Advanced Disease Group Research Articles

Salvage radiotherapy for relapsed/refractory non‐Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell (CART) therapy

CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting. Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n=9 [43%], all disease encompassable within an RT field) and advanced disease (n=12 [57%]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed. Median time from CART infusion to SRT was 4.0months (range, 0.6-11.5months). In the locoregional disease group, 8/9 patients (89%) were treated with comprehensive SRT to a median dose of 37.5Gy in a median of 15 fractions. In the advanced disease group, all patients (n=12) were treated with focal SRT to a median dose of 20.8Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2months. In-field response was observed in 8/9 (89%) in the locoregional disease and 8/9 (89%) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94%) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4months; 21months for locoregional disease versus 2.4months for advanced disease (p=0.0002). Median PFS was 1.1month, and similarly poor regardless of group. No grade≥3 toxicities occurred. SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.

Salvage Radiotherapy for Relapsed/Refractory Non‐Hodgkin Lymphomas Following CD19 Chimeric Antigen Receptor T-Cell (CART) Therapy

<h3>Purpose/Objective(s)</h3> CD19-directed CART therapy has emerged as a promising treatment for relapsed/refractory non-Hodgkin lymphoma. However, sustained efficacy is limited with durable complete response rates of 40% (Schuster & Locke, 2019). Salvage radiotherapy (SRT) is potentially an important strategy post‐CART, but current data is limited to one series of 14 patients. <h3>Materials/Methods</h3> We retrospectively analyzed 21 patients who received SRT after commercial CART therapy between 8/2018 and 6/2020. Patients who relapsed after CART were divided into two groups: locoregional disease (LD, all relapsed disease encompassable within an RT field) and advanced disease (AD). SRT was defined as comprehensive (treated all sites of active disease) or focal. Post-SRT in-field objective response rates (ORR) were recorded according to Deauville or RECIST criteria with a response characterized as a complete response or partial response. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Acute RT toxicity was graded by CTCAEv5. <h3>Results</h3> Median time from CART infusion to SRT was 4.0 months (m) (range, 0.6-11.6m). Within the LD group, 8/9 patients were treated with comprehensive SRT (median SRT dose 37.5 Gy, range 8-45 Gy, and number fractions 15, range 2-25 fractions). The in-field ORR was 8/9 (89%). For the AD group, 12/12 patients were treated with focal SRT (median SRT dose 20.8 Gy, range 8-30 Gy, and number fractions 5, range 1-12 fractions). 11/12 AD patients were treated with hypofractionated SRT (≥2.5Gy fractions). Three patients died prior to subsequent imaging with an ORR of 8/9 (89%) for the remaining evaluable patients. Distant progression occurred in 17/18 patients post-SRT (Table). Three-month PFS was 24% for the entire cohort, and 33% and 17% for the LD and AD groups, respectively (<i>P</i> = 0.258). Median OS was 7.4m for the entire cohort, and 21.1m and 2.4m for the LD and AD groups, respectively (<i>P</i> < 0.001). Grade 1 (G1) and G2 acute SRT toxicities occurred in 10 and 4 patients, respectively. No G3 or higher toxicities occurred. <h3>Conclusion</h3> SRT post-CART therapy appears safe (no ≥G3 RT toxicities) in our series. SRT led to an ORR of 89% with only 1 observed local relapse. Patients with LD relapse post-CART had significantly improved survival compared with AD relapse. Unfortunately, prognosis remains poor as 17/18 patients with evaluable imaging progressed outside of the RT field. Thus, prolonged RT courses may not be warranted given the practical inevitability of out of field disease progression. Multi-institutional review of SRT following CART is warranted to further elucidate the impact of RT dose and fractionation on disease outcomes.

RetiNerveNet: using recursive deep learning to estimate pointwise 24-2 visual field data based on retinal structure

Glaucoma is the leading cause of irreversible blindness in the world, affecting over 70 million people. The cumbersome Standard Automated Perimetry (SAP) test is most frequently used to detect visual loss due to glaucoma. Due to the SAP test’s innate difficulty and its high test-retest variability, we propose the RetiNerveNet, a deep convolutional recursive neural network for obtaining estimates of the SAP visual field. RetiNerveNet uses information from the more objective Spectral-Domain Optical Coherence Tomography (SDOCT). RetiNerveNet attempts to trace-back the arcuate convergence of the retinal nerve fibers, starting from the Retinal Nerve Fiber Layer (RNFL) thickness around the optic disc, to estimate individual age-corrected 24-2 SAP values. Recursive passes through the proposed network sequentially yield estimates of the visual locations progressively farther from the optic disc. While all the methods used for our experiments exhibit lower performance for the advanced disease group (possibly due to the “floor effect” for the SDOCT test), the proposed network is observed to be more accurate than all the baselines for estimating the individual visual field values. We further augment the proposed network to additionally predict the SAP Mean Deviation values and also facilitate the assignment of higher weightage to the underrepresented groups in the data. We then study the resulting performance trade-offs of the RetiNerveNet on the early, moderate and severe disease groups.

Rotational thromboelastometry (ROTEM) profiling of COVID–19 patients

We evaluated coagulation abnormalities via traditional tests and rotational thromboelastometry (ROTEM) in a group of 94 patients with confirmed SARS-CoV-2 infection and different severity of pneumonia (34 moderate, 25 severe, 35 critical) with the hypothesis that ROTEM parameters differed by coronavirus disease 2019 (COVID-19) severity. Shorter than normal clotting time (CT) and higher than normal maximum clot firmness (MCF) in extrinsic rotational thromboelastometry (EXTEM) and fibrinogen rotational thromboelastometry (FIBTEM), shorter than normal EXTEM clot formation time (CFT), and higher than normal α-angle were classified as markers of hypercoagulable state. Increment in the number of patients with ≥2 hypercoagulable parameters, higher EXTEM (P = .0001), FIBTEM MCF (P = .0001) and maximum lysis decrement (P = .002) with increment in disease severity was observed (P = .0001). Significant positive correlations between IL6 and CT EXTEM (P = .003), MCF EXTEM (P = .033), MCF FIBTEM (P = .01), and negative with ML EXTEM (P = .006) were seen. Our findings based on analysis of different disease severity groups confirmed that a hypercoagulable ROTEM pattern characterized by clot formation acceleration, high clot strength, and reduced fibrinolysis was more frequent in advanced disease groups and patients with high IL6. These results supported the need for different thromboprophylaxis approaches for different severity groups.

Eye Salvage with Intra-Arterial and Intra-Vitreal Chemotherapy in Patients with Retinoblastoma: 8-Year Single-Institution Experience in Colombia

Introduction: Intra-arterial chemotherapy (IAC) is useful for eye preservation in advanced retinoblastoma (Rb). Intra-vitreal chemotherapy (IvitC) is the latest treatment for vitreous seeds. Methods: The present study is a retrospective assessment of 100 eyes, treated with primary or secondary IAC alone or with IvitC. We evaluated demographic and clinical variables, eye salvage, associated adverse events, and patient survival. Data were analyzed using descriptive statistics. Kaplan-Meier survival curves and Cox hazard ratios were utilized to assess the effect of demographic and clinical variables over eye salvage. Results: Bilateral Rb was observed in 61% of patients, and 57% of eyes received secondary treatment. Forty eyes needed intra-arterial plus IvitC and 62 presented advanced disease (group D and E). Three- and 5-year ocular survival probabilities were 75 and 68%. We found a higher risk in group D and E eyes and those requiring 2 or more routes for ophthalmic artery catheterization. Patients coming from other countries also showed increased risk. Using primary or secondary treatment, or IvitC, did not affect this risk. Overall rates of survival and eye salvages were 98.8 and 73%, and we had a 100% catheterization success and none ophthalmic arterial occlusions. Conclusions: In an upper middle-income country such as Colombia, a specialized institution counting with therapeutic alternatives and a multidisciplinary team can reach rates of patient survival and eye salvage similar to those of high-income countries.

Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study

Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.

Characterization and Clinical Significance of Natural Variability in Hepatitis B Virus Reverse Transcriptase in Treatment-Naive Chinese Patients by Sanger Sequencing and Next-Generation Sequencing.

Mutations in hepatitis B virus (HBV) reverse transcriptase (RT) are associated with nucleos(t)ide analogue (NA) resistance during long-term antiviral treatment. However, the characterization of mutations in HBV RT in untreated patients has not yet been well illustrated. The objective of this study was to investigate the characterization and clinical significance of natural variability in HBV RT in treatment-naive patients. HBV RT sequences were analyzed in 427 patients by Sanger sequencing and in 66 patients by next-generation sequencing. Primary or secondary NA resistance (NAr) mutations were not found, except A181T in RT (rtA181T) by Sanger sequencing, but they were detected by next-generation sequencing. Mutations were found in 56 RT amino acid (aa) sites by Sanger sequencing, 36 of which had mutations that could lead to changes in B or T cell epitopes in the RT or S protein. The distribution of mutations was diverse in different sections within the RT region. Multiple mutations showed significant association with HBV DNA, HBsAg, HBeAg, age, and severity of liver fibrosis. Mutations at rt251, rt266, rt274, rt280, rt283, rt284, and rt286 were found most in the advanced liver disease (ALD) group by next-generation sequencing. The present study demonstrates that next-generation sequencing (NGS) was more suitable than Sanger sequencing to monitor NAr mutations at a low rate in the treatment-naive patients, and that mutations in the RT region might be involved in the progression to ALD.

Relevância diagnóstica dos Gráficos de Recorrência na caracterização de Saúde, Doença ou Morte, em humanos

Gráficos de recorrência (GR) têm sido utilizados para avaliar sistemas dinâmicos complexos, sendo o corpo humano um excelente modelo. Foram analisados ​​os elementos quantitativos e qualitativos do GR na diferenciação de Saúde, Doença e Morte. Séries temporais de batimentos cardíacos normais foram coletadas em recém-nascidos saudáveis ​​(Grupo A1), crianças saudáveis ​​(Grupo A2), adultos jovens saudáveis ​​(Grupo A3), adultos saudáveis ​​de meia-idade (Grupo A4), idosos residentes em casas de repouso (Grupo B), indivíduos com doença renal crônica avançada (Grupo C) e indivíduos com morte encefálica declarada ou em estado de morte iminente (Grupo D). O grupo A3 apresentou a melhor homeostase (menor recorrência). Os grupos A1 e D apresentaram os maiores valores de recorrência. Em termos visuais qualitativos, o Grupo A3 apresentou distribuição mais difusa e uniforme, um indicativo de melhor homeostase e o Grupo D foi totalmente linear, a pior condição. Um padrão parabólico foi claramente evidenciado. Em conclusão, foi possível, utilizando a correlação de apenas duas variáveis ​​(SDNN e TT), diferenciar tanto de modo quantitativo como qualitativo os estados de Saúde, Doença e Morte usando GR.

Risk of death without appropriate defibrillator shock in patients with advanced renal dysfunction.

Heart failure patients with advanced chronic kidney disease (CKD) may experience an increased rate of non-arrhythmic mortality due to associated comorbidities. We aimed to evaluate the risk of mortality without appropriate implantable cardioverter-defibrillator (ICD) shocks in this high-risk population. The study population comprised 3542 patients who received an ICD, were enrolled, and prospectively followed-up in the Israeli ICD registry. Study patients were categorized into two groups: those with advanced CKD [defined by a glomerular filtration rate of <30 mL/min/1.73 m2 or being on dialysis at time of implantation (n = 197)], and those without advanced CKD (n = 3344). The primary endpoint was the risk of death without receiving appropriate ICD shock. Kaplan-Meier survival analysis showed that at 5 years of follow-up the rates of death without prior ICD shock were significantly higher in the advanced kidney disease group (46%) compared with the non-advanced CKD group (19%; log-rank P-value <0.001). Consistently, multivariate analysis showed that the risk of death without receiving appropriate ICD shock therapy at 5 years was 2.5-fold (P < 0.001) higher among advanced CKD patients. In contrast, the rate of appropriate ICD shock therapy at 5 years among advanced CKD patients was only 9%, with a very high mortality rate (63%) within 3.5 years subsequent to shock therapy. Nearly one-half of ICD with advanced CKD die within 5 years without receiving an appropriate ICD shock. These findings stress the importance of appropriate patient selection for primary ICD implantation in this high-risk population.

Healthcare resource utilization and costs by disease severity in an insured national sample of US patients with chronic hepatitis B

Chronic hepatitis B (CHB) affects over 2 million people in the US, with little reported on healthcare utilization and cost. We aimed to quantify annual CHB utilization and costs by disease severity and payer type. Using Commercial, Medicare, and Medicaid databases from 2004 to 2015 and ICD9 codes, we retrospectively identified adults with CHB, analyzing all-cause inpatient, outpatient, and pharmaceutical utilization and costs by disease severity. We compared healthcare utilization and costs between patients with CHB, without advanced liver disease, and matched non-CHB controls. All-cause inpatient, outpatient, and pharmaceutical utilization and costs were reported for each year and adjusted to 2015 dollars. Our sample consisted of 33,904 CHB cases and 86,072 non-CHB controls. All-cause inpatient admissions (average stay 6-10 days) were more frequent in advanced liver disease states. Across all payers, patients with decompensated cirrhosis had the highest emergency department utilization (1.6-2.8 annual visits) and highest mean annual costs. The largest all-cause cost components for Commercial and Medicaid were inpatient costs for all advanced liver disease groups (Commercial: 62%, 47%, 68%; Medicaid: 81%, 72%, 74%, respectively), and decompensated cirrhosis and hepatocellular carcinoma groups for Medicare (Medicare 49% and 48%). In addition, patients with compensated liver disease incurred costs 3 times higher than non-CHB controls. Patients with CHB, regardless of payer, who experienced decompensated cirrhosis, hepatocellular carcinoma, or a liver transplant incurred the highest annual costs and utilization of healthcare resources, but even patients with CHB and compensated liver disease incurred higher costs than those without CHB. All stakeholders in disease management need to combine efforts to prevent infection and advanced liver disease through improved vaccination rates, earlier diagnosis, and treatment. Hepatitis B virus can be a progressive disease leading to cirrhosis, hepatocellular carcinoma, liver transplant, and death. These progressive disease states are associated with a higher rate of hospitalizations, emergency room visits, outpatient visits, and costs compared to similar patients without hepatitis B. The most ill patients have the highest costs, but even patients who are less sick experience higher costs than patients without hepatitis B.

Clinico-Pathological Features and Outcome of Treatment of Saudi Patients with Oral Cavity Cancer

Background: This study presents the epidemiological data and clinico-pathological features of oral cancer in patients treated in Prince Sultan Military Medical City, Oncology Department over the last 7 years. Methods: We reviewed all available data in our electronic and paper files for patients who had a confirmed pathology diagnosis of oral cavity malignancies between the years 2009-2015. Results: We had a total of 87 patients with pathological confirmed oral cancer. The majority of patients were males (Male:Female=1.63:1). Median age at diagnosis was 62 years (24-95). History related to risk factors was completed in only 59 patients (68%). Forty-five patients (76%) have a positive history for tobacco usage either smoking and/or chewing (shamma). The use of shamma, (a mixture of powdered tobacco, lime, ash, black pepper, oils and flavorings), was confirmed in 31/59 patients (either alone or associated with smoking). Oral Tongue as a primary site represents about half of the patients 44(50.6%), followed by alveolar ridge (16.1%) and floor of mouth (11.5%), buccal mucosa (10.3%) and other sites (11.5%). Two thirds of patients (66.6%) presented with advanced stages (III and IV). The estimated 5-year overall survival rates were 77.1% for the early stage disease group and 45.9% for the advanced stage disease group (P=0.028). The 5-year progression-free survival rates were 65.6% for the early stage disease group compared with 28.1% for the advanced stage disease group (P=0.02). Conclusions: Most of our cases have a positive history of tobacco usage. This together with the high percentage of advanced diseases that carried a significantly poor outcome warrant the need for effective anti-tobacco campaigns, public awareness and primary care physicians education for early detection of disease.

Abstract CT109: HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases

Abstract OBJECTIVES: There are no effective treatment options for patients with unresectable CEA+ liver metastases (LM) from gastrointestinal adenocarcinoma refractory to conventional systemic therapy. In the previous Hepatic Immunotherapy for Metastases (HITM) phase I study we demonstrated the safety and biologic activity of anti-CEA CAR-T cell hepatic artery infusions (HAI). HITM-SIR was a single arm phase Ib trial testing anti-CEA CAR-T HAI followed by selective internal radiation therapy (SIRT) in patients with refractory CEA+ LM. METHODOLOGY: We enrolled 8 patients with unresectable, chemotherapy refractory CEA+ LM and 6/8 completed the study. Two patients were withdrawn for disease progression prior to CAR-T infusion and biliary obstruction due to centrally located disease. Limited extrahepatic disease (EHD) was permitted. Subjects received 3 HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with low dose continuous IL-2 infusions (50,000 IU/kg/day). SIRT was administered in standard fashion 2 weeks following the 3rd CAR-T HAI. Primary objective was to establish safety of the CAR-T/SIRT combination. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics. RESULTS: The mean age for enrolled subjects was 54.6 years (39-61) with 3 women and 5 men. Histologies (completed patients): 2 colon, 2 rectal, and 2 pancreas. This heavily pre-treated, advanced disease group of patients received an average of 2.3 lines of prior chemotherapy, 3/6 had &amp;gt;10 LM, and the average largest LM size was 7.3 cm. The average transduction efficiency as measured by CAR expression was 60.4%, with 90.9% viability, and an average production time for &amp;gt;3e10 cells of 13.8 days. There were no grade (G) 4/5 events related to the CAR-T, SIRT, or combination. Toxicities included G 1/2 liver function test elevations (n=5/6), fever (n=5/6), hypereosinophilia (n=2/6), and edema (n=2/6). G3 toxicities included colitis (n=2/6), fever (n=2/6), and edema (n=2/6). One patient experienced a hypertensive crisis during a single CAR-T infusion but tolerated 2 infusions without incident. All colitis episodes resolved with IL-2 dose reductions. Post-SIRT serum CEA decreases were noted in 2/6 patients (-40% and -71%) with CA19-9 decreases in 2/5 detectable patients (-31% and -32%). When considering all on-study time points, 5/6 patients had CEA responses (mean decrease 59.7%) and 4/5 patients expressing CA 19-9 decreases (mean 59.6%). At completion of the study, 3/6 patients had stable disease (SD) in the liver by mRECIST and irRC, and 3/6 SD overall by irRC. Target liver lesion decreases in size among patients with SD ranged from 6-28%. Regression of extrahepatic tumors or abscopal effects were noted in 2/6 at lung and bone sites. One patient remains without evidence of viable liver disease at 10.8 months follow-up. The median overall survival time for all patients is 6.9 months (range 3.8-10.8+). CONCLUSIONS: Following this phase Ib trial, the recommended phase 2 dose for anti-CEA CAR-T HITM infusions is 1010 cells with or without SIRT. The favorable safety profile and evidence of biologic activity indicate that CAR-T HITM infusions should be further studied in a phase 2 trial. Clinical trial information: NCT02416466. Citation Format: Steven C. Katz, Ethan Prince, Marissa Cunetta, Prajna Guha, Ashley Moody, Vincent Armenio, Li J. Wang, N. Joseph Espat, Richard P. Junghans. HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT109. doi:10.1158/1538-7445.AM2017-CT109

Neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of prospective studies.

There is a strong rationale and many theoretical advantages for neoadjuvant therapy in pancreatic cancer (PC). However, study results have varied significantly. In this study, a systematic review and meta‐analysis of prospective studies were performed in order to evaluate safety and effectiveness of neoadjuvant therapy in PC. Thirty‐nine studies were selected (n = 1458 patients), with 14 studies focusing on patients with resectable disease (group 1), and 19 studies focusing on patients with borderline resectable and locally advanced disease (group 2). Neoadjuvant chemotherapy was administered in 97.4% of the studies, in which 76.9% was given radiotherapy and 74.4% administered with chemoradiation. The complete and partial response rate was 3.8% and 20.9%. The incidence of grade 3/4 toxicity was 11.3%. The overall resection rate after neoadjuvant therapy was 57.7% (group 1: 73.0%, group 2: 40.2%). The R0 resection rate was 84.2% (group 1: 88.2%, group 2: 79.4%). The overall survival for all patients was 16.79 months (resected 24.24, unresected 9.81; group 1: 17.76, group 2: 16.20). Our results demonstrate that neoadjuvant therapy has not been proven to be beneficial and should be considered with caution in patients with resectable PC. Patients with borderline resectable or locally advanced disease may benefit from neoadjuvant therapy, but further research is needed.

Survival of patients with pancreatic cancer treated with varied modalities: A single-centre study

The present retrospective chart review examined the overall survival (OS) of patients with pancreatic ductal adenocarcinoma based on the disease stage in a sample of 296 patients with pancreatic cancer. Secondary outcome measurements included OS in chemotherapy vs. supportive treatment groups among metastatic patients, OS based on response to chemotherapy among metastatic patients, and OS and disease free survival (DFS) in surgically resected disease with vs. without adjuvant therapy. Data were analyzed using Kaplan-Meier and multivariate cox-regression analyses based on a 95% confidence interval (CI) or an α-value of 0.05. OS was significantly different based on the disease stage, with 3.63 (95% CI, 2.84-4.43), 6.57 (95% CI, 4.06-9.08) and 15.57 (95% CI, 11.79-19.35) months in the advanced, locally advanced, and localized disease groups, respectively. OS was higher in metastatic-stage patients who received chemotherapy [6.07 months (95% CI, 4.75-7.39)] compared with those who received supportive therapy alone [2.50 months (95% CI, 2.16-2.84; P<.001)]. Metastatic-stage patients with partial or stable response to chemotherapy had higher OS [10.53 months (95% CI, 6.35-14.72)] in comparison with those with progression [6.33 months (95% CI, 5.79-6.88)] or an undocumented response [3.30 months (95% CI, 1.76-4.84; P<0.001)]. In patients who underwent surgical resection of localized disease, adjuvant therapy increased the adjusted OS and DFS as compared with surgical excision alone (P=0.013; 95% CI, 0.278-0.862). Positive margins reduced OS [hazard ratio (HR) 2.670; 95% CI, 1.467-4.860]. The present single-site study has demonstrated that OS may markedly differ on the basis of the disease status at the time of diagnosis. Metastatic-stage patients with stable or partial response to chemotherapy had an increased OS, as did surgical patients with localized disease who received adjuvant treatment, after adjusting for margin status.

Early Evidence of Cardiotoxicity and Tumor Response in Patients with Sarcomas after High Cumulative Dose Doxorubicin Given as a Continuous Infusion.

Background Despite the dose-dependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. This study evaluates early evidence of cardiotoxicity in patients treated with high-dose doxorubicin given as a continuous infusion. Methods Data was collected on patients who received 90 mg/m2 doxorubicin as a continuous infusion and 10 gm/m2 ifosfamide for up to 6 cycles as part of a phase II study. Cardiotoxicity was assessed with serial echocardiograms or multigated acquisition scans and serum brain natriuretic peptide and troponin levels. Tumor responses were determined by serial radiographic imaging per RECIST. Result Out of the 48 patients enrolled, no patient developed heart failure symptoms; however, 4 out of the 38 (10%) patients with serial left ventricular ejection fraction assessments developed subclinical cardiotoxicity (asymptomatic drop in LVEF ≥ 10%). Twenty-three patients received all six 72-hour cycles of doxorubicin with a mean cumulative dose of 540 mg/m2. Among these patients, 4% (n = 1) developed subclinical cardiotoxicity. In the advanced disease group (n = 39), patients with a complete or partial response received a higher mean cumulative dose than those with stable disease (p < 0.033). Conclusions Doxorubicin cardiotoxicity can be limited by administering doxorubicin as a continuous infusion, allowing higher cumulative dosing to maximize efficacy.

Failure to Achieve Early Molecular Milestone within 3 Months Is Associated with Higher Risk of Relapse and Worse Survival after Allogeneic Hematopoietic Stem Cell Transplant for Chronic Myeloid Leukemia Patients, Especially after Tyrosine Kinase Inhibitor Failure

BACKGROUNDEarly molecular response (EMR) of less than 10%IS of BCR-ABL transcript level at 3 months has become widely accepted as the earliest milestone in CML treatment. Close monitoring and switch of TKI therapy is recommended if the patient continues to fail to achieve less than 10%IS at 6 months. Thus EMR has guided our treatment intervention in the high risk group of patient before they progress to advanced stage CML. After multiple TKI therapy failure, the only available curative treatment is allogeneic hematopoietic cell transplantation (HCT). Around 20-30% of patients still progress or relapse after HCT. Accordingly, there is obligatory requirement for early molecular monitoring to guide pre-emptive treatment to reduce the risk of imminent relapse. The current study reviewed and analyzed transplant outcomes in 223 CML patients.METHODSA total of 223 patients were reviewed who received HCT across 6 transplant centers in Canada between 2002 and 2014. According to their response to TKI therapy and disease state prior to HCT, patients were divided into 4 groups: TKI resistance (n=132), TKI intolerance (n=29), TKI naïve/response chronic phase (CP) (n=27) or advance disease stage but TKI responsive (n=35). Using the binary recursive partitioning method with BCR-ABL transcript levels taken within 3 months post-HCT, patients were further divided into 3 groups: 1) those failing to achieve less than 1.3 log reduction (Group1.3), 2) the group achieving between 1.3 and 4.4 log reduction (Group1.3-4.5), and 3) the patients who achieved 4.5 log reduction or deeper response (Group4.5). According to the 4 groups stratified by TKI response/disease risk or to the 3 groups based on BCR-ABL transcript level within 3 months, transplant outcomes were analyzed with respect to overall survival (OS), non-relapse mortality (NRM), relapse and incidence of complete hematologic response (CHR) loss. Post-HCT TKI therapy for relapsed CML was also reviewed and analyzed for response/long-term outcomes.RESULTSThe OS was the highest in TKI naïve/responsive CP group (88.6% at 5 years), followed by TKI intolerance (70.6%), advanced disease group responsive to TKI therapy (63.4%) and the lowest in TKI resistance group (50.3%; p=0.003 among 4 groups). The incidence of relapse was high in TKI resistance group (30.6% at 5 years) and in advanced disease group (30.6%) compared to TKI intolerance group (16.0%) or TKI naïve/responsive CP group (12.1%; p=0.067).According to BCR-ABL transcript levels 3 months post-HCT, Group1.3 showed the lowest rate of molecular response (MR) 4.5 (7.1% at 2 years) compared to 49.9% in Group1.3-4.5 vs 72.7% in Group 4.5 (p<0.001). Group1.3 also showed the highest relapse rate of 78.6% at 5 years, compared to 23.9% in Group 1.3-4.5 and 26.4% in Group 4.5 (p<0.001).In multivariate analysis for OS, Group1.3 increased the risk of death by 2.3 fold in addition to advanced disease at diagnosis (HR 2.5), acute GVHD (HR 2.3) and chronic GVHD (HR 0.28). For relapse, Group1.3 increased the risk of relapse by 6.6 fold, while chronic GVHD decreased it by 57% (HR 0.43). However, none of TKI failure, disease stage prior to HCT, additional cytogenetic abnormalities in Ph+ clone, clonal evolution in Ph neg clone, or ABL1-kinase domain mutation was found to be prognostic.Of 223, 61 patients experienced relapse in 10 months post-HCT, among which 47 patients were treated with TKI therapy. Of 45 evaluated, 26 patients (57.8%) achieved molecular response. Response was lower in the group with CHR loss as 34.6% than those with MR2 loss (100%) or MR3 loss (88.2%; p<0.001). For OS after post-HCT TKI therapy (OSTKI), OSTKI was the highest in the group with MR3 loss (81.9%), followed by those with MR2 loss (66.7%), then lowest with CHR loss (27.0%; p<0.001). Multivariate analysis confirmed that relapse type is an independent risk factor for response (p=0.002) and for OSTKI (p=0.004). The group with hematologic relapse as CHR loss had 8.9 times higher risk of death compared to those with loss of MR2/MR3.CONCLUSIONThe present study confirms that the EMR within 3 months post-HCT is associated with transplant outcomes: failure to achieve 1.3 log reduction of BCR-ABL transcripts in 3 months post-HCT for CML, significantly increases the risk of relapse. Thus pre-emptive post-HCT TKI therapy is warranted in failing patients to reduce imminent risk of relapse after allogeneic HCT in CML patients. [Display omitted] DisclosuresSavoie:Jazz: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Lundbeck: Consultancy. Bence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees. Lalancette:Celgene: Honoraria; BMS: Honoraria. Hillis:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

Clinical Impact of CD8+ Cells in Hodgkin Lymphoma Lymphadenopaties. Contribution of Flow Cytometry

CONTEXT: Microenvironment of Hodgkin and Reed Sternberg(H-RS) cells is a current focus of interest to define risk and predict evolution of Hodgkin′s Lymphoma.OBJECTIVES: To determine the role of infiltrating CD8+ cells, using flow cytometry (FCM), in the evolution of patients with HL.DESIGN: Cell suspensions obtained after mechanical disintegration of ganglion biopsies of patients with newly diagnosed HL were analyzed using FCM. Definitive diagnosis was made by conventional histology and immunohistochemistry. Clinical data were collected from medical records. Statistical analysis was performed using SPSS 20.0 software.SETTING: In the University Hospital of Salamanca, we consecutively analyzed by FCM all lymph nodes with suspected lymphoma at diagnosis. There was no selection bias when collecting patients, except for some cases with inadequate quality(insufficient cells).PATIENTS OR OTHER PARTICIPANTS: From 1996(earliest available FCM data) to 2014, 104 of that samples had a definitive diagnosis of HL. Treatment depended on stage: a)early diagnosis received ABVD(x3) & local radiotherapy(RT) (20-30 Gy), b)advanced: ABVD(x6 to 8), plus RT in selected cases. Median follow-up was 10 years.INTERVENTIONS :This was a retrospective observational study.MAIN OUTCOMES MEASURES: Primary end points were overall survival(OS) and freedom from treatment failure(FFTF), considered from diagnosis to progression or relapse.RESULTS: Most cells obtained were lymphocytes (Median17.1±86.9%) with a T/B/NK distribution of 72%/27%/1.6%(median) and predominance of CD4+ (median CD4:51%-CD8:12%). Median CD8+ cells(12%) was used to divide patients into 2 groups.FFTF was longer in patients with more than 12% of CD8+cells(93% vs. 71%, p=0.01). When analyzed separately patients with early/advanced disease, the clinical benefit remained in the group with advanced disease (p=0.006), whereas the statistical significance was lost in the group with early disease, possibly due to the excellent prognosis for those patients(FFTF 10 years > 95%). No differences were observed in the OS, because second line therapy was highly effective. In the multivariate analysis using Cox regression, advanced stage (HR=9.6 with 95% CI 1.2 to 73.9) and>12% CD8+ tumor infiltrating T-cells were independent variables(HR=0.26, 95% CI 0.07 to 0.9).CONCLUSIONS: Increased number of CD8+ in the H-RSC microenvironment of HL is associated with better FFTF, particularly in the advanced-disease group. This should be considered as a new biomarker to identify high-risk patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical presentation of intraocular retinoblastoma; 5-year hospital-based registry in Egypt

PurposeTo study the presenting signs of Retinoblastoma in Egypt at Egypt’s main pediatric oncology referral center. MethodsThis is a prospective descriptive study (hospital-based registry) conducted at Children’s Cancer Hospital Egypt between July 2007 and December 2012. ResultsOut of 262 patients diagnosed with retinoblastoma, 244 were suffering from intra-ocular disease at presentation. One hundred thirty-nine (57%) patients presented with unilateral disease, while 105 (43%) suffered bilateral disease. The mean age at presentation was 20.6±17months, averaging 18.87±11.76months for bilateral and 25.72±18.78months for unilateral disease. The most common clinical presentation was leukocoria in 180 (73.8%) patients, strabismus in 32 (13.1%) patients and decreased visual acuity in 12 (4.9%) patients. Group D and E disease represented 62% of all affected eyes. Patients with advanced disease (Group C–E) had longer duration of symptoms. ConclusionIn Egypt, retinoblastoma patients present more frequently with advanced disease. There is an ever-increasing need to develop a national team dedicated to studying disease significance and formulating a national awareness program.

The Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Patients with Unresectable Hepatocellular Carcinoma Treated with Radioembolization

PurposeTo assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with unresectable intermediate- or advanced-stage hepatocellular carcinoma (HCC) treated with yttrium-90 radioembolization (RE). Materials and MethodsRetrospective chart review was performed for 176 patients with intermediate- or advanced-stage HCC treated with RE between August 2000 and November 2012. The appropriate NLR cutoff was determined by receiver operating characteristic curves. Demographic, clinical, radiographic, and pathologic parameters were compared between patients with a normal NLR (< 5) and those with an elevated NLR (≥ 5) before RE. Barcelona Clinic Liver Cancer (BCLC) stage–stratified univariate and multivariate analyses were conducted to determine variables associated with overall survival. ResultsUnder univariate analyses, patients with a normal NLR were found to have longer survival than individuals with a high NLR in intermediate/advanced-disease and advanced-disease cohorts. A multivariate Cox proportional-hazards model in the advanced-disease group confirmed that elevated NLR, high α-fetoprotein level, and low albumin level were independent predictors of worse survival. ConclusionsThis study provides stage-dependent evidence for the prognostic role of NLR in the radioembolized HCC cohort. Patients with BCLC stage C disease with elevated NLR may not derive benefit from RE, and other intervening modalities should be explored in this subpopulation.

IN VITRO AND IN VIVO EVALUATION OF 2-CHLOROE THYLN ITROSOUREA DERIVATIVES AS ANTITUMOR AGENTS

To evaluate potential of Naphthal-NU, Napro-NU and 5-Nitro-naphthal-NU, 2-chloroethylnitrosourea compounds with substituted naphthalimide in the pre-clinical studies. In vitro cytotoxicity of three nitrosoureas was determined in human and mouse tumor cell lines by MTT assays. In vivo anti-tumor potential was evaluated in Sarcoma-180 (S-180) and Ehrlich's carcinoma (EC) solid tumors. Apoptosis in S-180 cells was analyzed by using Annexin V-Propidium Iodide (PI). Histological analysis of liver and kidney was performed at optimum dose (50 mg/kg). Expression status of CD4(+), CD8(+) and CD25(+) cells in treated mouse were also examined. Significant tumor growth retardation by the compounds was noted in early and advanced disease groups, as the life span of drug treated mice increased considerably. Drug induced killing was observed by induction of apoptosis. Naphthal-NU and 5-Nitro-naphthal-NU were effective to normalize the tumor induced structural abnormalities of liver and kidney. The compounds have no immunotoxic effect on CD4(+) and CD8(+) T cells and down regulate CD4(+)CD25(+) regulatory T cells. Overall data holds promise for the antitumor activity with lower toxicity of the compounds that can be utilized for the treatment of human malignant tumors.