bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of comorbidities on overall survival of high-risk and advanced melanoma.
Authors: Peddi Prashanth , Oh Jeong Hoon , Kim Kevin B. , Gershenwald Jeffrey E. , Palla Shana L. , Schacherer Christopher W , Jakkoju Rakesh , Suarez-Almazor Maria 
Published: March 2020

8536 Background: Comorbidities have been shown to adversely affect survival among patients with cancer. Currently, the most important prognostic factor in patients with melanoma is AJCC stage. However, little is known regarding the impact of comorbidities on melanoma prognosis. The aim of our study was to determine the impact of the severity of concurrent comorbidities on the overall survival of patients with high-risk and advanced melanoma (defined as AJCC stages IIc, III and IV). Methods: We conducted a retrospective cohort study of eligible adult melanoma patients available in the MelCore prospective database at MD Anderson Cancer Center (MDACC) from 01-2003 to 12-2006 who were diagnosed and completed staging within 3 months of presentation to MDACC. Patients with ocular melanoma were excluded. Demographic, AJCC staging, and survival data were collected. The Adult Comorbidity Evaluation-27 (ACE-27) was utilized to collect comorbidity information and grade its severity. A Cox proportional hazards model was used. Results: Of 444 patients that met enrollment criteria, 176 (39.6%) had grade 0 (no comorbidities), 222 (50%) had grade 1 or 2 (mild or moderate comorbidities) and 46 (10.4%) had grade 3 (severe comorbidities). The median age of the entire cohort was 56.4 years (19.7-98.9), 141 (32%) were female, and 406 (91.4%) were white. The median overall survival after presentation to MDACC was 5.0 years for the entire cohort. Adjusted hazard ratios are shown in the table. Comorbidity and AJCC Stage were significantly associated with survival. Age, gender and race did not have a significant impact on overall survival. Conclusions: In our study, the presence of comorbidities at presentation were independent predictors of decreased survival, even when adjusted for AJCC stage. Our findings suggest that comorbidity should be incorporated into prognostic models and therapeutic decision-making for patients with high-risk or advanced melanoma. [Table: see text]
Prognostic value of BRAFV600 mutations in melanoma patients after resection of metastatic lymph nodes.
Authors: Saiag Philippe , Moreau Stephanie , Aegerter Philippe , Bosset Daphne , Longvert Christine , Helias-Rodzewicz Zofia , Marin Cristi , Peschaud Frederique , Chagnon Sophie , Zimmermann Ute , Clerici Thierry , Emile Jean-François 
Published: March 2020

8540 Background: Prognosis of AJCC stage III melanoma is heterogeneous. BRAFV600 mutations are frequent in melanomas. BRAFV600-targeted therapy has dramatic, but often transitory, efficacy in stage IV patients (pts). We aimed to determine for the first time the prognostic value of BRAFV600 mutations and other known prognostic criteria in stage III pts with sufficient nodal invasion. Methods: We searched all pts with cutaneous melanoma who had radical lymphadenectomy in our institution between 1/1/00 and 15/6/10 and included those with a nodal deposit >2 mm. BRAFV600 mutations were detected by DNA sequencing and pyrosequencing in formalin-fixed nodal samples containing >60% melanoma cells. Samples were considered mutated when >15% of DNA was positive. Endpoints were overall survival (OS) and distant metastasis free survival (DMFS). 92 patients had to be included to demonstrate a doubling of OS in patients without (40 months (m)) and with BRAFV600 mutation (20 m). Log-rank test and multivariate Cox proportional hazards regression model were used. Results: 105 consecutive pts were included, with 72% prospectively followed-up pts. BRAFV600 mutations (E: 83%; K: 14% of pts) were detected in 40% of pts. Median follow-up was 19 m (range: 3-139). Death occurred in 83% and 60% of pts with and without BRAF mutations, respectively, with median OS of 1.4 and 2.8 years. Pts’ age, primary melanoma ulceration, number of invaded nodes, AJCC staging, and BRAF status influenced OS and DMFS in the univariate analysis. The multivariate analysis showed the major prognostic role of BRAF status and of the number of invaded nodes (table). Conclusions: Provided our findings are independently replicated, BRAFV600 status should be used to stage melanoma pts with nodal metastasis. Our results also help to plan adjuvant trials with BRAFV600-targeted therapy in such patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies. [Table: see text]
BEVATEM: Phase II single-center study of bevacizumab in combination with temozolomide in patients (pts) with first-line metastatic uveal melanoma (MUM): First-step results.
Authors: Piperno-Neumann Sophie , Servois Vincent , Bidard Francois-Clement , Mariani Pascale , Plancher Corine , Asselain Bernard , Vago-Ady Nora , Desjardins Laurence 
Published: March 2020

8546 Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 470 MUM pts, median OS was 13 months, ranging from 3 to 12 and 21 months for best supportive care, systemic treatment and surgery groups respectively, stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma. Intravitreal application of antiangiogenic agents is used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental uveal melanoma. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and bevacizumab. Methods: Phase II study, modified 2-step Fleming plan; with expected 6-month progression-free survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 35 pts are to be recruited for a power of 94% (α and β risk 3 and 6%). After the first 17 pts, the study will be continued and another 18 pts will be enrolled in the second step if ≥3 evaluable pts show stable disease or response. Primary endpoint: 6-month PFS according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then Bevacizumab maintenance until toxicity or progression. Results: From May 2010 to January 2011, 17 pts were enrolled according to the first step of the study: 3/17 achieved disease control at 6 months, second step is on going with 26/35 pts already recruited. One patient with minor response in liver and lung metastases is under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as good as expected. Liver perfusion CT study showed decrease in blood flow and blood volume before lesion size decrease in one stable patient. Conclusions: BEVATEM study in first line MUM pts is on going, showing promising results in the first step of 17 pts.
Targeted agents matched with tumor molecular aberrations: Review of 160 patients with advanced melanoma treated in a phase I clinic.
Authors: Henary Haby Adel , Hong David S. , Falchook Gerald Steven , Tsimberidou Apostolia Maria , George Goldy , Wheler Jennifer J. , Fu Siqing , Naing Aung , Piha-Paul Sarina Anne , Janku Filip , Kim Kevin B. , Hwu Patrick , Kurzrock Razelle 
Published: March 2020

8551 Background: Identification of activating mutations in melanoma has increased the number of novel targeted agents for this disease. Methods: Weretrospectively reviewed clinical outcomes of 160 consecutive metastatic melanoma patients (pts) treated in the Dept of Investigational Cancer Therapeutics (Phase I program) at M. D. Anderson since 2008, and compared their median progression free survival (PFS) to their first and last standard systemic therapy PFS. In addition, we compared those pts’ outcomes tested for tumor molecular aberrations on a phase I trial with a matched targeted agent with those of pts who were treated without regard for their molecular profiles. Results: Of 160 pts treated on 35 different phase 1 clinical trials, 110 pts (69%) had ≥ 1 molecular aberration. Of those pts who had adequate tissue for molecular analysis, 63% (85/134) pts had BRAF mutation, 20% (22/109) NRAS mutation, 20% (1/5) GNAQ mutation, 11% (1/9) P53 mutation, 2.5% (1/39) PIK3CA and 1.3% (1/76) had KIT mutation. 77 (48%) pts were treated on a phase I trial with a matched targeted agent and 83 (52%) pts were treated on a non-matched phase 1 trial. The overall response rate was 39% (complete response [CR], 9%; partial response [PR], 30%) in the 77 pts treated with matched therapy and 9% (all PRs) in the 83 pts treated without matched therapy (P = 0.0018). 139 (87%) pts received at least one systemic therapy before referral to phase I, median PFS was longer on phase 1 therapy than on last line standard therapy prior to referral to phase 1 (4.2 vs. 2.8 months, P = 0.002). Median PFS was greater for pts on matched vs. non-matched therapy (5.3 vs. 3.7 months, log rank P = 0.004). Also, median PFS was longer on phase 1 matched trial than on first standard treatment (5.3 vs. 3.9 months, log rank P = 0.045).PFS did not differ between first standard and non-matched phase 1 study. Univariate analyses with the log rank test revealed that matched therapy (P = 0.004) was positively associated with longer PFS on phase I clinical trials. Conclusions: Matching melanoma pts with targeted drugsbased on specific molecular aberrations in the phase I setting can be associated with superior outcomes compared to prior standard systemic therapies.
Everolimus in combination with paclitaxel and carboplatin in patients with advanced melanoma: A phase II trial of the Sarah Cannon Research Institute (SCRI).
Authors: Hauke Ralph J. , Infante Jeffrey R. , Shih Kent C. , Rubin Mark S. , Arrowsmith Edward , Whorf Robert C. , Hainsworth John D. 
Published: March 2020

8556 Background: The PI3k/AKT pathway is activated in most metastatic melanomas; mTOR is a critical component of this pathway. Everolimus, an mTOR inhibitor, has demonstrated single-agent activity in patients with advanced melanoma. We evaluated the efficacy and toxicity of everolimus in combination with paclitaxel/carboplatin in patients with advanced melanoma. Methods: Eligible patients had stage IV or unresectable stage III melanoma, unselected for braf status, previously untreated with chemotherapy or targeted agents. Previous immunotherapy was allowed. Additional eligibility criteria: ECOG PS 0 or 1; measurable disease; no active brain metastases; adequate bone marrow, kidney, and liver function; informed consent. All patients received paclitaxel 175mg/m2, 1-3 hour IV infusion, and carboplatin AUC 6.0 IV on day 1 of each 21-day cycle. Everolimus 5mg PO was given daily. Patients were evaluated for response every 6 weeks; treatment continued until progression or undue toxicity. Median progression-free survival (PFS) for paclitaxel/carboplatin treatment is 4 months; we looked for a median PFS of 6 months with this novel combination. Results: Seventy patients were treated between 2/2010 and 2/2011; median age 63, 90% had stage IV melanoma. 91% of patients received at least 2 cycles of therapy; median cycles received: 4 (range: 1-25+). Twelve patients (17%) had partial responses; an additional 42 patients (60%) had stable disease at first reevaluation. After a median 13 months of followup, the median PFS for the entire group was 4 months (95% CI: 2.8 – 5.0 months); 96% had progressed during the first 12 months. Median survival was 10 months (95% CI: 7.3 – 10.9 months). Toxicity was as previously described with these agents; neutropenia was the most common grade 3/4 toxicity (27%). Only 3 patients stopped treatment due to toxicity. Conclusions: The addition of everolimus to paclitaxel/carboplatin was feasible and well-tolerated; however, efficacy results were similar to those reported with paclitaxel/carboplatin alone. Further development of this combination regimen for treatment of metastatic melanoma is not recommended.
mTOR pathway activation in KIT-mutated melanoma with acquired imatinib resistance.
Authors: Si Lu , Xu Xiao wei , Kong Yan , Flaherty Keith T. , Chi Zhi Hong , Cui Chuan Liang , Sheng Xi Nan , Li Si Ming , Tang Bi Xia , Guo Jun 
Published: March 2020

8562 Background: c-Kit mutation is a common genetic abnormality in certain melanoma subtypes, and is a target for treatment. However, the mechanisms of secondary (acquired) resistance and how to treat patients in the second line are unknown. Methods: Tissuesamples were obtained from c-Kit-mutated melanoma patients who failed of imatinib after having PR or SD for at least 6 months pre- and post-imatinib therapy. Somatic mutations in genes in MAP kinase (c-Kit, BRAF, NRAS, etc) and PI3K-AKT-mTOR (AKT1, TSC1, PTEN, etc) pathways were detected by DNA sequencing. The expression of pS6RP, p4E-BP1, pAKT and pERK1/2 were examined by immunohistochemistry (IHC) assays. Results: Four paired samples (formalin-fixed, paraffin-embedded) were analyzed. 1) Laboratory results: No secondary mutations in addition to the c-Kit mutations identified at baseline were identified. However, IHC showed increased pS6RP and p4E-BP1 (two targets of mTOR activation) as well as increased pAKT and pERK1/2 in imatinib-resistant samples, suggested that mTOR signaling pathway was selectively activated in these secondary imatinib-resistant melanomas. 2) Treatment: Everolimus is an orally administered inhibitor of mTOR. The four patients received everolimus (10 mg/day) by continuous daily dosing. The tumor response revealed 1 PR and 3 SD (all >3 months) with grade 1-2 toxicities consisting of myelosupression, hyperglycemia, hypercholesterolemia and hypertriglyceridemia, consistent with previously reported toxicities for everolimus. Conclusions: The case series provides an important clue that activation of the mTOR signal pathway may be one of the mechanisms for secondary imatinib resistance in c-Kit-mutated melanomas. The results also show that everolimus may be effective and safe for melanoma patients who develop resistance to imatinib and could be investigated in combination with c-Kit inhibitors in treatment-naive patients.
Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after vemurafenib.
Authors: Ackerman Allison , McDermott David F. , Lawrence Donald P. , Gunturi Anasuya , Flaherty Keith T. , Giobbie-Hurder Anita , Hodi F. Stephen , Ibrahim Nageatte , Atkins Michael B. , Cho Daniel C. , Sullivan Ryan J. 
Published: March 2020

8569 Background: Treatment of patients (pts) with BRAF mutant malignant melanoma (MM) with vemurafenib (vem), a BRAF inhibitor (BRAFi), is associated with a high response rate (RR) and improvement in progression free survival (PFS) and overall survival (OS) compared to standard chemotherapy. Responses to vem are typically not durable and most pts require additional therapy. However, there is little data to guide sequencing of vem with other standard therapies such as ipilimumab (ipi) or interleukin 2 (IL-2). Methods: 43 pts treated with vem as part of clinical trials from 2009-2012 were retrospectively identified. RR of vem was calculated for all pts as well as for pts treated with immunotherapy (IT) prior to vem. The OS from first systemic and vem treatment, duration of vem therapy, OS from when pts came off vem, and PFS and OS for post-vem ipi was determined using Kaplan-Meier estimates. Results: Of the 43 pts, 11 remain on vem and 32 are off vem (19 deceased) with a median follow up of 19 mo. Pre-vem LDH was elevated in 46% (17/37 evaluable pts). The RR to vem was 52% (22/42 evaluable pts), the median duration of therapy 5.6 months (mo), and the median OS 19.3 mo, similar to results in trials. The median OS from initiation of any treatment was 27 mo. 16 pts received IT (11 IL-2, 4 ipi, 1 IL-2 then ipi) prior to vem with a median OS of 31.2 mo; the RR of vem following IT was 75% (12/16). At time of vem discontinuation 50% of pts (12/24 evaluable) had an elevated LDH, and the median OS of the 32 pts who stopped vem was 4 mo from last vem dose. 10 of these pts then received single-agent ipi; six of whom had an elevated LDH. Five pts died within 3 mo of last vem dose, and all 10 pts had disease progression (PD) at 6 months with a median PFS of 0.7 mo and OS of 2.2 mo. The 3 pts who lived beyond 1 year following vem and then ipi were subsequently treated with a BRAFi following PD on ipi. Conclusions: Response to vem following IT appears similar to that seen in previously untreated pts. Median PFS and OS for pts receiving ipi after discontinuation of vem are poor, possibly due to rapid PD at the time of vem discontinuation. Prolonged OS is primarily seen with resumption of BRAF inhibition. Our data suggests that in appropriately selected pts, IT should be considered prior to BRAFi.
Use of Cobas 4800 BRAF mutation test for the analysis of BRAF V600 mutations in cytological samples (CS) from metastatic melanoma (MM).
Authors: Martin-Algarra Salvador , Labiano Tania , Echeveste Jose Ignacio , Gomez Nerea , Montañana Myriam , Aguirre Mercedes , Echarri Mari­a Eugenia , Sanmamed Miguel F. , Gurpide Alfonso , Perez-Gracia Jose Luis , Idoate Miguel A. , Lozano Maria D. 
Published: March 2020

8572 Background: Vemurafenib is currently the most active first-line treatment in MM patients that harbor BRAF-V600E mutations. The Cobas 4800 BRAF V600 Mutation Test is an FDA-approved, CE-marked test that identifies formalin-fixed-paraffin-embedded samples (FFPE) carrying the BRAF V600E mutation. Fine needle aspirates are frequently the only samples available in MM patients, but the use of CS has not been validated in this platform. We have evaluated the capability to identify BRAF-V600E mutations in CS of MM with the Cobas 4800 BRAF Mutation Test, and results have been compared to the conventional Sanger direct sequencing method. Methods: BRAF mutations have been studied in 117 samples from 98 MM patients with the conventional Sanger method: 37 (32%) FFPE and 80 (68%) CS. DNA was extracted from 4-micron sections in FFPE and from stained smears in CS. All CS contained >50% of tumor cells. In a second step, 57 out of the 117 samples have been studied using Cobas (25 CS and 32 FFPE). In CS, Nucleospin Tissue (Macherey-Nagel) DNA extraction was used in 17 cases and the Cobas procedure in 8. FFPE and CS paired samples were available in 9 patients. Results were compared using the Kappa coefficient. Results: There was 93% (53/57) agreement between Cobas and direct sequencing. All V600E+ cases were detected with both methods. Four V600R+ cases were negative using Cobas. Mean DNA concentrations using Nucleospin and Cobas procedures were 55.20 ng/µl and 11.37 ng/µl respectively. Concordance using Cobas in FFPE and CS paired samples was 100%. The table shows the results with Cobas and direct sequencing in 25 CS. One V600R+ case was not detected with Cobas. Conclusions: The Cobas 4800 BRAF Mutation Test results using CS containing >50% of tumor cells are identical to those obtained with FFPE. In our experience, DNA concentrations from CS with the Cobas method are lower than those obtained with Nucleospin procedure. These results provide a strong rationale for a larger validation study. [Table: see text]
Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3mg/kg).
Authors: Postow Michael Andrew , Yuan Jianda , Panageas Katherine , Bogatch Kita , Callahan Margaret , Cheng Michael , Schroeder Sebastian Edoardo Artur , Kendle Ryan F. , Harding James J. , Dickson Mark Andrew , D'Angelo Sandra P. , Carvajal Richard D. , Schwartz Gary K. , Wolchok Jedd D. 
Published: March 2020

8575 Background: Ipilimumab (ipi) has demonstrated an overall survival (OS) benefit in 2 phase III trials. Only ~30% of patients (pts) achieve clinical benefit, and factors that determine which pts benefit are unclear. For pts treated with 10mg/kg of ipi, we previously reported that an absolute lymphocyte count (ALC) ≥1000/μL prior to dose 3 [week (wk) 7] was associated with improved OS. Since the mean increase in ALC during ipi treatment correlates with dose, we investigated if ALC is also associated with improved OS at 3mg/kg, the currently FDA approved, commercially available dose. Methods: In an IRB-approved analysis, we evaluated landmark survival data from 137 pts treated with 3mg/kg of ipi at Memorial Sloan-Kettering Cancer Center. 67 pts were treated on an expanded access protocol (CA 184-045). 70 pts were treated per FDA approval (commercial ipi) with 4 standard induction doses. These 2 groups were analyzed separately because some pts in CA 184-045 received re-induction ipi. ALC was determined at first ipi dose (baseline, wk 1) and at subsequent doses (wks 4, 7, and 10). Results: Pts treated with 3mg/kg on CA 184-045 with a wk 7 (prior to dose 3) ALC ≥1000/µL had significantly improved OS compared to pts with an ALC at wk 7 <1000/μL (Median OS: not reached vs. 4.24 mos, p<0.001). This OS difference was also seen for pts treated with commercial ipi (Median OS: not reached vs. 4.44 mos, p<0.01). This difference remained significant in a multivariable model accounting for Karnofsky performance score, LDH, M-stage, and number of prior therapies for pts in the CA 184-045 group and commercial ipi group (p=0.01 and p=0.05, respectively). Baseline ALC ≥1000/µL was associated with improved OS (p=0.02) for pts in the commercial ipi group, though follow-up is limited. Conclusions: At the FDA approved dose of ipi, 3mg/kg, ALC at wk 7 remains significantly associated with improved OS. Our preliminary finding of improved OS for pts treated with commercial ipi whose pre-treatment baseline ALC ≥1000/µL deserves confirmation with longer follow-up and prospective validation. Baseline or on treatment ALC may be a marker of overall prognosis, regardless of therapy.
Efficacy and safety of the hedgehog pathway inhibitor vismodegib in patients with advanced basal cell carcinoma (BCC): ERIVANCE BCC study update.
Authors: Sekulic Aleksandar , Migden Michael R , Oro Anthony E , Lewis Karl D , Hainsworth John D , Yoo Simon , Dirix Luc , Hou Jeannie , Yue Huibin , Hauschild Axel ,   on behalf of the ERIVANCE BCC Study Investigators
Published: March 2020

8579 Background: The ERIVANCE BCC study is the pivotal trial of vismodegib (GDC-0449), a first-in-class small-molecule inhibitor of Hedgehog signaling, for treatment of locally advanced (laBCC) and metastatic BCC (mBCC), for whom there are no other effective therapy options. The study met the primary endpoint of overall response rate by independent review (Sekulic, Melanoma Res 2011). Here we report a 6-mo update of investigator-assessed (I-A) efficacy and safety endpoints as of May 26, 2011. Methods: This multicenter, international, nonrandomized 2-cohort study enrolled patients (pts) with laBCC (deemed inoperable or for whom surgery would be significantly disfiguring), and mBCC pts with RECIST-measurable disease. Pts received 150 mg oral vismodegib daily. Results: 104 pts (71 laBCC/33 mBCC) enrolled at 31 sites in the US, Europe, and Australia. I-A efficacy endpoints are shown in the table. One-year survival rate was 77.3% (95% CI 62.48–92.09%) for mBCC and 93.1% (95% CI 86.49–99.63%) for laBCC. Adverse events (AEs) in >30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea (33.3%; 2/6 pts). Serious AEs were reported in 32 pts (31%). No additional fatal AEs were reported since the prior data cut (n=7, 7%; none considered related to vismodegib). Conclusions: This 6-mo update of I-A efficacy and safety endpoints from the ERIVANCE BCC study supports the significant clinical benefit of vismodegib in both laBCC and mBCC reported at the primary analysis. Median DOR and PFS increased numerically with follow-up. The AE profile was consistent with the prior data cut. These results further support the efficacy of vismodegib for treatment of advanced BCC. [Table: see text]