bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood mRNA signature to predict survival in patients with metastatic melanoma treated with tremelimumab.
Authors: Saenger Yvonne M. , Magidson Jay , Liaw Bobby Chi-Hung , Wassmann Karl , Barker William , Harcharik Sara , Fisher David , Oh William K. , Friedlander Philip 
Published: March 2020

9080 Background: Tremelimumab (Ticilimumumab, Pfizer), a monoclonal antibody targeting CTLA-4, a T cell inhibitory molecule, has shown activity in metastatic melanoma. Ipilimumab (Yervoy, BMS), another antibody targettingCTLA-4, improves survival relative to a peptide vaccine and is now FDA approved. A minority of patients will achieve durable tumor control with CTLA-4 blockade and biomarkers are urgently needed to identify those patients. Methods: 170 inflammatory, melanoma-specific and CTLA4-pathway related mRNA transcripts were measured using RT-PCR in pre-treatment peripheral blood samples from 218 patients with refractory melanoma receiving tremelimumab in a multi-center phase II study. A 2-class latent model yielded a risk score based on 4-genes that was highly predictive of survival (p<0.001), and was used to categorize patients into low, medium and high-risk groups. An independent cohort of 260 treatment naïve melanoma patients receiving tremelimumab as part of a multi-center phase III study was then used to validate the risk score as well as the 3 risk groups defined using the pre-specified cut-points. Results: There was no significant difference between the two cohorts in terms of age, gender, stage of disease or ECOG status. Median time of follow up was 297 days for the training cohort and 386 days for the validation cohort. 67% of patients in the training cohort and 70% of patients in the validation died during time of follow-up. Collectively, the ability of the 170 genes to predict survival exhibited a high degree of consistency across the cohorts (p < 0.001). A 4-gene model including cathepsin D (CTSD), Phopholipase A2 group VII (PLA2G7), Thioredoxin reductase 1 (TXNRD-1) and Interleukin 1 receptor associated kinase 3 (IRAK3) predicted survival in the validation cohort (p=0.001 by log rank test). Multivariable cox analysis showed that the 4-gene model added to the predictive value of clinical predictors (p<0.0001). Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in melanoma patients treated with ticilimumab (αCTLA-4). Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.
Cetuximab with or without chemotherapy for recurrent, unresectable squamous cell carcinoma of the skin (SCCS).
Authors: Nadiminti Kalyan , Shao Ryan , Clamon Gerald H. , Wehbe Ahmad Mouhamad 
Published: March 2020

9090 Background: With an increasing aging population and a growing number of people with organ transplant on immune suppression, patients presenting with locally advanced, unresectable and metastatic SCCS are on the rise. Options of therapy are limited to platinum or taxane doublets but the tolerability of these regimens is poor. Data regarding use of cetuximab in advanced SCCS is scarce and consists of a few case series and one phase II trial. The purpose of this study is to evaluate the use of cetuximab alone or in combination with chemotherapy in patients with SCCS treated at the University of Iowa Hospitals (UIHC). Methods: Patient data was compiled through medical record review of all patients diagnosed with locally recurrent, unresectable or metastatic SCCS seen at UIHC and treated with cetuximab alone or in combination with chemotherapy. Pathology was centrally reviewed. Results: A total of nine patients with SCCS received cetuximab as part of a definitive or palliative therapy with a loading dose of 400 mg/m2 followed by weekly 250mg /m2.Median age of patients is 64. Four patients had locally recurrent or unresectable disease, and five had distant metastases. Three patients had prior history of organ transplant. Chemotherapy included carboplatin AUC 5 with 5 fluorouracil 1000mg/m2/day for four days in two patients and weekly paclitaxel 80mg/m2 in four patients. One patient received concurrent definitive radiation with 6600 cGy. In total, six patients completed at least 6 weeks of cetuximab. All these patients showed clinical improvement in pain, tumor ulcer and bleeding as compared to pretreatment. Median time to disease progression after stopping treatment was 3 months. Three patients could not complete 6 weeks of cetuximab due to disease progression. The most common side effect was skin rash and hypomagnesemia. Conclusions: Cetuximab alone or in combination with chemotherapy is well tolerated and does show promise in treatment of patients with unresectable or metastatic SCCS. Most common side effect was skin rash. A larger trial with longer follow up is warranted to establish the role of cetuximab and an optimal combination therapy in improving quality of life in this patient population.
Targeting BET proteins in melanoma: A novel treatment approach.
Authors: Paoluzzi Luca , Segura Miguel F. , Fontanals-Cirera Barbara , Gaziel-Sovran Avital , Guijarro Maria V , Hanniford Douglas , Gonzales-Gomez Pilar , Zhang Weijia , Zhang Guantao , Darvishian Farbod , Ohlmeyer Michael , Osman Iman , Zhou Ming-Ming , Hernando Eva 
Published: March 2020

9091 Background: Manipulation of key epigenetic regulators in melanoma proliferation is emerging as a new therapeutic strategy. Bromodomain-containing proteins such as the extraterminal domain (BET) family are components of transcription factor complexes and determinants of epigenetic memory. We investigated the expression of BRD4, a BET family member in melanoma cell lines and tissues, and the effects of its inhibition with the small molecule compounds MS436 and MS417 in in vitro and in vivo models of melanoma. Methods: BRD2 and BRD4 expression were analyzed by immunohistochemistry. We tested the effects of pharmacological or RNAi-mediated inhibition of BRD4 in melanoma cells using crystal violet-based assays for proliferation/colony formation and flow-cytometry for cell cycle analysis. The molecular effects of BRD4 suppression were examined using RNA sequencing, Real-Time quantitative PCR and western blots for p27, p21, MYC, ERK1 and SKP2. In the in vivo xenograft experiments NOD/SCID/IL2γR-/-mice were injected with melanoma cells and treated with MS417. Statistical significance was determined by unpaired t-test (GraphPad). Results: BRD4 was found significantly upregulated in primary and metastatic melanoma tissues compared to melanocytes and nevi (p<0.001). Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. Rapidly after BET displacement, key cell cycle genes (SKP2, ERK1 and c-MYC) were downregulated concomitantly with the accumulation of CDK inhibitors (p21, p27), followed by melanoma cell cycle arrest. BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status. Conclusions: Our results demonstrate for the first time a role for BRD4 in melanoma maintenance and support the role of BET proteins as novel targets in melanoma. Further investigation in the clinical setting is warranted.
Assessment of absolute lymphocyte count (ALC) as a predictor of progression-free survival (PFS) and overall response rate (ORR) in metastatic melanoma (MM) patients (pts) treated with high-dose interleukin-2 (HD IL-2).
Authors: Yorio Jeffrey Thomas , Fox Patricia S , Joseph Richard Wayne , Bassett Roland , Davies Michael A. 
Published: March 2020

9096 Background: HD IL-2 is an approved immunotherapy that can achieve durable cures in MM pts. Due to toxicity and low ORR, identification of predictors of clinical benefit would enhance pt selection and outcomes with HD IL-2. Recent research identified a positive correlation for ALC ≥ 1000 (either at baseline or at dose 3) with OS among MM pts treated with the immunotherapy agent ipilimumab. We tested the hypothesis that ALC (≥ 1000) or other hematological parameters correlates with clinical benefit from HD IL2. Methods: Results of hematologic testing in patients (n=98) treated with HD IL2 at MD Anderson Cancer Center were collected, including absolute levels of neutrophils (ANC), lymphocytes (ALC), monocytes (AMC), eosinophils (AEC), and platelets (APC) at baseline, after cycle 1 (C1), and after cycle 2 (C2) of HD IL-2; changes in each parameter for each interval were also calculated. Hematologic values were assessed as categorical (for ALC, ≥ 1000 Yes/No; other parameters, above upper limit of normal [ULN] Yes/No) and continuous variables. Associations between these parameters and PFS and ORR were analyzed. Results: ALC was≥ 1000 in 75 pts (76%) at baseline, in 81 (83%) after C1, and in 80 of 86 pts (93%) after completion of C2 of HD IL-2. PFS was not significantly associated with ALC ≥ 1000 at baseline (HR 0.69, p=0.13), after C1 (HR 1.32, p=0.33), or after C2 (HR 1.01, p=0.98). ALC ≥ 1000 at each timepoint was not significantly associated with ORR or OS. There was no significant difference in the change in ALC with HD IL2 treatment among responders versus non-responders. Among baseline hematological factors, APC > ULN was significantly associated with PFS (p=0.001), but it was rare (2/98 patients). Exploratory analyses identified significantly shorter PFS for patients with baseline APC > 300 (11%, HR 2.75, p=0.002). Analysis of hematologic factors as continuous values identified significant associations with PFS for AMC (HR 2.42, p=0.03) and AEC (HR 1.73, p=0.009) after C2. Conclusions: ALC ≥ 1000 did not correlate with PFS, ORR, or OS with HD IL-2 therapy in this cohort of metastatic melanoma pts.
Analysis of stage of melanoma diagnosis in relation to insurance type and income as indicator of early/late diagnosis.
Authors: Lamie Peter Makram 
Published: March 2020

9099 Background: This study compares the average stage of diagnosis for melanoma by insurance status and household income. This is the largest such study for melanoma to date. Methods: Using the National Cancer Database we examined 299K patients with melanoma between 2000 and 2009 at 1,408 hospitals. The relationship of average stage of diagnosis is compared across insurance types and by income for 293K patients. Results: The VA patients had the lowest average stage of diagnosis 0.8 with the Medicaid population exhibiting the highest 1.8. The VA was lower than Tricare which had an average diagnosis of 1.1, private insurance 1.2, Medicare 1.3, and uninsured 1.7. The lowest rate of stage IV was private insurance 3.3%, Tricare 3.6%, VAH 4.4%, Medicare 5.7%, uninsured 10%, and the highest rate was among Medicaid 14.3%. The highest income category ≥$49K had the lowest average stage at diagnosis of 1.1 compared to $39K to $48K 1.2, $33K to $38K 1.3, $28K to $32K 1.4, and <$28K had the highest average stage of diagnosis 1.4. Stage IV rate increased from the highest income 3.6%, $39K to $48K 4.6%, $33K to $38K 5.1%, $28K to $32K 5.8%, and <$28K 6.9%. Data available. Conclusions: VA, higher income and private insurance had earlier stage of melanoma compared to uninsured and Medicaid who had higher frequency of stage IV disease. [Table: see text]
Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538).
Authors: Sznol Mario , Kluger Harriet M. , Hodi F. Stephen , McDermott David F. , Carvajal Richard D. , Lawrence Donald P. , Topalian Suzanne Louise , Atkins Michael B. , Powderly John D. , Sharfman William Howard , Puzanov Igor , Smith David C. , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Sosman Jeffrey Alan 
Published: March 2020

CRA9006^ The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608.
Authors: Hodi F. Stephen , Lee Sandra J. , McDermott David F. , Rao Uma N. M. , Butterfield Lisa H. , Tarhini Ahmad A. , Leming Philip D. , Puzanov Igor , Kirkwood John M. ,   Eastern Cooperative Oncology Group
Published: March 2020

CRA9007 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Concurrent bevacizumab (BEV) with biochemotherapy (BC) followed by ipilimumab for advanced melanoma: A phase I-II trial.
Authors: Minor David R. , Wang Wei , Kashani-Sabet Mohammed 
Published: March 2020

e20001 Background: Decrescendo biochemotherapy (BC) has become a common regimen for advanced melanoma; however only a minority of patients are long term survivors, and 6 cycles of BC may be complicated by severe neuropathy, asthenia, and other toxicities. The BEAM trial (JCO 30: 34-41, 2012) suggested that BEV added to chemotherapy improved response rate and survival. We felt BEV might improve the efficacy of biochemotherapy, and wanted to explore the feasibility of sequential ipilimumab to improve duration of response. Methods: 24 patients with advanced metastatic melanoma (79% stage M1C) were treated with temozolomide 150mg/m2,cisplatin 20mg/m2, vinblastine1.2mg/m2 all days1-4, IL-2 36miu day1, 18miu day2, 9miu days 3-4, and interferon 5miu/m2 d1-5 with BEV 15mg/kg q21d patients1-6 and BEV 7.5mg/kg patients 7-24 After 4 cycles of BC patients received ipilimumab at 3mg/kg. Results: 6 patients received BEV at 15mg/kg. Two had dose-limiting toxicities: one with brain metastases had CNS hemorrhage and one (thrombocytopenic) had gastrointestinal hemorrhage. Per protocol the next 18 patients received BEV at 7.5 mg/kg q 21d. One patient had posterior reversible encephalopathy syndrome but no other unusual toxicities were seen either with the BEV-biochemotherapy or the ipilimumab phase. Responses (3CR, 6 PR) were seen in 45% of 20 evaluable patients with cutaneous melanoma. Median PFS was 7 months and overall survival 12 months; these results are similar to BC alone. (Oncologist, Oct. 14 (10) 995-1002, 2009). Conclusions: Bevacizumab at 7.5mg/kg q 21days can be safely added to 4 cycles of decrescendo biochemotherapy. Further study of this combination is justified. Clinical trial information: NCT01743157.
A phase I/I b study of GSK1120212 (trametinib) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Kurata Takayasu , Furuse Junji , Okamoto Isamu , Kasuga Akiyoshi , Fujisaka Yasuhito , Kitamura Hiroshi , Shimizu Toshio , Takasu Atsuko , Okamoto Wataru , Naruge Daisuke , Nagashima Fumio , Katsura Koichi , Mukaiyama Akihira , Matsushita Hideki , Nakagawa Kazuhiko 
Published: March 2020

e20004 Background: Trametinib is a potent and selective allosteric MEK1/2 inhibitor. In Western countries, trametinib was investigated as monotherapy and in combination with various agents including gemcitabine in the studies with pancreatic cancer, melanoma and other types of cancer. According to these studies, the recommended dose (RD) and maximum tolerated dose (MTD) were determined as 2.0 mg QD and 3.0 mg QD respectively as monotherapy, and as 2.0 mg QD for both in combination with gemcitabine. The objectives of this study are to assess its tolerability and safety, and to evaluate the RD and the MTD in Japanese patients (pts). Methods: This open-label, dose-escalation study evaluated the tolerability/safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of trametinib alone (part 1) and in combination with gemcitabine (1000 mg/m2on Days 1, 8, and 15 of each 28-day cycle) (part 2) in Japanese pts with advanced solid tumors (NCT01324258). After confirming the tolerability and safety in part 1, part 2 was investigated. Results: (Part 1) Thirteen pts received trametinib at doses of 1.0 mg (n=4), 2.0 mg (n=6), and 3.0 mg (n=3). Various cancer types including melanoma were enrolled. One DLT (Grade 3 infectious pneumonia) was observed in part 1 in a subject at the 2.0 mg dose. The most common AE was Grade 1/2 rash (n=12). One PR (salivary gland cancer) and 3 long SDs (appendix cancer (n=1) and melanoma (n=2)) were observed. Preliminary PK results showed no obvious ethnic difference. (Part 2) Five pts with pancreatic cancer received trametinib (2.0 mg QD) in combination with gemcitabine. Although there was no DLT in the first 28 days (DLT observation period), interstitial lung disease (ILD) was observed in 3 pts after DLT observation period. Best responses were 3 PRs and 2 SDs. Conclusions: The RD (2.0 mg QD) and the MTD (3 mg QD) of trametinib that were determined in Western countries were tolerated in Japanese patients as monotherapy. In combination with gemcitabine, although trametinib was tolerated in the short term and showed promising antitumor efficacy, it is required to closely monitor patients for ILD while the combination is administered to patients. Clinical trial information: NCT01324258.
Spanish Melanoma Multidisciplinary Group (GEM): Long-term survivors treated with ipilimumab (IPI) in the expanded access programme (EAP).
Authors: Hernando Cristina , Soriano Virtudes , Berros Jose Pablo , Arance Ana Maria , Mujika Karmele , Rodriguez Abreu Delvys , Alonso Lorenzo , Alonso Martina , Yapur Lorena , Berrocal Alfonso ,   Grupo Español Multidisciplinar de Melanoma
Published: March 2020

e20007 Background: Advances in metastatic melanoma treatment have demonstrated improvement in survival. After 5 year follow-up of clinical trials with IPI, LTS have been reported. Current follow-up of patients treated within IPI EAP in Spain is 2 years. Methods: we performed a retrospective subgroup analysis of 138 treated patients (pts) within the IPI not randomized EAP (48% of the total EAP population). LTS were defined as pts with ≥ 12 months overall survival (OS). Pts were treated with IPI at 3 mg/kg q 3 w x 4. Data was registered using a socio-demographic and therapeutic questionnaire, collecting overall response (RR), survival (OS) and toxicity (T). Results: In our analysis of138 treated pts 39 were LTS (28.2%), 14 pts were alive at 12 months (M), 12 pts between 13-19 m and 7 pts 20-24m, for all this patients the follow up continues. Median age was: 56.5 (30-81). Gender: Male 48.7%. Stage: IVa 25.6%, IVb 17.9%, IVc 56.8%. Primary tumor site: skin 56.4%; accral 12.8%; mucosal 10.3%; ocular 10.3%; rest unknown. Metastases (mts): soft tissue 38.5%, lung 33.3%, visceral 28.2%. Median number of prior treatments: 1 (1-5), 20.5% received more than one chemotherapy (chx) line. 92.3% of total pts population have completed the induction schema (4 IPI doses). Response assessment: CR 15.4%; PR 38.5%; SD 33.3%; P 12.8%. Mean duration of response: 10.6m. Mean survival: 16.6m. 56.4% received thx after IPI, in those pts 41% received chx; 17.9% radiotherapy; 12.9% B-RAF inhibitor. 18 pts (46.2%) presented T: 12.8% Grades (G) 3-4 were reported; 23.1% G2; 7.7% G1. The most frequent T was cutaneous (17.9%). When compared with the overall EAP pts population LTS have less visceral disease, lower median LDH, more objective responses and completion of the four induction ipilimumab doses. Conclusions: Ipilimumabin the Spanish EAP experience in pretreated patients has shown to improve long term survival similar to that seen in studies in patients with advanced melanoma. Further research and analysis are needed to identify the patient population most likely to achieve a long term survival benefit with ipilimumab treatment.
Ocular melanoma liver metastases treated by percutaneous hepatic perfusion with melphalan followed by ipilimumab: A case report.
Authors: Idris Ahmad Fitri , Martin Michael John , Davidson Ian R , O'Sullivan Gerard J , Jamaludin Ahmad A , Donnellan Paul P. 
Published: March 2020

e20008 Background: Patients with unresectable liver metastases from ocular melanoma have a poor prognosis with just 10% surviving 1 year with standard treatments. High-dose melphalan via percutaneous hepatic perfusion (PHP) and filtration system (ChemoSat, Delcath Inc.) is licensed in Europe for treatment of liver-only metastases from ocular melanoma and neuroendocrine tumours. Ipilimumab (Ipi), anti-CTLA4 immunotherapy is licensed in US and Europe for treatment of metastatic malignant melanoma. A 32-year-old man was referred to our unit with unresectable liver metastases from primary ocular melanoma treated 8 years earlier. Here we describe the first report of sequential ChemoSat and Ipi in this setting. Methods: With assistance of an international proctoring team, and following on-site training, we treated this patient with ChemoSat according to manufacturer’s instructions (details at meeting). There were no immediate complications or subsequent hematological or other systemic chemotherapy side-effects. On day 4, the patient developed acute epigastric pain, pyrexia, ST elevation, and elevated troponin. Cardiac ECHO, coronary angiogram, CT pulmonary angiogram, abdominal USS and gastroscopy were normal. Blood cultures were repeatedly negative. He developed acute kidney injury secondary to intravenous contrast and NSAIDs. Repeat abdominal USS showed a thickened wall of gall bladder. A diagnosis of acute chemical cholecystitis was made. His symptoms settled, kidney function improved and he was discharged on day 23 of procedure. 10 weeks post ChemoSat the patient underwent treatment with Ipi 3mg/kg i.v. day 1, q 3/52 x 4 cycles which he received without significant side-effects. Results: MRI scan of liver 8 weeks post-ChemoSat (pre-Ipi) showed the liver lesions to be unchanged. CT scan 6 weeks post-Ipi treatment showed significant improvement. Conclusions: ChemoSat treatment is feasible and safe but can cause unexpected gall-bladder toxicity. Subsequent treatment with ipilimumab seems to be effective in this single case with short-term follow up.
BKM120 combined with vemurafenib in vemurafenib-refractory BRAF mutant metastatic melanoma: Two cases.
Authors: Algazi Alain Patrick , Posch Christian , Ortiz-Urda Susana , Cockerill Alyson , Munster Pamela N. , Daud Adil 
Published: March 2020

e20010 Background: PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause of acquired resistance to BRAF inhibitors. Two vemurafenib refractory were treated with the potent BRAF inhibitor, vemurafenib, and the pan-class I PI3K inhibitor BKM120. Methods: The study enrolled BRAF-V600E/K mutant metastatic melanoma patients with an ECOG PS ≥ 2 and adequate organ function. Vemurafenib refractory BRAF-V600E/K mutant melanoma patients started both vemurafenib twice daily and BKM120 daily on cycle 1, day 1 after a vemurafenib washout of at least 14 days. Serial biopsies prior to treatment, on cycle 1 day 15, and at progression were obtained for pharmacodynamics analysis in patients with visible or palpable tumors. Results: 3 BRAF inhibitor refractory patients were treated on study with vemurafenib 720 mg PO bid and BKM120 60 mg PO daily. One patient was inevaluable due to non-compliance and had minimal exposure to study drug. Pre-treatment biopsy specimens were available in the remaining 2 vemurafenib-refractory patients. Both patient expressed PTEN at baseline and had demonstrable pAKT and pS6 staining. One patient had a mixed response to treatment with a 35.9% reduction in target lesions and two new small subcutaneous lesions. This patient also developed dose limiting febrile neutropenia on trial. The second patient tolerated treatment well but had widespread disease progression at 8 weeks. Conclusions: Combination therapy with vemurafenib and BKM120 in BRAF-V600E/K mutant melanoma led to substantial regression of several tumors in a PTEN+ patient with prior disease progression on vemurafenib alone. A phase I dose escalation trial in ongoing. Clinical trial information: NCT01512251.