bluuebunny/crossref_metadata_2025 huggingface dataset:
EGFR-TKI benefit for NSCLC patients with EML4-ALK rearrangement.
Authors: Wang Zhijie , Wang Jie , Wu Yi Long , Bai Hua , Zhang Xu-Chao , An Tongtong , Zhuo Minglei , Duan Jianchun , Yang Lu , Wu Meina
Published: March 2020

e18035

Background: EML4-ALK rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). To identify the biological profiles of these patients, we examined the clinico-pathologic characteristics and treatment outcomes of NSCLC patients based on EML4-ALK and EGFR mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization (FISH) confirmed by immunohistochemistry (IHC), and EGFR mutations were determined using denaturing high-performance liquid chromatography (DHPLC). Results: Of the 151 patients screened, 113 had complete follow-up data as an analysis set. The incidence of EML4-ALK was 9.7% (11/113) using FISH, in which 10 cases had sufficient specimens for IHC confirmation and all were positive. Overall, EML4-ALK and EGFR mutations were largely mutually exclusive (p = 0.033), although two patients harbored concurrent mutations. EML4-ALK rearrangement was associated with resistance to EGFR-TKIs compared with the EGFR mutant type and WT/Nonrearrangement type (p = 0.001 for objective response rate; p = 0.004 for disease control rate; p = 0.021 for progression-free survival [PFS]). In terms of patients who received platinum-based doublet chemotherapy, no significant differences were observed in PFS between the EML4-ALK type, EGFR mutant type, and WT/Nonrearrangement type. Moreover, two patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared with single EML4-ALK-rearranged patients. Conclusions: This study presents several biological features of EML4-ALK NSCLC. It is largely mutually exclusive to EGFR mutations, resistant to EGFR-TKI. Coexistence of ALK rearrangement and EGFR mutation in patients with advanced NSCLC might represent a separate genotype with unique biological characteristics.
A static diagnostic biopsy in patients with mutated EGFR lung adenocarcinom to guide therapeutic decisions.
Authors: Altavilla Giuseppe , Santarpia Mariacarmela , Arrigo Carmela , Tomasello Chiara , Benecchi Sara , Picone Antonio , Monaco Francesco , Pitini Vincenzo
Published: March 2020

e18039

Background: Approximately 70% of the pts. whose lung cancers harbor EGFR mutations acquire drug resistence after a response to EGFR tyrosine kinase inhibitors (TKIs) treatment; this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30%, and SCLC transformation in some patients. Furthermore, clinical experience revealed that cancers with acquired resistance can respond again to TKIs, after a drug-free interval. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 21 lung adenocarcinomas pts. (10 male, 11 female, median age 53 years) with EGFR mutations at 19 or 21 exons received TKIs, as first line of treatment. All showed a clinical response and all relapsed ( mTTP 10 months). At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR and MET amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all pts. retained their original activating EGFR mutations, 9 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 3, 2 pts. developed MET amplification, 8 biopsies did not reveal any new mutations, two pts. were found to have a diagnosis of small cell lung cancer in their drug resistant tumor biopsies and responded well to conventional chemotherapy regimen.15 of 19 confirmed lung adenocarcinoma patient underwent to a cisplatin - pemetrexed chemotherapy regimen and at the time of progression 10 of them accepted to undergo a new biopsy. Three pts. ( after 4, 5 and 6 months break from treatment with TKIs ) lost T790M mutation and their disease responded to a second-line course of erlotinib. Conclusions: In our cohort of pts. with acquired EGFR resistence some patients lost acquired T790M mutation and become sensitive to EGFR inhibitor, in addition, two pts. underwent the histologic transformation from NSCLC to SCLC at the time of TKI resistence.
Phase Ib study of oral PPARγ agonist efatutazone (CS-7017) in combination with erlotinib in Korean patients with metastatic or unresectable locally advanced non-small cell lung cancer (NSCLC) who progressed after first-line therapy.
Authors: Kim Sang-We , Choi Chang-Min , Lee Dae Ho , Lee Jae Cheol , Suh Cheolwon , Lee Jung Shin
Published: March 2020

e18052

Background: Efatutazone is a novel, third-generation thiazolidinedione (TZD) showing higher potency over second generation TZDs, such as pioglitazone. In non-Asian patients with advanced solid tumors, the recommended dose is 0.50 mg twice-daily (BID) in accordance with PK, PD and safety analyses in a US phase 1 study. This study assessed the safety, tolerability, PK, antitumor activity, PD, and determined the recommended dose of efatutazone in combination with erlotinib in Korean patients. Methods: This was an open-label, dose-escalation study using a 3+3 design in combination with erlotinib. Each patient participated in only 1 dose group and received oral efatutazone 0.25 or 0.50 mg BID with administration of erlotinib 150 mg QD. After determining the recommended dose of efatutazone, 9 additional patients were enrolled to the recommended dose for further assessment. PK samples were collected at day 1 and 22. PD samples were collected weekly until day 36. All subjects provided written informed consent. Results: A total of 14 patients were enrolled (10 male and 4 female; age range: 39–73 years; 12 Adenocarcinoma and 2 Squamous cell carcinoma; EGFR mutation: 5 positive, 4 negative and 5 not conducted) and received treatment at doses of 0.25 and 0.50 mg BID (n= 3 in 0.25mg, n= 11 in 0.50mg cohort). DLT were not observed, and the MTD was not reached. Efatutazone was well tolerated. The majority of patients experienced edema (78.6%, 11 out of 14 patients) and weight increase (64.3%, 9 out of 14 patients), often requiring diuretics. Five out of 14 patients showed PR (3 confirmed in 0.50mg cohort) and 4 patients showed SD. Efatutazone increased plasma adiponectin levels in a dose-dependent manner. Conclusions: Efatutazone is a novel anticancer therapy and in combination with erlotinib was tolerated and demonstrated early evidence of antitumor activity. Although the MTD for efatutazone was not reached, 0.50 mg BID, corresponding to the global recommended dose, was selected as the recommended dose for Korean patients. Full safety data and clinical activity data will be presented.
Clinicopathologic and molecular factors associated with early progressive disease after front-line platinum-doublet chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC).
Authors: Giroux Leprieur Etienne , Antoine Martine , Vieira Thibault , Duruisseaux Michael , Poulot Virginie , Rabbe Nathalie , Belmont Laure , Gounant Valérie , Lavole Armelle , Milleron Bernard , Lacave Roger , Cadranel Jacques , Wislez Marie
Published: March 2020

e18075

Background: The majority of cases of NSCLC are diagnosed at an advanced stage and treated with a platinum-doublet CT. However, some patients are resistant to this treatment and develop early progressive disease. We investigated the clinicopathologic and molecular characteristics of such patients. Methods: All consecutive patients with NSCLC IIIB−IV treated with a platinum-doublet CT between 2003 and 2006 were included. Platinum resistance was defined as early progressive disease at the first tumor assessment according to WHO criteria. The clinical, histologic and molecular characteristics (EGFR:exon 19, 20, 21 and KRAS:exon 2 by PCR sequencing; ALK by IHC, confirmed by FISH) and survival of patients with early progression (P) and controlled disease (C) were compared by univariate analysis. Factors differing between the two groups with a p-value <0.25 in univariate analysis were entered into multivariate analysis. Results: 178 patients were included (mean age 59.1 years, 66.3% male, 54.5% smokers). Platinum was associated with gemcitabine (52.2%), paclitaxel (32.6%) or docetaxel (11.8%). The first tumor assessment was carried out after a median of three cycles [range 1−4]. Forty-six (25.8%) patients had early progression. Overall survival of P-group was significantly shorter than that of C-group (median 5 months vs. 15.1 months, respectively; p <0.0001). Clinical presentation was similar in the two groups. The sarcomatoid histologic subtype was more common among P-group than C-group (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, respectively; p=0.224) and KRAS mutations (11.1% vs. 5.7%, respectively; p=0.357), and expression of ALK (6.3% vs. 2.5%, respectively; p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histologic subtype was the only factor associated with early progression [OR=7.50, 95%CI: 1.02−55.45; p=0.048]. Conclusions: Patients with early progression had a shorter survival than controlled patients. Sarcomatoid histologic subtype was the only independent factor associated with early progressive disease.
The impact of renal function on therapeutic options for advanced non-small cell lung cancer (NSCLC).
Authors: Kutluk Cenik Bercin , Rasco Drew Warren , Sun Han , Gerber David E.
Published: March 2020

e18076

Background: Certain commonly used chemotherapeutic agents for advanced NSCLC require minimum threshold renal function for administration. To determine how such requirements affect treatment options, we evaluated renal function patterns in a real-world cohort of patients. Methods: Retrospective analysis of consecutive patients treated for stage IV NSCLC from 2000 to 2007 at the UT Southwestern Medical Center. Clinical data obtained from tumor registries and medical records. Creatinine clearance (CrCl) was determined using the Cockcroft-Gault formula. Mixed model analysis was used to evaluate associations between patient clinical factors and longitudinal renal function. Results: 296 patients (3,930 Cr measurements) were included in the analysis. Mean age was 63 years, 43% were women, and 47% were white. Patients had a median of 5 (IQR 4-18) Cr measurements. The median overall CrCl was 92 (IQR 68-124) mL/min; the median pre-treatment CrCl was 96 (IQR 74-123) mL/min; and the median nadir CrCl was 78 (IQR 56-100) mL/min, occurring a median of 35 (IQR 1-235) d after diagnosis. Renal function was significantly associated with age (P<0.001), race (P=0.009), and gender (P=0.001). 22% of patients had a recorded CrCl < 60 mL/min (a commonly used threshold for cisplatin administration), with median onset of 89 d after diagnosis and median time to recover to ≥ 60 mL of 20 (IQR 3-85) d. The incidence and median duration of CrCl < 60 mL/min varied by age (<65 y: 8%, 17 d; ≥65 y: 30%, 43 d), gender (male: 9%, 15 d; female: 28%, 36 d), and race (white: 30%, 42 d; non-white: 13%, 21 d). 10% of patients had a recorded CrCl < 45 mL/min (threshold for pemetrexed), with median onset 228 d after diagnosis and median time to recover to ≥ 45 mL/min of 33 (IQR 3-73) d. The incidence and median duration of CrCl < 45 mL/min also varied by age (<65 y: 6%, 6 d; ≥65 y: 8%, 72 d), gender (male: 4%, 5 d; females: 9%, 68 d), and race (white: 4%, 68 d; non-white 8%, 8 d). Conclusions: In a real-world cohort of patients treated for stage IV NSCLC, renal function falls below commonly used thresholds for cisplatin and pemetrexed in fewer than a quarter of patients. When such declines in renal function do occur, their duration may preclude administration of these drugs for prolonged periods.
Prognostication in non-small cell lung cancer.
Authors: Gagnon Bruno , Gioulbasanis Ioannis , Cohen Victor , Pepe Carmela , Small David I. , Yang Lin , Perdikouri Eleni Isidora , Kasymjanova Goulnar , Morris David , MacDonald Neil , Agulnik Jason Scott
Published: March 2020

e18098

Background: For modern evidence-based medicine, a well defined risk scoring system on survival has important clinical implications for identifying patients with a poor prognosis. The objective of this study was to develop a Montreal Prognostic Score (MPS) based on risk scores of the baseline clinical markers. Methods: A training Cohort (TC) and confirmatory cohort (CC) of patients with non small-cell lung cancer were used to develop a Montreal Prognostic Score (MPS) and were assembled of patients from 3 different oncology centres: Jewish General Hospital in Montreal, Quebec, Canada; the University General Hospital of Heraklion Crete, Greece; and at the University General Hospital of Larissa, Greece. Stage, performance status, smoking status, CRP, Albumin, LDH and WBC from TC were entered in a Cox’s model on survival. Independent prognostic factors (p ≤ 0.1) were assigned a relative risk score by dividing their Proportional Hazard by the lowest one rounding to the closest integer. A 3 risk groups’ regression based total score (MPS) was finally developed by regrouping subgroups of patients with similar median survival. The MPS was tested on the CC. C-statistics was used to test the accuracy of the MPS. Results: 638 pts were included in the study: 314 in the TC and 324 in the CC. Majority of patients were stage 4 adenocarcinomas with good performance status treated with platinum-based chemotherapy. Stage, performance status, CRP, Albumin, LDH and WBC retained independent prognostic value and were used to create the MPS. The MPS predicted 3 well defined risk groups of patients with the following median survival and (95% CI) in months: high risk group (87 patients), 5.0 (4.2—7.0); intermediary risk group (98 patients), 9.6 (8.4—11.9); and low risk group (84 patients) 15.2 (12.4—25.1). When the MPS is applied to CC, the results were replicated for each risk group. Overall the TC had a C-stats of 0.673 (95% CI: 0.668, 0.679) while the CC of 0.702 (95% CI: 0.696, 0.708). Conclusions: We have developed a Montreal Prognostic Score based on stage, performance status and the baseline value of CRP, Albumin, LDH, WBC. This MPS has a high capacity of discriminating survival and might have wide implications in clinical practice and research.
A phase I/II trial of erlotinib S-1 therapy in patients with non-small cell lung carcinoma: Thoracic Oncology Reseach Group (TORG) 0808/0913.
Authors: Nogami Naoyuki , Shinkai Tetsu , Kozuki Toshiyuki , Ogino Atsuko , Kato Yuka , Hosomi Yukio , Hida Naoya , Shimokawa Tsuneo , Seki Nobuhiko , Okamoto Hiroaki , Shibuya Masahiko , Watanabe Koshiro ,   Thoracic Oncology Reseach Group (TORG)
Published: March 2020

e18099

Background: Gefitinib has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported. Erlotinib also reduced TS expression and activity. The present studies were designed as study aimed at evaluating the efficacy and safety of erlotinib/ S-1 combination therapy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC. Methods: Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily after meals from days 1 to 14 of each 21-day cycle. In phase I trial(TORG0808), the primary endpoint was to evaluate the DLT and the MTD for the following phase II study, and the secondary endpoint was to evaluate the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary endpoints were PFS, disease control rate, OS, and safety. Results: 7 patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and phase II trial. In phase I trial, the recommended doses for the phase II study were determined to be 150mg/body and 80mg/m2. The ORR was 67%, and 3/4 responders are EGFR positive patients. In phase II trial, the ORR was very low (only one patient).Myelosuppression was relatively mild, but Grade 3 or worse non-hematological toxicities including diarrhea, mucositis, and dermatitis were observed in 6 patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination, and the clinical trial was terminated due to adverse events. Conclusions: Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR positive patients, but less effective and too toxic in EGFR negative patients in phase II trial.
An analysis of target-specific patient resource utilization in NSCLC clinical trials.
Authors: Somaiah Neeta , Simon George R.
Published: March 2020

e18112

Background: A plethora of targeted agents are currently being evaluated in patients with NSCLC. The number of targeted agents exceeds the number of targets leading to many targeted agents being evaluated against similar targets. The identification of new targets are likely to increase exponentially in the near future given the numerous currently ongoing molecular profiling efforts. The objective of this analysis is to estimate the target-specific patient resource utilization and its impact on routine clinical care. Methods: A comprehensive search for molecularly targeted agents in clinical testing that have accrued or are accruing NSCLC patients were performed by using publically available search engines and databases. Agents were grouped according to the primary target and the phase of development. We computed the number of patients allocated to completed and ongoing phase III NSCLC trials for advanced NSCLC alone. Results: There are more than 30 categories of molecular targets accruing NSCLC patients in clinical trials. By conservative estimates, approximately 215 agents are currently undergoing clinical testing. The median number of agents per target is 7 (range 2 (HIF-1α and PDGFRα) – 24 (EGFR)). There are 7 EGFR inhibitors and 10 VEGFR inhibitors that were evaluated in phase III trials; with 36,093 and 20,313 stage IV NSCLC patients enrolled or to be enrolled in these trials, respectively. No more than 2 agents per target have been FDA approved for NSCLC to date. Further details of the analyses will be more comprehensively presented at the meeting. Conclusions: Patient resource utilization is unevenly distributed across targets. The optimal number of targeted agents to be evaluated per target remains to be defined. More emphasis on identifying new targets and targeting these with limited number of optimal agents may accelerate the advancement of the field and the impact on patient care.
New prognostic loci related to the survival of patients with advanced non-small cell lung cancer receiving chemotherapy: A genome-wide association study.
Authors: Lee Young Joo , Yoon Kyong-Ah , Joo Jungnam , Lee Donghoon , Han Ji-Youn , Lee Jin Soo
Published: March 2020

e18119

Background: We investigated prognostic significance of genetic variants identified by genome-wide association study (GWAS) for the patients with advanced non-small cell lung cancer (NSCLC). Methods: Among the patients included in our previous GWAS paper for lung cancer risk, we selected 348 patients with stage IV NSCLC, who had started chemotherapy in May 2002 through December 2005 at the National Cancer Center Hospital, and had the follow-up data available. After applying quality control criteria, the association of 271,817 genotyped SNPs with overall survival was analyzed by the Cox proportional hazard regression model adjusted with known prognostic factors using the bootstrap resampling procedure. Results: Overall, the median age of patients was 56 years, 64.9% were female, 67.2% were never smokers, and 80.4% had adenocarcinoma; 73.0% received platinum-based chemotherapy and 73.6 % received EGFR-TKIs. The median survival time (MST) for all patients was 25 months. A total of 23 SNPs with MAF of >0.05 were selected using a cut-off minimum p-value of <5x10-5 (either in additive or dominant models) in at least 70% of a thousand bootstrap samples. Those SNPs were known to be located in the genomic coding region of the FAM154A, EGF, NCOA2, CDH8, ANKS1A, DLST, VGCNL1, SLC35D2, and THSD7B. Carrying a variant genotype of rs1571228 SNP located on the FAM154A, for example, was significantly associated with better overall survival with MST of 29.6 months for those with AG/GG (n=144/30) genotypes vs. 21.5 months for those with AA (n=173) genotype under the dominant model (hazard ratio of 0.52 [95% CI, 0.42-0.67], p = 2.03 x 10-7). This association remained consistent in a subgroup of patients who received platinum-based chemotherapy (n= 254, p = 1.69 x 10-6) or EGFR-TKIs (n = 256, p = 9.04 x 10-6). Conclusions: Genetic variants at multiple loci were found to be prognostically important for patients with advanced NSCLC, which warrants further investigation into its biological relevance and clinical implication.
DNA repair components modulating the function of breast cancer susceptibility gene 1 (BRCA1) in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based chemotherapy.
Authors: Bonanno Laura , Costa Carlota , Majem Margarita , Sanchez Jose Javier , Gimenez Capitan Ana , Vergnenegre Alain , Massuti Bartomeu , Mayo Clara , Molina-Vila Miguel Angel , Favaretto Adolfo G. , Pallares Cinta , Benlloch Susana , Rugge Massimo , Taron Miquel , Rosell Rafael
Published: March 2020

e18130

Background: The standard first-line treatment for advanced NSCLC p with wild-type epidermal growth factor receptor (EGFR) is platinum-based chemotherapy, but median overall survival (OS) is about 12 months, with great heterogeneity in terms of efficacy and tolerability. Low BRCA1 mRNA expression has been correlated with sensitivity to cisplatin, but BRCA1 function is modulated by other DNA repair components. For example, AEG1 can induce BRCA1 expression, and CASPASE 3 cleaves the mediator of DNA damage checkpoint 1 (MDC1) preventing the activation of the DDR pathway Methods: Paraffin-embedded samples were collected from 115 advanced NSCLC p treated with first-line platinum-based chemotherapy (not including taxanes and vinca alkaloids). Samples were screened for EGFR, KRAS and p53 mutations, and gene expression levels of BRCA1, RAP80, AEG1, MDC1, CASPASE 3, 53BP1, MMSET, PIAS4, UBC9, UBC13, NPM1 and HERC2 were quantified by real-time PCR. Results: Gene expression levels were significantly higher in squamous tumors, and the correlation among genes confirmed the biological model. Median OS was 11 months and median progression free survival (PFS) was 7.1 months. In p with low levels of both BRCA1 and RAP80, PFS was 12 months and OS was not reached, while in p with high level of both genes, PFS was 5.1 months and OS was 6.2 months and in p with other combinations, PFS was 7.4 months and OS was 10.9 months (P=0.02). Increased levels of AEG1 increased the risk of death (HR: 1.3; P=0.01) and of progression (HR: 1.2; P=0.04). When CASPASE 3 levels were divided into tertiles, intermediate levels were associated with improved PFS (P=0.005) and OS (P=0.05). The multivariate analysis confirmed the role of BRCA1 (P=0.02) and CASPASE 3 (P=0.008). Conclusions: The study showed the predictive value of combined BRCA1 and RAP80 mRNA levels. In addition, AEG1 and CASPASE 3 have emerged as potential predictive markers.
A retrospective study analyzing activity of ofatumumab in blastic variant mantle cell lymphoma.
Authors: Ghai Vikas , Sharma Kamal , Hasanali Zainul , Shimko Sara , Stuart August , Liao Jason , Epner Elliot E
Published: March 2020

e18500

Background: The blastic variant (BV) form of mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma (NHL) for which no standard of care exists. Ofatumumab is a CD20-directed monoclonal antibody (mAb) FDA approved for the treatment of patients with CLL. We retrospectively studied relapsed BV of MCL in patients treated with regimens containing ofatumumab and previous or concurrent epigenetic therapy (cladribine (2-CdaA) and vorinostat). Methods: BV was confirmed by histopathological patterns, ki-67 proliferation index, immunophenotyping, and t(11;14) by FISH and/or cyclin D1 overexpression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival and complete response. Correlative studies to support the hypothesis that epigenetic modulation of multiple genes in multiple pathways can potentiate the activity of mAbs were performed. Results: Ofatumumab administered to 5 Stage IV BV of MCL patients (Table). 3/5 patients had a radiological complete response, lasting 21.1, 13.4 and 12 months, The other 2 patients had partial response and are on the maintenance. Observed PFS in this cohort is a median 13 months (2.7-20.7). Correlative studies following epigenetic therapy found upregulation of the following genes by RT-PCR: NOXA1 (3/5 patients), CEBP1 (2/5) and EZH2 (2/5). Conclusions: Epigenetic drugs can augment the activity of mAbs. In this case, a more potent mAb improves response in MCL. Correlative studies to support the hypothesis that epigenetic modulation of multiple genes in multiple pathways can potentiate activity of mAbs. The combination of 2-CdA and vorinostat synergistically activates genes silenced by histone deacetylation, histone methylation and DNA methylation and enhances the activity of the mAb ofatumumab. [Table: see text]
Unusual primary presentations of mantle cell lymphoma in the urinary tract and testes.
Authors: Peker Deniz , Kubal Timothy Edward , Sotomayor Eduardo M. , Sokol Lubomir , Cultrera Jennifer L. , Bello Celeste M. , Chervenick Paul A. , Sagatys Elizabeth , Naghashpour Mojdeh , Zhang Ling , Moscinski Lynn , Shah Bijal D.
Published: March 2020

e18503

Background: The initial clinical presentation of Mantle Cell Lymphoma is protean, ranging from single sites of indolent disease followed for years without therapy to aggressive disseminated disease that requires treatment within weeks of diagnosis. While many cases of Mantle Cell Lymphoma present with disseminated disease, other patients may present with symptoms related to a primary extranodal site of disease. The majority of these primary extranodal cases are diagnosed in the gastrointestinal tract, other cases have been noted in the skin, conjunctiva, testes and male genitourinary tract. Methods: Database review of 204 patients diagnosed with Mantle Cell Lymphoma at Moffitt Cancer Center between May 1992 and December 2010. Results: Three cases of Mantle Cell Lymphoma presented with symptoms related to primary extranodal sites in the urinary tract and male genital organs. Two cases of testicular involvement presented with gradual enlargement of the testes. In patient 1, the orchiectomy specimen harbored both seminoma and mantle cell lymphoma. Low level bone marrow involvement by mantle cell lymphoma was present and in the presence of indolent features he was treated for his primary seminoma and followed expectantly for mantle cell lymphoma. In patient 2, orchiectomy revealed a pleomorphic variant of mantle cell lymphoma with no other sites of disease on staging workup. He was treated with 6 cycles of R-CHOP and prophylactic IT methotrexate with a complete remission. A third patient presented with obstructive urinary symptoms and was found to have mantle cell lymphoma of the prostate. Additional staging revealed diffuse lymphadenopathy, colon and bone marrow involvement. A complete remission was obtained with 6 cycles of R-CHOP. None of these three patients was found to have evidence of CNS involvement at diagnosis or in followup with only the second patient receiving intrathecal prophylaxis. Conclusions: Mantle Cell Lymphoma may present with unusual extranodal involvement at diagnosis including sites and symptoms related to the genitourinary tract and testes. Diagnostic lumbar puncture and intrathecal prophylaxis should be considered in these patients.
Positron emission tomography scan (PET) in human T-cell lymphotropic virus-1 (HTLV) associated adult T-cell leukemia lymphoma (ATLL): Single center experience.
Authors: Sidhu Gurinder Singh , Preet Mohan , Latif Rabia , Axiotis Constantine A , Braverman Albert S.
Published: March 2020

e18504

Background: Serologic positivity for HTLV and ATLL are endemic amongst Caribbean populations. Kings County and University Hospital of Brooklyn serve population with large number of immigrants from this region. ATLL in this population is mostly of aggressive (leukemia/lymphomatous) type. Responses to chemotherapy (CT) are brief, and 90% succumb to ATLLwithin 18 months (m) of presentation. Lactic dehydrogenase (LDH) levels are high, but PET is not used in routine staging. Methods: Records of all patients with ATLL presenting to these institutions between 2001-11 were reviewed. The results of PET, including maximum standard uptake value (SUVmx) were recorded for scans obtained before (12) and after (19) initial CT, and at relapse (13). Results: Of 95 T cell lymphoma patients, 73 had ATLL. PET was performed in 26 of the 73 patients; 20 of the 26 had ATLL, 5 had other T cell lymphomas. Infusional etoposide, vincristine, doxorubicin and prednisone (EPOCH) was the CT of 17 of the 20 ATLL patients; relapse occurred after a median of 9.5 m, often followed by salvage CT. Of the 6 male and 6 female patients scanned pre-CT, the median SUVmx was 9.9; range 2.9-33. Their initial median LDH level was 390 (321-683). The median overall survival (OS) was 11.5 (1-24 m). Thirteen patients had 19 post-CT scans, with a median SUVmx of 3.0; only one SUVmx was elevated (8.4); that patient had progressive disease, but the others variously displayed complete and partial remissions, or progression. Their median OS was 13 m (range 4-39 m). Their median LDH at presentation was 523. Eight patients had 13 scans at relapse, with a median SUVmx of 10.6, range 3.7-21. Their median OS was 17 m (range 12-21). OS and SUVmx were not correlated. Conclusions: Like Hodgkin’s and large B cell lymphomas, the pre-CT PET SUVmx levels of ATLL patients were significantly elevated; most fell to normal or slightly elevated levels after CT. PET is thus likely to have some value in staging ATTL. Our results suggest that PET response of ATLL patients to CT correlates poorly with durable relapse-free survival. The latter parameter is probably dependent on factors other than proliferative rate or control of aerobic glycolysis.
Anaplastic large cell lymphoma (ALCL) ALK positive and ALCL ALK negative uniformly treated with intensive alternating chemotherapy at a single institution.
Authors: Romejko-Jarosinska Joanna , Domanska-Czyz Katarzyna , Ostrowska Beata , Paszkiewicz-Kozik Ewa , Poplawska Lidia , Rymkiewicz Grzegorz , Walewski Jan Andrzej
Published: March 2020

e18512

Background: Anaplastic large cell lymphoma ALK positive (ALCL ALK+) is frequently referred to as easily curable disease, however, patients with more than 1 IPI risk factors have a poor outcome. ALCL ALK negative (ALCL ALK-) have usually higher IPI score and there is no general consensus on what treatment is the optimal. We evaluated data on 26 consecutive patients with ALCL ALK+ and ALCL ALK- treated uniformly at our institution between July 2004 and April 2011. Methods: 26 patients with ALCL ALK+ or ALCL ALK- were treated according to GMALL B-ALL/NHL 2002 protocol (Hoelzer D et al. Blood 2007; 110: Abstr. 518) without rituximab. Kaplan-Meier method and Cox’s model were used to analyze overall survival time and progression free survival time. Results: ALK protein expression was tested in 26 patients, 19(73%) were positive, 5(27%) were negative. Median age was 33 years (range 16-53). 14 pts (54%) were male, 20 (77%) were in clinical stage (CS) III or IV, 16 (61,5%) had B symptoms, 10(38,5%) had bulky disease, 10 (38,5%) had LDH > N, and 20 (77%) had IPI score >1. The overall response rate (ORR) was evaluated in 23 of 26 patients. The ORR was 87% (20/23 patients). After median follow up of 26 months (range; 6-90) overall (OS) and progression free survival (PFS) at 2 years was 67%: 95% C.I.=[48%, 86%] and 65%: 95% C.I.=[48%, 82%], respectively. On multivariate analysis none of factors: CS III and IV, B symptoms, bulky disease, IPI score>2, LDH>N, ALK expression influenced OS and PFS. The major toxicity was reversible myelosuppression: grade 4 neutropenia occurred after every cycle. Other complications included mucositis and infection. Two toxic deaths (7,6%) from sepsis occurred during neutropenia after first cycle of treatment. Conclusions: These results suggest that GMALL- B-ALL/NHL 2002 protocol is an effective treatment for both ALCL ALK + and ALCL ALK-, however, toxicity is remarkable, with neutropenia and infection being most frequent complications.
Prevalence of autoimmune conditions in patients with marginal zone lymphoma: Exploratory analysis of a series of consecutive patients.
Authors: Grabska Joanna , Bockorny Bruno , Codreanu Ion , Mewawalla Prerna , Dasanu Constantin , Silver Joel
Published: March 2020

e18543

Background: Recent literature suggests that an association exists between marginal zone lymphoma (MZL) and certain autoimmune conditions. Furthermore, MZL and autoimmune diseases may share same pathogenesis in these patients. The present study was set to identify the prevalence of autoimmune phenomena in MZL patients and compare it with same in general population. Methods: We conducted both retrospective and prospective analyses in a series of consecutive patients (n=24) with MZL that had been followed in outpatient setting. Median age was 71.8 years (range, 50-96). Records were reviewed for the presence of autoimmune abnormalities; length of the prospective analysis segment was ~24 months. Prevalence of autoimmune disorders in our cohort was compared to their respective prevalence in general population. Statistical analysis: The obtained values were tested for statistical significance using Fisher’s exact test for small number of observations (95% confidence); a p-value < 0.05 was considered significant. Results: A total of 50% patients included in our study had documented autoimmune conditions. Identified autoimmune disorders included Hashimoto thyroiditis (n=5), immune thrombocytopenia [ITP] (n=4), rheumatoid arthritis [RA] (n=1), Raynaud's phenomena (n=1), psoriasis (n=1), and autoimmune hemolytic anemia [AIHA] (n=1). Statistical analysis showed the following significance: Hashimoto thyroiditis (p=0.037), ITP (p<0.01), AIHA (p<0.01), RA(p=0.351), psoriasis (p=0.479), and Raynaud's phenomena (p=0.666). Conclusions: Circa half of MZL patients also have autoimmune conditions, thus significantly exceeding the overall prevalence in general population. Statistically significant differences in our MZL patients were recorded for Hashimoto thyroiditis, ITP, and AIHA. When compared to the prevalence in general population, the difference did not reach statistical significance for RA, psoriasis, and Raynaud's phenomena. However, this may be related to the relatively small size of the analyzed cohort. Therefore, larger studies would be useful before definitive conclusions can be drawn.
Patients with extramedullary manifestation of multiple myeloma: Prognostic factors and survival.
Authors: Wieczorek Agnieszka Anna , Balci Derya , Schmidt-Hieber Martin , Lohneis Philipp , Heider Ulrike , Pezzutto Antonio , Blau Igor Wolfgang
Published: March 2020

e18552

Background: Multiple myeloma is a plasma cell dyscrasia that primarily involves bone marrow but also occurs in the soft tissues. While observing striking differences in clinical courses of patients with extramedullary plasmacytoma (EMP), solitary bone plasmacytoma (SBP), multifocal form of multiple myeloma (MFM) and multiple myeloma (MM), we wanted to assess prognostic factors and outcomes in those groups. This retrospective analysis was performed to evaluate response rate and overall survival (OS) of patients with extramedullary manifestations. Methods: We evaluated the data from 54 patients with MM (n=17), MFM (n=19), EMP (n=12) and SBP (n=6) treated at our institution from 1994-2012 and initially selected based on provided tissue samples. The MM control cohort was matched with regard to age, gender and prior treatment regimens. In 3 of 19 cases of MFM extramedullary locations were found at initial diagnosis. Two patients with EMP converted into MFM during the treatment. All EMP lesions arised in the upper aerodigestive tract. However extramedullary involvement in MFM was found in the head and neck (37%), chest (53%), abdomen (21%) and extremities (31%). Results: The 5-year OS rate was 92% in the patients with EMP. Whereas, 5-year OS rates of MM patients achieved 70.6%. MFM patients reached only 58% 5-year OS. The 5-year probability of progression was significantly higher in the group with MFM than EMP (89.5% vs 33%, p=0.0076, log rank test). Median progression free survival was 34 months for MM and 20 months for MFM (p=0.18). Conclusions: The 5-year progression free survival could be reached in 10 out of 12 patients with EMP. Two of the patients with primary EMP developed MFM. Moreover, the secondary development of extramedullary manifestation was associated with worse prognosis. Since the differences in the disease development cannot be easily predicted, there is an need of additional predictors that take into account different genetically determined risk status. Our retrospective analysis of genetic variations in this cohort of patients indicates the need of additional predictors in future randomized studies in these rare subtypes of MM.
Individualizing the starting dose for MPT therapy in elderly myeloma patients.
Authors: Blau Gary E , Orcun Seza , Lainez Jose Miguel , Reklaitis Gintaras V , Suvannasankha Attaya , Fausel Christopher A. , Kiel Patrick , Anaissie Elias J.
Published: March 2020

e18555

Background: Many elderly or frail myeloma patients ineligible for autologous stem cell transplant (ASCT) receive non-myeloablative therapies such as the melphalan/prednisone/thalidomide (MPT) combination. These agents have variable pharmacokinetics (PK), and hence variable anti-tumor responses and toxicities. Yet, their dosing is uniform, partly because no convenient procedure exists to individualize dosage-schedules (costs and logistical difficulties with multiple blood samplings for a given patient). We herein propose a novel PK methodology that allows for individualized dosing of these agents. Methods: The MPT regimen is commonly used for older patients and consists of six cycles of 4mg/m2 M, 40mg/m2 P and 100mg T administered for seven days followed by a three-week rest period. To compare the peripheral blood concentrations between individuals, a marker combining the level and duration of exposure is the time weighted “average concentration” defined by CC=(Cumulative Area under the concentration time curve (AUC))/(Elapsed time from start of treatment). Using pattern recognition software, an individual’s PK profile was simulated from the population PK models using a single blood draw 2h after administration. The AUC for the individual is then used to adjust the starting dose to match the CC target profile based on the average population response. Results: Using PK data for the individual patients used to construct the PK population model, the simulated adjusted doses for initializing the therapy vary as follows: M 2.5-6mg/m2; P 12.5-140mg/m2; and T 76-130mg which is substantially different from the "standard" uniform dosing. Conclusions: The wide variability in dose levels obtained with the pattern recognition software may explain the marked differences in response and toxicities to the “standard” dosing protocol. An individualized starting dose can be applied using the proposed methodology which requires only a single blood draw after a lower “test dose” of these agents “prior” to commencing actual therapy.
Combinatorial treatment with CTO and temozolomide in sc-implanted human LOX 1MVI melanoma.
Authors: Karmali Rashida A. , Maxuitenko Yulia , Gorman Greg
Published: March 2020

e19006

Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1.(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide. CTO possesses increased solubility. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor –opertated calcium channel- mediated calcium influx. CTO can inhibit calcium sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cγ, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl. Methods: Different combinations of CTO and temozolomide (TEM) were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously –implanted human LOX 1MVI melanoma xenografts. Results: Oral CTO at doses of 513 or 342 mg/kg/dose Q1Dx14 resulted in inhibition of tumor growth (p<0.001 and p=0.004). Oral TEM at doses of 90 and 60mg/kg/dose Q4Dx3 resulted in dose-dependent inhibition of tumor growth (p<0.001 and p<0.001). Oral CTO at 513 or 342 mg/kg/dose in combination with TEM 90mg/kg/dose resulted in comparable tumor inhibition to TEM alone. However, oral CTO at 513mg/kg/dose in combination with TEM 60mg/kg/dose resulted in additive antitumor activity compared to each drug alone. Also, CTO at 342mg/kg/dose in combination with TEM 60mg/kg/dose had more than additive antitumor activity and was statistically different from the group treated with TEM 60mg/kg/dose alone (p=0.001). Conclusions: These results suggest that CTO enhances the sensitivity of TEM and may permit use of lower doses of TEM to obtain an optimum antitumor effect in combination therapy thus reducing toxicity of high TEM doses in this melanoma model.
Development of brain metastases in patients with metastatic melanoma treated with ipilimumab plus temozolomide.
Authors: Wang Jennifer , Patel Sapna Pradyuman , Hwu Wen-Jen , Kim Kevin B. , Papadopoulos Nicholas E. , Hwu Patrick , Radvanyi Laszlo George , Mahoney Sandy , Deburr Tawania L , Bassett Roland , Bedikian Agop Y.
Published: March 2020

e19014

Background: Melanoma has a high predilection for brain metastasis (BM), and despite treatment, survival is often 3 to 6 months. There have been a number of reports of disease regression in BM with each Ipilimumab (Ipi), an anti-CTLA 4 antibody, and temozolomide (Tem), an alkylating drug capable of crossing the blood-brain barrier, in patients with metastatic melanoma (MM). Previous Ipi trials excluded patients with BM. Previous Tem trials have BM incidence ranging from 20 to 36%. Here we describe our experience with the combination of Ipi+Tem and BM. Methods: Patients (pts) are from a 64-patient cohort with unresectable Stage III or Stage IV metastatic melanoma enrolled in a single-center Phase II trial of Ipi+Tem. Induction phase consisted of Ipi 10mg/kg intravenous (IV) on Day 1 and oral Tem 200mg/m2 Days 1-4 every 3 weeks for 4 courses. Maintenance phase was Ipi 10mg/kg IV every 12 weeks and oral Tem 200mg/m2 on Days 1-5 every 4 weeks. Brain MRI was obtained every 2 cycles as part of the protocol. We evaluated development of BM in these pts. Results: At a median follow-up of 41 weeks, 11 pts (17%) developed new BM. Two pts with a history of prior BM were enrolled; one developed new BM while the other achieved a complete response of disease in the lungs and remains on study. All pts who developed BM had Stage IV disease at baseline, five (45%) had elevated baseline LDH, and nodular melanoma was the most common histology (55%). The median time to development of BM with Ipi+Tem was 12 weeks. Mutation status, stage, and primary tumor location and depth were not significantly associated with the development of BM. Elevated baseline LDH was a significant predictor for development of BM (p=0.001, log-rank test). The median overall survival for both the BM and non-BM groups has not been reached. Conclusions: There is little known about the development of BM with various treatments for MM. To our knowledge, this is the first study to evaluate the development of BM in pts receiving Ipi-based treatment. Our data suggest that Ipi+Tem and Ipi monotherapy warrant further research in the prevention and treatment of BM in MM.
Genotype characterization and prognosis of unknown primary melanoma patients with nodal metastases.
Authors: Gos Aleksandra , Robert Caroline , Jurkowska Monika , Kamsu-Kom Nyam , Michej Wanda , Jeziorski Arkadiusz , Voit Christiane A. , Roewert-Huber Joachim , Siedlecki Janusz A , Van Akkooi Alexander Christopher Jonathan , Eggermont Alexander M. , Rutkowski Piotr
Published: March 2020

e19022

Background: Melanoma of unknown primary site (MUP) is unique, not completely understood entity with nodal metastases as the most common clinical manifestation. The aim of this multicentric study was to assess genetic alterations in MUP with clinically detected nodal metastases in terms of clinicopathological features and prognosis. Methods: We analyzed contemporary series of 37 MUP patients (median age 51 years) after therapeutic lymphadenectomy - LND (period: 1996-2010, 20 – axillary, 16 - inguinal, 1 – other basin) not treated with BRAF inhibitors and performed molecular characterization of BRAF/NRAS mutational status in nodal metastases using direct sequencing of respective coding sequences. Median follow-up time was 37 months. Results: BRAF mutations were detected in 23 (63%) cases (21 V600E - 91%, 2 others - 9%), and mutually exclusive NRAS mutations in 3 (8%) cases (Q61K, Q61R, Q13R). Presence of BRAF mutation correlated with younger age of patients (median 47 vs 60 years for BRAF+ vs. BRAF-, p<0.05). 3-year overall survival (OS) was 45%, median – 23 months (from date of lymph node dissection). We have not found any difference in terms of OS between BRAF mutated- and wild-type melanomas (p=0.99). Conclusions: This unique, comprehensive study on molecular characterization of MUP with nodal involvement stage showed that MUPs have similar molecular features as sporadic non-chronic-sun-damaged melanomas. BRAF mutational status has no prognostic value in this group of patients, what may have potential implications for adjuvant therapy.