated superfractionated radiotherapy with delayed concomitant boost (ASCBRT) in locally invasive carcinoma of the bladder. Methods and materials Between July 1997 and December 2001, 87 patients (unsuitable or refusing cystectomy) with invasive bladder cancer underwent ASCBRT. The mean patient age was 66 years (range 40–90). The stage distribution was as follows: 2 T1, 51 T2, 13 T3, and 21 T4. Initially, the whole pelvis was treated by 1.8-Gy conventional daily fractions up to a total dose of 45 Gy. A small field boost covering gross disease was added as a second daily fraction (1.5 Gy) during the last 3 weeks of the 5-week schedule up to a total dose of 67.5 Gy. The interfraction interval was a minimum of 6 h. The patients were evaluated in follow-up for toxicity, local control, and survival. Results All but 2 patients completed the study protocol. Grade 3 acute urinary toxicity was observed in 2 patients. Grade 2 and 3 late bladder toxicity was observed in 12 patients and 1 patient, respectively. Grade 2 and 3 late bowel toxicity was observed in 5 and 3 patients, respectively. The 3-year actuarial local control, distant disease control, cause-specific survival, and overall survival rate was 64%, 78%, 58%, and 46%, respectively. Multivariate analysis revealed T stage as independent predictor of complete response. For Stage T2 and T3, the 3-year local control rate was 77% and 48%, respectively. At the last follow-up, 53 patients (61%) were still alive with a survival time between 6 and 62 months. Conclusion ASCBRT is feasible with acceptable tolerance even in relatively old patients with Stage T3 or greater tumor. The encouraging locoregional control and survival results of this institutional experience, favorable compared with conventional radical and other accelerated fractionated (with or without a concomitant boost) RT series, make ASCBRT worthy of further study in a Phase III trial.

Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival.

Anti-Hu antibodies (HuAb) recognize antigens expressed by neurons and small-cell lung cancer (SCLC). High titers of HuAb were initially reported in serum from patients with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN) and SCLC. Preliminary studies have indicated that some SCLC patients without PEM/SN harbor low titer of HuAb in their serum, and that the SCLC of these patients may grow more indolently. Based on these observations, we conducted a multicenter prospective study of SCLC patients without PEM/SN to determine the incidence and prognostic implications of HuAb. Serum samples were collected at diagnosis of SCLC in 196 patients without PEM/SN. HuAb were determined by immunoblot of purified recombinant HuD antigen. HuAb were detected in 32 (16%) of the 196 patients. Of the 170 patients who received treatment for the tumor, 27 (16%) were HuAb positive. HuAb was associated with limited disease stage (59.3% v 38.6%; P = .047), complete response to therapy (55.6% v 19.6%; P < .001), and longer survival (14.9 v 10.2 months; P = .018). In a logistic regression analysis, HuAb status was an independent predictor of complete response induction. The probability of achieving a complete response was more than five times higher in HuAb-positive than in HuAb-negative patients (odds ratio, 5.4; 95% confidence interval, 1.71 to 16.89; P = .004). Cox multivariate analysis indicated that HuAb status was not independently associated with survival. The presence of HuAb at diagnosis of SCLC is a strong and independent predictor of complete response to treatment. This feature accounts for the association between HuAb and longer survival.