bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival patterns by line of treatment of stage IIIb/v NSCLC patients from community U. S. oncology practice.
Authors: Chaugule Shraddha , Foltz Boklage Susan H , Kreilick Charles , Sullivan Sean D , Ramsey Scott David , Haislip Sally , Gilmore James W. , Szabo Stephen , Sarma Syam , Asche Carl V , Seal Brian S.
Published: March 2020

e18097

Background: Lung cancer is the most common cause of cancer-related death in men and women worldwide. 80% of the lung cancer patients are diagnosed with NSCLC. Patients have varying survival results from multiple lines of treatment. The objective of this study was to evaluate in a real world context, treatment patterns with survival, and the impact of adding a third line of chemotherapy to a stage III/IV NSCLC population. Methods: The Georgia Cancer Specialist database (2005-2011) was used. Patients with stage III or IV primary NSCLC and treated with chemotherapy were followed from initial NSCLC diagnosis until death, study end or lost to follow-up. Patients were stratified into lines and type of protocol for treatments. Kaplan-Meier curves were used to compare the overall survival results between lines of therapy. Results: A total of 291 patients with advanced NSCLC were identified and included in the primary analysis. Of these, 40 patients received third line therapy. The most commonly used treatment regimens in third line were Pemetrexed with 11 patients (3.8%), Docetaxel with 10 patients (3.4%), Gemcitabine with 4 patients (1.4%), Vinorelbine with 3 patients (1%) Cisplatin/Gemcitabine/Bevacizumab with 2 patients (0.7%). No single treatment regimen was predominantly used in third line. No association of survival gain was seen in patients who received third line therapy over those who received second line therapy (Log-Rank test P=0.4926) Conclusions: In a large EMR physician practice based database of advanced NSCLC patients, we failed to find a difference in the median overall survival of patients who received third line therapy compared to those who received second line therapy. Limitations include a small sample size and no standardized timing of diagnosis and treatment. The lack of a standard of care in third line therapy necessitates the need of further randomized controlled clinical studies to establish a benefit for a particular combination.
Is conventional chemotherapy effective in advanced sarcomatoid lung cancers?
Authors: Vieira Thibault , Cazes Aurelie , Pierre Bonnette , Zemoura Leila , Monnet Isabelle , De Cremoux Hubert , Chouaid Christos , Duruisseaux Michael , Giroux Leprieur Etienne , Belmont Laure , Lavole Armelle , Cadranel Jacques , Wislez Marie
Published: March 2020

e18102

Background: Sarcomatoid lung cancers (SC) are associated with poor prognosis. A few studies suggest that these tumors are resistant to platinum-based chemotherapy. Methods: Between January 1994 and October 2011, all consecutive patients with SC were screened from six French centers. Patients with advanced disease and treated with first-line chemotherapy were included in this study. Clinical data, staging (TNM 2009 classification), drugs and response to chemotherapy (RECIST 1.1) at first tumor assessment were reported. Factors associated with progressive disease (PD) in univariate (p<0.2) were included in multivariate analysis. Results: 111 patients with SC were screened. 51 had advanced stage and were treated by a first-line chemotherapy. Among them, 27 (53%) had initial advanced disease and 24 (47%) had relapse after radical surgery or radiotherapy. Patients were 60.7±3 years old, 69% were male, 86% smokers and 86% were symptomatic. PS was 0 (57%), 1 (39%) 2 (4%). Stages at the diagnosis were I (15.5%), II (13.5%), IIIA (20%), IIIB (6%), IV (45%). Histological subtype were pleomorphic (70%), pure sarcoma-like (20%) unspecified (6%), carcino-sarcoma (4%). 38 (75%) received a platinum based-combination and 13 (25%) a monotherapy. Drug given alone or combined with platin were gemcitabine (23%), navelbine (16%), placlitaxel (16%), docetaxel (12%), pemetrexed (9.8%), ifosfamide (9.8%), vepeside (4%) and others (11%). At first tumor assessment, PD and disease control rates were 71% and 29%, respectively. Median progression free survival was 2 months IC95% [1.3, 2.7]. Median overall survival was 6 months [3.2, 8.8]. In univariate analysis, age, gender, smoking status, numbers of metastatic locations, histological subtypes, monotherapy vs platin-based combinations, relapse after radical treatment vs initial advanced disease were not associated with PD. In multivariate analysis, initial advanced disease was the only independent factor of PD (OR 4.59 [1.17, 18] p=0.03). Conclusions: Our series confirm that advanced SC are refractory to conventional chemotherapy. Molecular characterizations are needed to improve therapeutic strategy.
Assessment of EGFR mutations in patients diagnosed of squamous non-small cell lung cancer (NSCLC).
Authors: Lobo Francisco , Domine Manuel , Rojo Federico , Izarzugaza Yann , Leon Ana , Casado Victoria , Fernandez-Acenero Maria Jesus , Rubio Gustavo , Martin-Valades Jose Ignacio , Arranz Juan Luis , Serrano Gloria , Carames Cristina , Cordova Sharon , Madoz Juan , Zazo Sandra , Rincon Raul , Canadas Carmen , Perez-Gonzalez Nuria , Campos Angel , Garcia-Foncillas Jesus
Published: March 2020

e18106

Background: Mutations in the Epidermal Growth Factor Receptor (EGFR) predict a better outcome to EGFR tyrosine kinase inhibitors than platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Previous studies with Caucasian patients have shown a prevalence of EGFR mutation of 10-15%. The aim of this study is to analyze the prevalence of EGFR mutations in squamous-cell NSCLC patients from an area of influence of 500,000 habitants. Methods: Prospective mutation testing in NSCLC patients included in our institution since October 2010 to January 2012 was performed on DNA obtained from available tumor tissue and cytologic samples, using ARMS-scorpion TheraScreen EGFR 29 Mutation Test Kit (Qiagen). Results: From 218 consecutive NSCLC diagnoses, 18 (8.25%) patients showed EGFR mutations: 6 (33.3%) exon 19 deletion, 9 (50%) exon 21 mutations (7 L858R and 2 L861Q) and 3 (16.6%) cases exon 20 insertion. In the EGFR mutated population, 16 (88.88%) patients were diagnosed as adenocarcinoma and 2 (11.11%) as squamous cell carcinoma. The characteristics of these squamous cell cancer patients were: 2 male; 1 non-smoker, 1 former-smoker; 1 stage IV and 1 stage IB at diagnosis; one case exon 20 insertion and one exon 21 mutation (L858R). Conclusions: The EGFR mutation rate in squamous-cell NSCLC patients in our referral area is superior (11.17%) than previously reported, reinforcing the importance of including EGFR mutation testing in squamous-cell NSCLC population for selecting optimal therapy for these patients.
Statins (ASIs) may improve the outcome of erlotinib as second line treatment (tx) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC).
Authors: Maimon Natalie , Keizman Daniel , Gottfried Maya
Published: March 2020

e18108

Background: The EGFR inhibitor erlotinib is a standard second line tx for mNSCLC. Statins are used in the tx of hyperlipidemia. Pre-clinical and clinical studies in several cancer types have shown that they may inhibit tumor growth. Their effect on the outcome of erlotinib as second line tx in mNSCLC is poorly defined. We aimed to study the effect of statins on the outcome of erlotinib as second line tx for mNSCLC. Methods: We performed a retrospective study of an unselected cohort of pts with mNSCLC, who were treated continuously with 150mg of oral erlotinib. Pts were divided into 2 groups: (1) statins users and (2) statins naive. The effect of statins use on objective response, progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from cox model. Results: Between 2005-2011, 107 pts with mNSCLC were treated with second line erlotinib. There were 51 statins users (group 1) and 56 nonusers (group 2). All users started statins before erlotinib tx initiation. The groups were balanced regarding the following known clinical prognostic factors: female gender, ECOG performance status, active smoking, anemia, adenocarcinoma histology type, EGFR mutation (positive vs negative + unknown). Objective response in group 1 vs 2 was partial response (PR) 41% vs 29% (p=0.15), stable disease (SD) 41% vs 25% (p=0. 11), and progressive disease (PD) 18% vs 46% (OR=2.5, p=0.07). Median PFS was 12 vs 3 ms (HR 0.44 in statins users, p=0.02). Median OS was 35 vs 19 ms (HR 0.63, p=0.1). Conclusions: Statins may improve the outcome of pts with mNSCLC that are treated with erlotinib as second line tx. This should be investigated prospectively, and if validated, applied in clinical practice and clinical trials.
Chemosensitivity and clinical features of EML4-ALK-positive patients with advanced non-small cell lung cancer.
Authors: Park Jangchul , Kondo Chiaki , Shimizu Junichi , Horio Yoshitsugu , Yoshida Kimihide , Mitsudomi Tetsuya , Yatabe Yasushi , Hida Toyoaki
Published: March 2020

e18145

Background: Lung cancers that harbor EML4-ALK can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Recent reports showed that pemetrexed-based therapy might be an effective treatment in patients with ALK-positive NSCLC. However, the efficacy of other regimens is still not known. The purpose of this study is to investigate the clinical characteristics, the efficacy of the cytotoxic chemotherapy in the first and second line setting in EML4-ALK positive NSCLC with advanced stage. Methods: EML4-ALK fusion was screened with RT-PCR and immunohistochemistry. When positive results were obtained with either method, gene rearrangement of ALK was confirmed with fluorescent in-situ hybridization. The clinical efficacy of chemotherapy was evaluated retrospectively. Results: We evaluated 20 EML4-ALK positive patients with advanced stage. Twelve patients were without a history of smoking, and 6 light smokers and 2 smokers. Seventeen (85%) of 20 had stage IV disease. Nine cases were male, and 11 were female. The mean age was 46.3 years (range, 26-79 years). Most of the CT findings at the primary site were masses or nodules, while two cases showed air-space consolidation. In the first line chemotherapy, most of the treatment regimens included carboplatin or cisplatin in combination with one or more therapeutic agents, such as taxans, bevacizumab except one case who was treated only by S-1. In 13 cases which were evaluable, 7/13 (53.8%) had a PR, 4/13 (30.8%) had SD, and 2/13 (15.4%) had PD. The treatment regimens in the second line setting included one therapeutic agent such as docetaxel, pemetrexed, S-1 or an oral ALK inhibitor. Among 10 evaluable cases in the second line setting, 2/10 (20%) had a PR, 5/10 (50%) had SD, and 3/10 (30%) had PD. Two patients who had a PR were all treated by oral ALK inhibitor. Within 7 patients who were treated by cytotoxic agents, none had clinical response. Conclusions: Our study suggests that EML4-ALK positive patients may show relatively favorable response to cytotoxic drug in the first line setting, but low response in the second line setting. These data might be helpful for further clinical trials including EML4-ALK positive patients.
Natural history and clinical prognosis of in situ mantle cell lymphoma.
Authors: Kubal Timothy Edward , Peker Deniz , Sagatys Elizabeth , Zhang Ling , Naghashpour Mojdeh , Moscinski Lynn , Sotomayor Eduardo M. , Sokol Lubomir , Bello Celeste M. , Cultrera Jennifer L. , Chervenick Paul A. , Shah Bijal D.
Published: March 2020

e18506

Background: In-Situ Mantle Cell Lymphoma is a rare clinical entity that presents with involvement limited to the mantle zone of secondary follicles. Its true incidence may be underestimated and its natural history and clinical behavior remains poorly characterized given the small number of representative cases available in the literature. Current guidelines for patients diagnosed with In-Situ Mantle Cell Lymphoma advocate staging studies and close follow-up with treatment based on the clinical behavior of the disease. 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 In-Situ Mantle Cell Lymphoma were found and analyzed. Patients 1 & 2 had disease isolated to a single lymph node at diagnosis. In these cases, there were long latency periods of 5 and 9 years between initial resection of a single nodal site and later presentation with active, diffuse disease. Neither patient received therapy until progression with more advanced disease. Patient 2, who had a 9-year latency period was found to have complex cytogenetics suggesting evolution of the malignant clone during this prolonged latency period. Patient 3 presented with in situ disease in an inguinal node in conjunction with diffuse extranodal lung and forehead involvement, all noted at the time of diagnosis. Patient 1 obtained remission with Bendamustine & Rituxamab. Patient 2 obtained remission with HyperCVAD and Autologous HSCT consolidation. Patient 3 obtained remission after R-CHOP. Patients 1 & 2, both with long latency periods remain alive and free of disease, while patient 3 relapsed with extranodal disease 3 years after initial therapy. Conclusions: The natural history of In Situ-Mantle Cell Lymphoma varies with prolonged latency periods present in some patients. The genetic profile of the lymphoma may evolve during these latency periods portending a more aggressive clinical course at progression. Patients with newly diagnosed In-Situ Mantle Cell Lymphoma with no other evidence of active disease should be followed expectantly with therapy reserved for those patients whose disease progresses during followup.
Prognostic impact of immunohistochemically defined germinal center B-cell and nongerminal center B-cell subtypes of diffuse large B-cell lymphoma in rituximab era.
Authors: Cao Yabing , Huang Ying , Ye Sheng , Lin Tongyu
Published: March 2020

e18517

Background: Diffuse large B-cell lymphoma (DLBCL) can be molecularly subtyped as either germinal center B-cell (GCB) or non-GCB. The role of rituximab(R) in these two groups remains unclear. Methods: We studied 204 patients with de novo DLBCL (107 treated with CHOP; 97 treated with R-CHOP); patients being stratified into GCB and non-GCB on the basis of BCL-6, CD10 and MUM1 protein expression. The relationships between clinical characteristics, survival data and immunophenotype were studied. Results: The median follow-up was 51months for CHOP group and 56 months for R-CHOP group. The 5-year overall survival (OS) in the CHOP and R-CHOP group was 50.4% and 66.6% (p=0.031), respectively. GCB patients had a better 5-year OS than non-GCB patients whether treated with CHOP (65.0% vs. 40.9%; p=0.011). In contrast, there’s no difference in the 5-year OS for the GCB and non-GCB with R-CHOP (76.5% vs. 61.3%; p=0.141). In non-GCB subtype, additional rituximab improved survival than CHOP (61.3% vs. 40.9%; p=0.0303). Conclusions: These results indicated that addition of rituximab to standard chemotherapy eliminate the prognostic value of immunohistochemically defined GCB and non-GCB phenotypes in DLBCL by improving the prognostic value of non-GCB subtype of DLBCL
Impact of lower chemotherapy dose on treatment outcome and survival of patients with advanced Hodgkin lymphoma: Single institution experience.
Authors: Tomasevic Zoran , Tomasevic Zorica
Published: March 2020

e18531

Background: Combined chemotherapy regimen, although highly effective, still fail to cure about one third of patients with advanced Hodgkin lymphoma (aHL). On the other hand, similar proportions of patients are probably over treated and cure might be obtained with less intensive doses. The aim of this retrospective analysis is to evaluate chemotherapy dose intensity and cumulative dose in aHL, in the context of treatment outcome and survival. Methods: At the Institute for Oncology and Radiology of Serbia, during 1991-1993 all consecutive aHL patients have been treated with MOPP (M; 41 pts) and afterwards (1994-1996) with MOPP/ABVD (M/A; 40 pts). In accordance to previous local practice, chemotherapy was given in projected, absolute doses, calculated on average body surface area of 1.7 m2. Characteristics of patients in both regimens were well balanced for age, gender, PS, B symptoms, histology, stage, laboratory prognostic parameters (International Prognostic Score- IPS). Approximately 50% pts in both groups were in high/intermediate risk IPS. Relative dose intensity (RDI), defined as given/scheduled dose ratio per week and relative cumulative dose (RCD), defined as given/projected dose ratio, were retrospectively analyzed whether there is potential negative impact on response, time to relapse and survival. Results: The average RCD and RDI for both regimens were 85% and 58%. Complete remission (CR) was achieved in 60% (M/A 67% vs. M 54%) (p=NS); 90% of pts with CR in both groups had no relapse during follow up. Different cumulative doses and dose intensity had no significant impact on time to relapse and overall survival. However, trend for better overall survival for patients receiving RDI over 60% was observed (p=0.09). Hemoglobin level ≤10.5 g/dl had significant adverse effect on outcome regardless of treatment dosage (p=0.02). No second malignancy has been registered during follow up. Conclusions: Although this retrospective analysis does not pretend to recommend lower chemotherapy dose regimen for routine treatment, it seems that selected aHL patients could still be effectively treated with less chemotherapy dose intensity, because 90% of pts with CR are cured.
Expression of mTOR in diffuse large B-cell lymphoma.
Authors: Gopaluni Srivalli , Vajpayee Neerja , Newman Nancy , Thakral Charu , Husain Juhi , Gajra Ajeet
Published: March 2020

e18535

Background: The mammalian target of rapamycin (mTOR) pathway mediates protein synthesis, cell growth and survival of normal and malignant cells. This pathway is constitutively activated in several B-cell lymphomas. We studied immunohistochemical expression of mTOR, phosphorylated mTOR (pmTOR) and bcl-2 in 55 cases of diffuse large B-cell lymphomas (DLBCL) and their association with established prognostic factors as well as treatment outcomes in a retrospective single instituition study. Methods: After IRB review, 55 cases of DLBCL were identified. Immunostains for mTOR, pmTOR and bcl-2 were performed and their expression correlated with clinical and survival data. Associations of demographic (age and gender), clinical (stage, IPI score) and chemotherapy (RCHOP or other) with marker expression as well as association with recurrence and survival were studied using chi square and t-test for univariate analysis and logistic regression for multivariate evaluation. Results: Of the 55 patients, 44% were > age 65, 65% were males and 65% had advanced stage (III or IV) disease. High IPI scores were noted in 42% and 87% received the RCHOP regimen.On univariate analysis, high mTOR expression was associated with male gender (85% vs. 46%, p<0.01), high IPI score (67% vs. 18%, p, 0.001) and higher mean age (66 vs. 53 years, p < 0.001). With high mTOR expression a trend towards higher stage ( 78% vs 54% p=0.08) and likelihood of poor overall survival (defined as survival <3 years; 41% vs 18% p =0.08) was noted. Further, on univariate analysis bcl-2 expression was associated with higher risk of recurrence (35% vs.11%, p 0.05) whereas no association with clinical factors or outcomes was noted with pMTOR expression. On multivariate analysis the only parameter found to be significant was IPI [0R 11.6 95% CI 1.4-100]. Conclusions: High mTOR expression is associated with gender, age, IPI and showed a trend towards advanced stage and shorter survival. This target needs to be investigated prospectively in DLBCL as a prognostic factor and predictive marker. Given the availability of several mTOR inhibitors, the natural history of patients with poor risk DLBCL(high IPI) with high expression of mTOR may be favorably altered.
A phase II study of PXD101 (belinostat) in relapsed and refractory aggressive B-cell lymphomas (rel/ref ABCL): SWOG S0520.
Authors: Persky Daniel Oscar , Bernstein Steven H. , Goldman Bryan H. , Rimsza Lisa M. , Fisher Richard I. , Miller Thomas P.
Published: March 2020

e18536

Background: The mechanism of action of histone deacetylase inhibitors (HDACI) in lymphomas is unknown. Loss of major histocompatibility Class II antigens (MHC II) in diffuse large B-cell lymphomas (DLBCL) is associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHC II is controlled by CIITA, which is itself regulated by histone acetylation, We hypothesized that PXD101 (belinostat), an HDACI, would increase MHC II expression in tumor cells, enhance immunosurveillance and improve outcome. Methods: Theprimary objective was to evaluate response rate and toxicity of PXD101 in patients (pts) with rel/ref ABCL with up to 5 prior chemotherapy regimens. Secondary objectives were to estimate the 6-month progression-free survival (PFS) and to assess MHC II and TIL. In a two-stage design, if at least 1 response was observed in the first 20 pts, another 20 pts would be accrued. PXD101 was administered at 1000 mg/m2 IV days 1-5 of 21-day cycle for up to 2 years. Results: The study was closed due to lack of response in the first stage. Of 22 pts enrolled, 19 were evaluable. Median age was 69, and median number of prior treatments was 3 (range 1-4). 18 pts had DLBCL and 1 had B-cell lymphoma, unclassifiable. Grade 4 toxicities were fatigue and muscle weakness (1) and lymphopenia (1). Despite initially finding no responses, 2 partial responses (PR) were observed at 5 and 13 months after registration, for an overall response rate (95% CI) of 10.5% (1.3-33.1%); 3 pts had stable disease (SD), lasting 4.7, 30.4+, and 40.7+ months. With a minimum follow-up of 2.0 yrs, median and 6-month PFS are 2.1 months (1.3-3.8) and 21.1% (6.6-41.0%); median and 6-month overall survival are 13.4 months (95% CI not yet estimable) and 57.9% (33.2-76.3%), respectively. Conclusions: Despite early closure, delayed PR was seen in 2 of 19 pts, and 2 pts had SD lasting 30.4+ and 40.7+ months. Therefore 4 pts (21%) who did not achieve complete response, very unusually, have not progressed for ≥2.0 yrs. Standard chemotherapy response assessment may not be appropriate for HDACI, which may require development of new biomarkers of response. Further work focuses on combining HDACI with standard chemotherapy.
CHOP chemotherapy plus rituximab compared with CHOP alone in patients with diffuse large B-cell lymphoma, from Indian subcontinent.
Authors: Linga Vijay Gandhi , Digumarti Raghunadharao , Maddi Rahul Narayan , Goteke Vamshi Krishna Reddy , Gundeti Sadashivudu , Thota Narender Kumar , Coca Pragnya
Published: March 2020

e18545

Background: Outside the setting of the clinical trials there is very little data of CHOP chemotherapy plus Rituximab (CHOP-R) compared with standard CHOP in Indian population. We analyzed our cohort of patients diagnosed with Diffuse Large B cell Lymphoma (DLBCL). Primary objective was to compare CHOP with CHOP-R in term of PFS and OS. Methods: All the patients aged more than 21 years diagnosed with DLBCL (CD 20+) were retrospectively analyzed from Jan 2000 to June 2011. According to institute guideline staging and International Prognostic Index (IPI) risk grouping were done. Patients were started on standard cyclophoshomide 750mg/m2, doxorubicin 50mg/m2, vincristine 1.5mg/m2 on day 1 and prednisolone 60mg/m2 day 1-5 (CHOP). Rituximab 375 mg/m2 was given on day 1 depending on the affordability/Insurance. Clinical evaluation was done after each cycle and response assessment with CT scan was done after third and sixth cycle. Progression free survival (PFS) was defined as progression during therapy, relapse, death and lost to follow up. Overall survival was defined as time till death and lost to follow up. Statistical analysis was done using Graph pad software and p value less than 0.05 was taken significant. Results: There were 67 patients in CHOP-R and 206 patients in CHOP arm. Basic characteristics and survival data are described in table 1, which are not distributed equally in two arms. The PFS in R-CHOP and CHOP arms were 40 and 9 months respectively (p=0.0008). The OS in R-CHOP and CHOP arms were 47 and 13 months respectively (p=0.007). Conclusions: There was statistical difference between the PFS and OS between the two arms. [Table: see text]
Effect of berubicin, the 4'-o-benzylated doxorubicin analog, on growth inhibition and apoptosis in multiple myeloma.
Authors: Wang Michael , Sun Luhong , Fokt Izabela , Zhang Liang , Jayakumar Arumugam , Priebe Waldemar
Published: March 2020

e18557

Background: Doxorubicin (DOX), an anthracycline, topoisomerase II inhibitor, is routinely used for hematologic malignancies including multiple myeloma (MM); however, its efficacy is limited by drug resistance and cardiotoxcity. To overcome these limitations, we designed, synthesized and tested Berubicin (BRN). BRN has been evaluated in clinical trials in neuroblastoma multiforme. It is a representative of a novel class of mechanistically altered anthracycline analogs. The data obtained from this study will serve as the basis for the rapid translation of BRN from the bench to the clinic in a phase I clinical trial for patients with MM at MD Anderson Cancer Center. Methods: We investigated the effects of BRN, DOX and Bortezomib (BTZ) in 3 human MM cell lines, MM1S, ARP-1, U266, and freshly isolated primary samples from patients with MM. MM cells were treated with BRN, DOX, and BTZ. The effects of these compounds on cell proliferation, apoptosis, and the cell cycle were analyzed using MTS assay and flow cytometry analysis. Results: BRN potently inhibited the growth of the established MM cell lines, as well as the freshly isolated primary MM cells in a dose-dependent manner. It showed growth inhibition at IC50 of 5.99 nM (U266), 5.21 nM (MM1S) and 3.99 nM (ARP-1), and was more potent than doxorubicin (IC50 14.63 nM, 7.24 nM and 11.06 nM) and bortezomib (IC50 304.9 nM, 15.47 nM and 53.19 nM). In contrast, BRN did not affect the proliferation of patient-derived normal bone marrow cells (CD138- cells) at the concentrations that were lethal to MM cells. Conclusions: Berubicin not only induced apoptosis in 3 cell lines in dose-dependent manners but also induced G2/M cell cycle arrest in 3 cell lines. In conclusion, BRN was effective against MM cells in vitro and will be applied to our planned clinical trial.
Effect of 13q deletion on IL-6 production in patients with multiple myeloma.
Authors: Azim Hamdy A. , Kassem Neemat , Khalifa Rania H , Mohamed Tarek Yakout
Published: March 2020

e18570

Background: Numerous studies have shown a correlation between 13q deletion and poor prognosis in multiple myeloma (MM), but the mechanisms are not fully understood. Earlier studies suggest that this lesion involves large segments or the entire long arm involving the retinoblastoma (Rb) gene. In myeloma, Rb gene is believed to down regulate interleukin -6 (IL-6) which plays a central role in the pathogenesis of MM. Therefore, it has been hypothesized that loss of Rb gene might be associated with very high expression of IL-6 and subsequent bad prognosis. Methods: Forty MM patients and 20 matched controls were included in this study. Interphase fluorescence in situ hybridization (FISH) analysis was performed using LSI 13q14-specific probe. Serum levels of IL-6 were determined by ELISA. All patients received conventional chemotherapy. Refractory patients received other therapeutic regimen of thalidomide or bortezomib. Results: Significant increase (p < 0.001) of IL-6 production was recorded in patients with 13q deletion compared to patients with normal chromosome 13q status. These patients were also refractory to conventional chemotherapy but showed striking response to thalidomide or bortezomib. Conclusions: This study suggests that 13q deletions are associated with increased production of IL-6 in MM and this could be a possible cause of the associated bad prognosis. In addition, the results also show the potential to improve responses inpatients with refractory MM with the introduction of novel therapies.
Plasmacytoma: 10 years experience at a tertiary care center in India.
Authors: Baghmar Saphalta , Raina Vinod , Sharma Atul , Kumar Lalit
Published: March 2020

e18573

Background: To evaluate the clinical features, diagnoses, prognostic factors, progression to MM of the patients of solitary plasmacytoma (SP) treated at AIIMS in last 10 years(2001-2010). Methods: From 2001-2010, we identified 57 patients with SP. OS, EFS, progression to myeloma were calculated using the Kaplan-Meier method and log rank test. Results: Out of 57 patients; 48 patients were evaluable. The M:F ratio was 3.5:1 with the median age of 49 years. The primary site was osseous(SBP) in 49 patients, extramedullary(EMP) in 8; 5 lesions were located in the upper respiratory passages, ie nasal cavity and maxillary sinus and rest of the 3 were one each in bronchus, gluteal region and intracranial. 43.8% of the lesions involved the vertebral column. The thoracic spine was the single most commonly involved site (12/57 patients). Out of 25 patients with lesions in vertebral column, 12 presented with paraparesis. Monoclonal protein was present in 48% patients and Urine M- Band in additional 2 patients. Treatment consisted of RT [45 Gy (8-50 Gy)] alone in 27, excision in 2 and excision and RT(n=9) and combined modality(n=10). The median follow-up was 28 months(range 3-160 months). Local control was achieved in 41(85%) while progressive disease was seen in 4. Serum M protein became undetectable after treatment in 60% patients. 17(41%) patients progressed to MM after initial response. The median duration of progression to MM was 21 months. Even though there was a trend towards a better EFS and OS for EMP than SBP, in univariate analysis this was not statistically significant. Patients having vertebral lesion showed trend towards progression to MM (p=.057). 5 yr EFS & OS were 44.4% and 89 % respectively. Median EFS and OS were 38 and 122 months respectively. 5 yr survival rate in patients who developed MM and those who did not were 81% and 100% respectively. None of the baseline characteristics were predictive of survival. Conclusions: Out of 1129 patients of plasma cell dyscrasias registered between 2001-2010; 5% were of SP. Bone was the most common site. Attainment of local control is the predictor of significant EFS (p<0.0001) and OS (p<0.05). Progression to MM is the commonest pattern of failure. Vertebrae involvement was predictor for disease progression to MM.
Spanish experience with the ipilimumab Expanded Access Program.
Authors: Berrocal Alfonso , Lopez-Martin Jose A. , Arance Ana Maria , Soriano V. , Espinosa Enrique , Lopez Criado M Pilar , Muñoz Eva , Berros Jose Pablo , Soria A , Marquez I , Sancho P , Gil I ,   Grupo Español Multidisciclinar de Melanoma GEM
Published: March 2020

e19023

Background: Second line ipilimumab has proven efficacy in clinical trial but few is known outside this setting. Methods: We have retrospectively reviewed experience with the Expanded Access Program for Ipilimumab in Spain. We have collected data on demographics, response survival and toxicity. Ipilimumab was administered at a 3 mg/kg dose for four induction courses. Results: We have retrieved 99 expanded access ipilimumab applications that represent 40% of all possible applications. Five patients are not evaluable because they never received ipilimumab 4 due to progression and 1 declined consent. Median age is 58.5 years (30-81) and 54.3% of the patients are males. 59.6% have 3 or more metastatic locations, 50% have liver metastases, 16% have CNS metastasis and 74.6% have elevated LDH. ECOG performance status was 0 to 1 in 91.9%. Previous adyuvant treatment was received by 43.6% of the patients and consisted in high dose interferon in 85.4%. All except one patient have received previous first line chemotherapy and 34.2% have received 2 or more chemotherapy lines. Medium time from the start of metastatic disease to the start of ipilimumab was 11.2 months. 58.5% of the patients completed 4 doses of ipilimumab main reason for not completion was death or progression in 84.6% and toxicity in 5.1%. 8 patients are not evaluable for response, 5 have just completed the treatment and 3 are still on treatment. Responses are 1 (1.1%) CR, 6 (6.4%) PR, 6 (6.4%) PR with previous progression or new lesions, 13 (13.8%) SD, and 60 (63.8%) progressive disease. Reinduction treatment was offered to 5 patients 2 PR patients achieved a new PR, one PR patients a SD and 2 SD patients progressed after reinduction. Kaplan and Meier median survival is 150 days (95% CI 110,5-189.4). One year survival is 32.4% and 18 months survival 21.6%. Toxicity has been mild, skin, 20.2% grade I and 5.3% grade II, liver 7.4% grade I, 2.1% grade II, 3.2 grade III, and diarrhea 19.1% gI, 3.2% grade II and 1.1% grade IV. Only 7 patients experienced toxicity grade III to IV. Conclusions: Ipilimumab efficacy when it is used outside clinical trial is similar to the reported. There is room for improvement in patient selection as 40% of them did not completed treatment. Toxicity of the 3 mg/kg schedule is mild.
Predictable clinical responses to sorafenib in stage IV uveal melanoma.
Authors: Kaempgen Eckhart , Schmid Martina , Erdmann Michael , Keikavoussi Petra , Strobel Deike , Schuler-Thurner Beatrice , Schuler Gerold
Published: March 2020

e19032

Background: Uveal melanoma is an orphan disease with poor prognosis, once metastasized. There is currently no approved systemic treatment and all clinical trials so far failed to significantly improve OS in stage IV uveal melanoma patients (see results of the EORTC 18021 trial, abstract 95725). Sorafenib is a pleiotropic kinase inhibitor targeting tumor metabolism and related neoangiogenesis. Although sorafenib failed as monotherapy in metastasized melanoma, results from small phase II trials have indicated synergism with chemotherapy in some patients. We therefore offered compassionate use treatment with sorafenib to patients with documented progressive stage IV uveal melanoma after fotemustine iv or HIA treatment (EORTC 18021 trial). Methods: Sorafenib 400 mg orally bid was combined with fotemustine 100 mg/m² at 3 week intervals to treat a total of 7 patients with metastatic uveal melanoma. Patients were closely followed by repeated analyses of serum tumor markers and ultrasound scans of liver metastases. Complete staging by CT/MR scans was done every 3 months. Results: 3 of 7 patients with initially elevated tumormarkers showed an early rapid drop in serum MIA and/or S100 within two weeks of sorafenib treatment followed by partial responses and long term stabilization of the disease up to 20 months. Responder patients could also be identified by a rapid drop in tumorperfusion as shown by contrast enhanced ultrasound of liver metastases. Due to hematologic toxicity treatment had to be modified in all responder patients. Neither reduction of sorafenib dosage to 200 mg orally bid nor omittance of fotemustine treatment resulted in early disease progression, pinpointing potential high sorafenib responsiveness in uveal melanoma patients. Conclusions: Patients with stage IV uveal melanoma may benefit from treatment with the kinase inhibitor sorafenib. Our observations suggest selection of responder patients by early drop of elevated tumor markers S100 / MIA and early drop in tumor perfusion. Stimulated by these data a first phase II trial investigating sorafenib in uveal melanoma patients has been initiated in Germany (ClinicalTrials.gov NCT0137702: A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma (STREAM).
Analysis of BRAF, NRAS, cKIT, and EGFR alterations in melanoma lung metastases.
Authors: Ulivieri Alessandra , Cardillo Giuseppe , Manente Liborio , Mancuso Andrea Petricca , Vigna Leonardo , Gasbarra Rita , Leone Alvaro
Published: March 2020

e19033

Background: About 25% of pts will eventually develop lung metastases from primary melanoma. Activating mutations in BRAF, NRAS, CKIT and EGFR genes are involved in melanoma progression. Trials with drugs targeting oncogenic BRAF in melanoma have shown that a V600E mutation may identify a subgroup of pts with a high response rate. Methods: We analysedtheprevalence of BRAF, NRAS and CKIT mutations by direct sequencing and of EGFR copy number alterations by FISH, in pts affected by melanoma lung metastases, and explored their correlation with lung metastasis-free survival (LMFS) and post surgical progression-free survival (psPFS). Results: Over 10 years, 33 cases of pts with melanoma lung metastases were diagnosed at our institution, of which 22 underwent surgery with curative intent. The mean age was 64 years, and 19 (57.5%) were male. 51% carried a BRAF V600E mutation while 18% had a NRAS codon 61 mutation. The two events were mutually exclusive. No alterations were observed in exon 11 of the CKIT gene. FISH analysis indicated an EGFR low amplification in 3 cases and chromosome 7 polysomy in 13 cases. The presence of a BRAF V600E mutation was associated with a longer LMFS (median 6.1 vs 4.4 years, p<0.05), but it had no impact on psPFS (26.9 vs 29.6 months, p=0.6). NRAS mutations were associated with a reduction in both LMFS (3.7 years vs 4.7 years, p = 0.008) and, more significantly, in psPFS (12,5 months vs 41,1 months, p = 0.005; hazard ratio, 2.7). Conclusions: The frequency of mutations in BRAF (51%) and NRAS (18%) observed in lung metastatic melanomas was similar to the rates reported in other metastatic sites. BRAF mutations don't appear to be related with a more aggressive clinical course, while NRAS might be an independent negative prognostic factor after resection of melanoma lung metastases. The presence of BRAF mutations should be tested in melanoma lung metastases to identify the patients eligible for anti BRAF targeted therapy.
An imaging study of vemurafenib in patients with BRAFV600-mutated metastatic melanoma.
Authors: Lastoria Secondo , Grimaldi Antonio M , Aloj Luigi , Simeone Ester , Romano Anna , Caraco Corradina , Curvietto Marcello , Esposito Assunta , Caraco Corrado , Mozzillo Nicola , Torri Valter , Ascierto Paolo Antonio
Published: March 2020

e19034

Background: Targeted therapy against the mutated form of BRAF V600 is a proven effective therapy for melanoma. Objective of this exploratory study was to describe the change over time of PET-scan results and verify the association of PET-scan examination with the objective response (OR) (defined by RECIST criteria) in melanoma pts treated with vemurafenib. These preliminary results reported here regards the description of changes over time of PET-scan. Methods: Patients treated with vemurafenib at our institution were considered eligible. Patients were evaluated with PET-scan at baseline and at day 7, 15 and 30 from the start of therapy. Maximal Standardized Uptake Value (SUVmax) and Total Lesion Glycolysis (mean SUV x lesion volume) were recorded and compared for single lesions in the 4 exams. Differences between each PET-scan performed during therapy and baseline were calculated and coded as yes/no response basing on predefined criteria. Association of PET responses and achievement of OR were estimated by means of logistic regression models. Odds ratio and C statistics were used to define strength of association and discriminant capability. C statistics obtained with PET/CT at different timepoints were compared. Results: As of January 2012, 7 out of 20 required pts have been enrolled. A total of 48 lesions were available for evaluation. A reduction in lesion SUVmax and TLG values compared to baseline was evident in all the post-therapy studies (reduction in SUV max at day 7 – 51 ± 28 %, day 14 – 67 ± 24 % and day 30 –69 ± 29 %, reduction in TLG at day 7 – 41 ± 83 %, day 14 – 69 ± 35 % and day 30 – 68 ± 37 %). A comparison of the day 15 and day 30 studies showed essentially stable uptake values (SUV max variation -3 ± 41 %, TLG 5 ± 56 %). However, 14/23 lesions in 3 patients showed increased SUV max and TLG values between the day 15 and day 30 studies likely indicating early signs of treatment resistance. Conclusions: Our preliminary results suggest that PET/CT may be an early surrogate marker of treatment response to vemurafenib. Sequential monitoring of targeted therapy with PET/CT may be useful in identification of treatment resistance, aid in tailoring alternative strategies and deserves further investigation.
Nab-paclitaxel salvage chemotherapy for metastatic ocular melanoma.
Authors: Guminski Alexander David , Lee Adrian , Lumba Sumit , Maher Richard
Published: March 2020

e19042

Background: Metastatic ocular melanoma is an incurable malignancy characterised by liver predominant involvement. Conventional systemic chemotherapy using drugs such as fotemustine or dacarbizine have low response rates. In liver only disease hepatic arterial infusion of fotemustine has reported a higher response rate. Methods: We report four prospectively followed patients who all received salvage treatment with Nab-paclitaxel after previous intra-arterial fotemustine for metasatic ocular melanoma. Results: One patient who did not respond to to intra-arterial chemotherapy had a radiological response to Nab-paclitaxel with a duration of six months (5 cycles of treatment) with subsequent progression inliver and CNS. Another patient had rapidly progressing liver, peritoneal and nodal metastases with elevated bilirubin. He received dose reduced Nab-paclitaxel sith significant biochemical, radiological and functional improvement. He continues on Nab-paclitaxel in ongoing partial remission and remains clinically improved after six months. Two patients with similarly advanced disease, including one with abnormal bilirubin, did not respond. Subsequent treatments for the three patients progressing after Nab-paclitaxel have been SIR-Spheres followed by Ipilumumab, Ipilumumab and palliation respectively. Typical side effects of Nab-paclitaxel have occurred including alopecia, fatigue, peripheral neuropathy and neutropenia. Conclusions: In summary we have seen clinically useful responses in two of four patients treated. We continue to recruit further patients to better understand the role of Nab-paclitaxel as salvage chemotherapy for metastatic ocular melanoma.
Surgery, radiation, and systemic therapies in patients with metastatic melanoma.
Authors: Wang Song , Zhao Zhongyun , Barber Beth , Wagner Volker Jean
Published: March 2020

e19044

Background: To describe treatment patterns with surgery, radiation, and systemic (drug) therapies in patients with metastatic melanoma in the U.S. Methods: Using a large U.S. medical claims database, patients were identified between 2005 and 2010 using ≥2 melanoma diagnoses (ICD-9-CM: 172.xx, V10.82) and ≥2 diagnoses for metastasis (ICD-9-CM: 197.xx, 198.xx). The index date was the first date of metastasis diagnosis. Patients were followed from the index date to death, disenrollment, or end of the study period (6/30/2010), whichever occurred first. Surgery, radiation, and systemic therapies were examined descriptively. Factors influencing treatment were examined using a logistic regression separately for surgery, radiation, and systemic therapy. Results: A total of 2,546 patients with metastatic melanoma were included in the analyses. Mean (± standard deviation) age was 60.6 (± 14.0) years old with 22.8% under 50 and 36.5% were female. Overall, 66.8% of patients had cancer treatment related surgery, 38.7% received systemic therapies, 44.7% received radiation, and 17.7% of patients received all three treatments. Logistic regressions revealed that patients with lung (p <.0001), brain (p <.0001), liver (p <.0001), or bone (p <.0001) metastases were less likely to have surgeries; patients with lung (p = 0.04), brain (p < 0.001), or liver metastases (p = 0.03) were more likely to receive systemic therapies; as expected patients with brain (p < 0.0001) or bone metastases (p < 0.0001) were more likely to have radiation therapy. Patients being treated by oncologists were more likely to receive systemic therapy (p < 0.0001) or radiation (p < 0.0001) while patients being treated by dermatologists were more likely to receive surgery subsequently (p = 0.002). Older age and female gender were associated with a lower likelihood to receive surgery, systemic, or radiation therapy. Conclusions: Sites of metastases and treating physician specialty might influence treatments for patients with metastatic melanoma.
Association of pyrexia and durable response in advanced melanoma patients treated with the combination of dabrafenib and trametinib.
Authors: Cha Edward , Kantor Andrea , Algazi Alain Patrick , Hwang Jimmy , Luan Jennifer , Venook Alan Paul , Ziani Leslie , Little Shonda M , Patel Kiran , Daud Adil
Published: March 2020

e19046

Background: Pyrexia (fever) is a common adverse event associated with combined BRAF and MEK inhibition (dabrafenib and trametinib). Although the mechanism of fever is unclear, we explore pyrexia as a pharmacodynamic marker for clinical response. Methods: A phase II international trial with dabrafenib and trametinib in metastatic melanoma (MM) and colorectal cancers (CRC) harboring BRAF mutations is ongoing. Twenty-nine patients (pts) were enrolled at UCSF between January 2011 and January 2012. Fevers were graded based on temperature and coinciding symptoms, and an episode of pyrexia was defined as a temperature of >100 °F at least once a day for one or more consecutive days. Tumor assessments were performed every 8 weeks (wks). Results: To date, 13 pts with MM and 5 with CRC had tumor assessments up to 24 wks. In MM, pyrexia was reported 2 or more times in 7 pts; 5 had none, and 1 reported one episode of Grade 1 pyrexia. Episodes occurred 2-4 wks after starting treatment, and time between subsequent recurrences ranged from 1 to 25 wks. Neutrophil counts showed early fluctuations, but none had neutropenia. Of the 7 pts with recurring fevers, 5 had partial responses and 2 had stable disease at 8 wks. Of the 6 pts with nonrecurring or no fevers, 2 had partial responses at 8 wks, and 1 progressed. At 24 wks, all 7 pts with ≥ 2 fever episodes remained progression-free, whereas 0/6 pts with < 2 fever episodes were progression-free (p < 0.001). Pts without progression continued to have recurring fevers (median = 4). There were no differences by disease stage (12 of 13 with M1c) or mutation status (10 with V600E; 2 with V600K; 1 with V600E + V601I). While pts with CRC had pyrexia, no association between pyrexia and response was noted; however, only 5 pts are included in this analysis. Conclusions: In this limited analysis of pts with MM, recurrent fevers were associated with durable response (≥ 24 wks). These results suggest that pyrexia could be a marker for inflammation and antitumor activity. Further studies are underway to characterize cytokine profiles and immune responses. [Table: see text]