bluuebunny/crossref_metadata_2025 huggingface dataset:
DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma.
Authors: Gupta Avinash , Love Sharon , Schuh Anna , Collins Linda , Thomason Adelyn , Asher Ruth , Lisle Richard , Churchman Michael , Shanyinde Milensu , Plummer Ruth , Nathan Paul D. , Danson Sarah , Ottensmeier Christian H.H , Lorigan Paul , Larkin James M. G. , Middleton Mark R.
Published: March 2020

9068

Background: Inhibitors of mutant BRAF have transformed the treatment of melanoma for the 40% of patients whose tumors harbor V600 mutations. ERK1/2 is constitutively active in melanoma cells regardless of mutation status, and plays key roles in cell cycle entry, invasion, angiogenesis and in resistance to apoptosis. Selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma independent of BRAF and NRAS mutation status. In melanoma cells, docetaxel induces mitochondrial dependent apoptosis by activation of Bax. Activation of ERK1/2 results in degradation of the BH3-only protein Bim and phosphorylation of Bad, inhibiting apoptosis. Selumetinib and docetaxel have demonstrated synergy in a variety of xenograft models, including melanoma. Methods: DOC-MEK (NCT01256359) is a randomised, double-blind, placebo-controlled multi-centre study in patients with wild-type BRAF advanced melanoma. Patients were randomised (1:1) to docetaxel with placebo or selumetinib, with stratification for M stage and performance status. Docetaxel was administered intravenously every 3 weeks at a dose of 75mg/m2 for a maximum 6 cycles. Placebo or selumetinib 75mg was given orally twice per day until disease progression or unacceptable toxicity. Results: Between October 2010 and April 2012 eighty three patients were randomised at 18 sites from 257 patients screened. Progression free survival (PFS) favored combination therapy (HR 0.753, p=0.13), as did response rate (32 vs 14%, p=0.059) and 6 month PFS (40 vs 26%, p=0.19). Patients on docetaxel with selumetinib experienced more rash, diarrhea, febrile neutropenia and edema, but less neuropathy. Overall survival data and outcomes according to tumor NRAS mutation status will be presented. Conclusions: Although PFS and response rates favored docetaxel with selumetinib further interest in the regimen will be dependent on overall survival outcomes and/or the identification of a sub-population that benefit most from this approach. Clinical trial information: NCT01256359.
High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience.
Authors: Davar Diwakar , Saul Melissa , Tarhini Ahmad A. , Tran An , Trent Kerry , Sander Cindy , Kirkwood John M. , Tawbi Hussein Abdul-Hassan
Published: March 2020

9075

Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR+PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p < 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).
Trends and variations in the use of adjuvant immunotherapy for stage III melanoma in the U.S. population.
Authors: Nasabzadeh Teresa J. , Tsai Huei-Ting , Tefera Eshetu , Venna Suraj S. , Potosky Arnold L. , Atkins Michael B. , Jang Sekwon
Published: March 2020

9077

Background: High dose Interferon alfa-2b (IFN), an adjuvant immunotherapy for patients (pts) with stage III melanoma, was the only approved treatment option in the US from 1995-2011. There is limited information on how high dose IFN has been disseminated to eligible pts in general clinical practice, and whether variations exist in its adoption according to non-clinical factors. Methods: We obtained data on 34,208 pts diagnosed between 1998-2010 with stage III melanoma from the National Cancer Data Base (NCDB). IFN treatment was abstracted as immunotherapy. We investigated the use of immunotherapy according to pt demographic, socioeconomic, and clinical variables. We conducted multiple logistic regression analysis to examine the effect of these variables on the receipt of immunotherapy. Results: 62% of pts in our study population were male, 88% were Caucasian and 31% were over age 65. Overall, 27% of the pts received immunotherapy. There was no significant trend in its adoption between year 1998 and 2010. After adjustment for clinical variables, age at diagnosis, facility type, and geographic region are predictors strongly associated with use of immunotherapy. Only 16% of pts aged 65-74 and 3% over 75 received immunotherapy compared to 42% of those ages less than 45 (adjusted ORs 0.44 [0.32-0.59], 0.05 [0.04-0.14), respectively). Also 24% of pts treated at a comprehensive community cancer program received immunotherapy compared to 30% of those treated at an academic/research program (OR, 0.71 [0.51-0.99]). The frequency of immunotherapy was 25% in the Atlantic region and 17% in the Western region compared to 33% in Northeast (ORs 0.42 [0.18-0.99], 0.31 [0.13-0.74], respectively). Median household income, insurance type and comorbidity were not associated with adoption of immunotherapy after adjustment for all other variables. Conclusions: Less than one-third of all eligible patients received adjuvant immunotherapy in US general practice over the past decade. There is significant variation in its adoption according to non-clinical factors. Further exploration of the reasons for these variations and whether they are linked to important patient outcomes is needed.
A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma.
Authors: Kudchadkar Ragini Reiney , Gibney Geoffrey Thomas , Weber Jeffrey , Chen Ann , Smith Kim , Merek Stephanie
Published: March 2020

9079

Background: Peginterferon alfa-2b (Sylatron) as adjuvant therapy has been shown to benefit patients with high-risk resected melanoma and some interferon studies have shown that the induction of autoantibodies may correlate with benefit. Ipilimumab (IPI, Yervoy) is a fully human anti-CTLA-4 antibody that induces autoimmune toxicity that in some cases appears to correlate with clinical benefit. This study was performed to assess whether ipilimumab can be safely administered with peginterferon alfa-2b. Methods: This study combined IPI at 3mg/kg every 3 weeks for 4 doses along with concurrent peginterferon alfa-2b at 3 mcg/kg weekly for up to 156 weeks or until disease progression, unacceptable toxicity or patient decision to discontinue. The study was designed to obtain toxicity, tolerability and autoimmune antibody data and to define a well-tolerated dose of the combination. Results: Median age was 61 with 9 female and 8 male subjects. There were 3 patients (pts) with partial responses, 1 stable disease, and 6 with progressive disease in 10 pts evaluable for response thus far. Six pts have not yet completed cycle 1 and therefore are not evaluable for response at the time of this publication but will be presented. One pt withdrew consent prior to finishing cycle 1. Toxicities from peginterferon alfa-2b 3mcg/kg were dose-limiting with 7 pts requiring dose reduction in peginterferon alfa-2b secondary to toxicity. The Grade 3 events leading to dose reductions were nausea and vomiting, leucopenia, dehydration, and hyponatremia. peginterferon alfa-2b was dose reduced to 2 mcg/kg weekly in future pts after these toxicities were noted. No Grade 3 or 4 toxicities attributable to ipilimumab have occurred thus far. No Grade 3 or 4 events have been noted to date in the10 pts initiated at 2 mcg/kg of peginterferon alfa-2b. There was no significant change in the presence autoantibodies (ANA, anti-double stranded DNA, antithyroglobulin, antimicrosomal antibodies, and anticardiolipin antibodies) between responders and non-responders in the evaluable pts. Conclusions: Peginterferon alfa-2b added to IPI results in an excellent response rate in this small population. Peginterferon alpha-2b at 2 mcg/kg weekly with IPI at 3 mg/kg every 3 weeks appears well-tolerated and the combination warrants further exploration. Clinical trial information: NCT01496807.
Response rate to vemurafenib in BRAF-positive melanoma brain metastases.
Authors: Dzienis Marcin Radoslaw , Atkinson Victoria
Published: March 2020

9081

Background: Brain is a common site for melanoma metastases. Responses to dabrafenib have already been reported in over 50% of patients. We aimed at assessing response rate (RR) to vemurafenib (Vem). Methods: Patients with BRAF positive melanoma and asymptomatic brain metastases at initiation of Vem were eligible. Records were analysed retrospectively to calculate RR (at least 30% decrease in the sum of diameters of target lesions), duration of response and time to CNS progression (TTP). Results: 18 patients with CNS metastasis received Vem (M/F=8/10; median age 50); 9 received no prior therapy to the brain (group A), 6 had previous surgery and/or radiotherapy with residual disease (group B; n=6), 3 patients had prior "brain therapy" but with evidence of progression in CNS before the start of Vem and were added to group A (n=9+3=12). 50% RR was observed in group A; 5 had no prior therapy, 1 relapsed after resection/WBRT. Duration of response was: 8, 8, 8, 16, 32 weeks and 1 not reached yet. Similarly, 50% RR was observed in group B; however contribution of Vem to CNS control in this group was more difficult to assess. Duration of responses: 4, 26, 33 weeks. All except 2 patients progressed in CNS before, or at the time of, systemic progression. Median TTP in group A was: 21 weeks (16-41) in responding patients and 12 weeks (4-22) in those without a response (includes SD). Median TTP in group B = 44 weeks (16-60) in responders, 8 weeks (3-16) in non-responders. Conclusions: Vemurafenib resulted in 50% CNS response rate. Prospective comparison to dabrafenib may be warranted.
Updated interim analysis of UCI 09-53: A phase II, single arm study of pazopanib and paclitaxel as first-line treatment for subjects with unresectable advanced melanoma.
Authors: Ein-Gal Shlomit Y. , Tsang Walter , Alger Beverly , Parmakhtiar Basmina , Jakowatz James G. , Bettis Claudette , Fruehauf John
Published: March 2020

9082

Background: Metastatic melanoma lacks effective therapy. Pazopanib is an inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 31 patients are evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib 800mg continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGFR-2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST 1.1 criteria were used to define treatment response (SD criteria was a minimum interval of 8 weeks). Results: For the 31 evaluable patients treated to date the following results were seen: 1 CR, 9 PR’s, 13 SD’s and 8 PD’s. The overall RR (CR+PR) was 32%. Total disease control rate was 74% (CR+PR+SD). The most common AEs/lab abnormalities were diarrhea (66%) nausea (60%), hypertension (63%), fatigue (63%) and vomiting (29%). Grade 3-4 AEs included hypertension (26%), transaminitis (23%) and neutropenia (17%).One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 15 patients and for paclitaxel in 4 patients. Conclusions: Updated interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 32% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients. Clinical trial information: NCT01107665.
Graded prognostic assessment index for melanoma with brain metastases (MBM).
Authors: Osei-Boateng Kwabena , Alva Venur Vyshak , Dahiya Saurabh , Du Lingling , Garje Rohan , Elson Paul , Chao Samuel T. , Ahluwalia Manmeet Singh
Published: March 2020

9086

Background: The Graded Prognostic Assessment (GPA) is a commonly used prognostic index in patients with brain metastases (BM). GPA for melanoma consists of Karnofsky Performance Scale (KPS) and the number of BM present. The purpose of this study was to evaluate the utility of GPA index in a contemporary cohort of patients (pts) with MBM at a single institution to predict Overall Survival (OS). Methods: With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify pts with MBM treated between 2000-2012. The primary endpoint was OS from diagnosis of MBM. Cox proportional hazards models were used for data analysis. Stepwise variable selection was used to identify independent prognostic factors. Results: 90 MBM (51 females) median age 57 years (range 24-87) were included for analysis. The median number of BM was 2 (range, 1-11). KPS was 90-100(52%), 70-80 (43%) and <70 (6%). Extracranial metastases was present in 75 patients (83%). Initial treatment included Stereotactic Radiosurgery (SRS) (49%), Whole Brain Radiotherapy (WBRT) (8%), WBRT + SRS (22%), WBRT + Surgery (S)(14%) and SRS + (S) (7%). Median OS was 7.8 months (95% C.I. 6.8-10.1). GPA was prognostic for OS ( p=0.01), however this was because pts with scores of 4 had worse outcomes (median 5.1months) than the other 3 groups, which had similar OS (median 9.0-12.8 months). In addition, number of BM was not associated with OS (p=0.19). In contrast, KPS (p=0.02), Liver (p=0.04) and hemorrhagic metastasis (p=0.02) were independently prognostic for OS. These factors can be used to derive a new prognostic index with 3 groups: Unfavorable, Intermediate and Favorable (see Table). Conclusions: GPA was prognostic for OS in pts with MBM, however separation of the groups was not clear. A new prognostic index consisting of KPS, liver and hemorrhagic metastases is proposed for MBM. [Table: see text]
Metastatic melanoma patients: Prospective follow-up of pigmented lesions under vemurafenib by digital dermoscopy.
Authors: Perier-Muzet Marie , Dalle Stephane , Duru Gerard , Thomas Luc , Debarbieux Sebastien , Poulalhon Nicolas , Balme Brigitte
Published: March 2020

9093

Background: Vemurafenib is the first approved by the FDA BRAF V600 inhibitor for the treatment of metastatic melanoma. Many cutaneous side-effects such as squamous cell carcinoma, xerosis, photosensitivity are observed. We first reported the occurrence of second primary melanomas (SPM) under BRAF inhibition. These SPM were shown to be wild-type for BRAF. The exact occurrence of these changes is still unknown. We wanted then to explore prospectively the impact of vemurafenib on cutaneous pigmented lesions using sequential digital dermoscopy. Methods: We registered prospectively following inform consent the pigmented lesions of patients under vemurafenib. We examined the total body surface and captured from 9 to 134 pigmented lesions on 24 patients. Each single lesion was followed monthly from vemurafenib initiation to vemurafenib disruption due to disease progression. Dermoscopic modifications of the melanocytic lesions including external diameter, dermoscopical pattern, pigmentation, network thickness, dots distribution and keratosis appearance were analyzed. Results: The median duration of dermoscopic follow up was 6,9 months ( range from 2 to 16 months), 1098 pigmented lesions were included. At least one modification occurred in 56% of the lesions. Most frequent modifications were the occurrence of dark globules (56%), change in the pigmentation coloration (47%), variations in network thickness (32%), increase of the external size (20,1%), onset of black areas (14%), onset of keratosis (4,4%). Up to 5,3% of lesions spontaneously disappeared; 21 excisions were performed due to significant dermoscopic changes and revealed 10 early melanomas in 5/24 patients (20,8%). The 11 remaining lesions were benign. Conclusions: More than fifty percent of the patients under vemurafenib will experiment significant modifications on their pigmented lesions. In our experience 10/21 removed lesions were early melanomas that could not be otherwise diagnosed using naked-eyes examinations only. Digital dermoscopy is one of the tool that can be use to discriminate earlier the modifications. Such careful monitoring will improved the safety when evaluating BRAF inhibitors in adjuvant setting.
Melanomas of the head-and-neck skin with mutation BRAF-V600K or BRAF-V600R define a melanoma subtype with particular clinical features.
Authors: Starz Hans , Moody Justin , Welzel Julia , Haas Christian J
Published: March 2020

9098

Background: “Malignant melanoma” is a melting pot of diverse melanocytic tumor entities, which arise in different organs under varying pathogenetic circumstances. Chronic sun exposure is a major factor for the development of cutaneous melanomas of the head-and-neck (HN) region. Methods: 131 patients with metastatic cutaneous melanomas were included in a monocentric retrospective study. The HN skin was the primary tumor site in 41 patients. The mutational hotspots of BRAF and NRAS were analysed by Sanger sequencing. In BRAF and NRAS wildtype cases, additionally exons 11, 13 and 17 of the KIT gene were investigated. HN patients with the mutations BRAF-V600K or BRAF-V600R were defined as group A (n = 11), those with other mutations or wildtype as group B (n = 30). A and B were compared with regard to the emergence of different categories of metastases, using the Kaplan-Meier method and log rank tests. The average follow-up time was 50 months. Results: BRAF-V600K occurred in 10 of the 41 HN patients and in 2 of the 90 non-HN patients (p = 0.003 by T-test), BRAF-V600R in 1 HN and in 1 non-HN patient. KIT mutations were restricted to 2 HN patients. Inversely, NRAS mutations were rare in the HN (3 of 41) versus the non-HN (26 of 90) cohort (p = 0.001). Lymphatic metastasis became apparent in each of the 11 group A patients not later than 35 months after the diagnosis of the respective primary melanoma. 5 out of the 8 group A patients, who underwent sentinel node biopsies (SNB), had nodal micrometastases. During follow-up, regional nodal macrometastases emerged earlier and at a higher rate in group A compared to B (p = 0.044 by log rank test). The same applied even more significantly for satellite/intransit metastases (p = 0.002), whereas for distant metastasis no significant difference was found. Conclusions: BRAF-V600K/R mutations in HN melanomas define a distinct melanoma subtype with an especially high risk of lymphatic metastasis. Clinical implications may be mutation analyses already for primary HN melanomas, and SNB even for thin melanomas of this subtype. Extra-guidelines should be considered for the monitoring of these patients. Special attention to this subgroup is also necessary in clinical trials.
V600E mutations in metastatic melanoma: Case report.
Authors: Inic Momcilo , Inic Zorka Momcilo , Zegarac Milan , Pupic Gordana , Inic Ivana
Published: March 2020

e20002

Background: Vemurafenib, a selective BRAF kinase inhibitor, is a new medicine against carcinoma.This work will discuss new approaches to the treatment of patients with metastatic melanoma, who have been proved to have BRAF V600 mutation. Methods: The 62-year-old patient was initially diagnosed in 2002 when the excision of melanoma of the left calf was performed. HP was Melanoma invasivum nodular, Breslow III, Clark IV, p T3, without angioinvasion. The stadium of illness was M1a (AJCC). Afterwards, she was operated four times. Chemyotherapy was performed with DTIC and in the further treatment secundary HT VLB-BLM-CDDP. In June 2012 the examination of the control ultrasound of the abdomen and pelvis registered the progression of illness. The liver indicated multiple changes of seundary deposit type, the largest of which was 24mm parailiac left lgl 53mm, inguinal left 23mm. It was confirmed that the patient had the mutation on the BRAF gene and she was included in the clinical study in the illness stadium M1c (AJCC). Subsequently the therapy with vemurafenib 960 mg twice a day was introduced, after which side effects were registered: rash gr. 2, arthralgia gr. 1 (pain in the hand joints) and the swelling of ankle joints gr. 1. The patient continued the vemurafenib therapy. At the latest examination in October 2012, the control CT screening registered the regression of secundary deposit by 40%. Results: Identifying the significance of BRAF has led to the development of numerous new medicines against carcinoma. One of them is vemurafenib (PLKS4032), a medicine inhibiting particularly BRAF V600 mutation. Stage I of studying this medicine showed a complete or partial tumor regression in 81% patients with V600 BRAF mutation, while stage showed a relative reduction of death risk in 63% patients, as well as a relative reduction of tumor progression risk in 74% patients in comparison to dakarbazin. Still, patients who take vemurafenib develop resistance to this medicine within 7 months on average. Conclusions: The development of vemurafenib and the role of BRAF targeted therapy in the treatment of metastatic melanoma ensure a new basis for the clinical research. Further clinical studies will research complex molecular mechanisms underlying resistance and toxicity to vemurafenib.
Multicentric ipilimumab experience in Turkish patients with metastatic melanoma: MIPI-TURK at 30 months of follow-up.
Authors: Sevinc Alper , Turna Hande , Ozdogan Mustafa , Buyukberber Suleyman , Demir Gokhan , Gokmen Erhan , Mandel Nil Molinas , Paydas Semra , Akbulut Hakan , Celik Ismail
Published: March 2020

e20006

Background: Ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen) monoclonal antibody has been shown to enhance immune responses and improve overall survival in patients with metastatic melanoma. The authors report retrospectively on metastatic melanoma patients treated under the Expanded Access Program in Turkey among 13 centers. Methods: Patients with metastatic melanoma were treated with ipilimumab 3 mg/kg every 3 week for 4 doses. Response evaluation was done on week 12. Patients with complete response (CR), partial response (PR), and stable disease (SD) at week 12 were eligible for re-treatment. Results: A total of 97 patients enrolled with 77 evaluable. Ipilimumab treatment was given as 2nd (20.0%), 3rd (64.3%), and 4th(15.7%) line. The rate of the patients receiving ipilimumab for 1, 2, 3, and 4 doses were 5.2%, 11.7%, 16.9%, and 62.3%, respectively. Seven of 77 patients were eligible for re-treatment. G1/2, G3/4, and G5 adverse events were reported in 23.4% (18/77), 14.3% (11/77), and 2.6% (2/77) of the patients, respectively. The most common G1/2 immune related adverse events were rash (14.3%), muscle weakness (10.0%), and gastrointestinal side effects (8.6%). There were seven G3 side effects (diarrhea in 4, muscle weakness in 1, hypothyroidism in 1, and GI bleeding in 1 patient) and four G4 side effects (thrombocytopenia in 1, diarrhea in 1, sinus tachycardia in 1, and multiple organ failure in 1 patient). Two deaths (G5) were associated with hepatic AEs. Regarding the response evaluation, there was no CR within 16 months of follow-up period and the median overall progression free survival duration was 2 months (95% CI, 1.6-2.5). The disease control rate was 38.8% (PR: 16.3% and SD: 22.5%). Median time to progression was 2 months (95% CI, 1.8-3.1 months). Of the patients, 31.9%, 22.2%, and 19.2% survived within 12, 24, and 30 months of follow-up period, respectively, and the median overall survival duration was 6 months (95% CI, 3.5-8.5). Conclusions: Ipilimumab treatment resulted in favorable clinical benefit for metastatic melanoma patients. Data generated by 13 centers revealed an efficacy and safety profile consistent with the currently available ipilimumab trials.
Ugly is not only skin deep: A case of osteogenic melanoma.
Authors: Williams Joshua C.M. , Sheehan Natale Tate , DeDelva Pierre , Barr Jennifer
Published: March 2020

e20009

Background: Although the incidence of malignant melanoma is high, the incidence of metaplastic malignant melanoma is low. Within the various subtypes of malignant metaplastic melanoma, the manifestation of osteogenic melanoma remains a rarer event. Current review of the literature reveals only 12 reported cases. Of these reported cases, scant discussion is made on treatment whereas the histopathology is discussed in great detail. Methods: We present the case of a 64 year old Caucasian man that was diagnosed with synchronous tumors of the foot and lung. Initial biopsy of the foot revealed metastatic osteogenic melanoma. As a result of the initial biopsy results and imaging, the patient underwent a right lower lobe resection and lymph node dissection followed by a left lower extremity Pirigoff’s amputation and inguinal lymph node dissection. Results: Immunohistochemical staining of the extirpated tissue from the lung revealed strong reactivity to S100, vimentin, Sox10, diffuse reactivity to low molecular weight cytokeratin and HMB-45/MART-1 and no lymph node involvement. Whereas the IHC of the extirpated tissue of the left foot remained consistent with the initial biopsy of strong reactivity to S100 and MART-1 and negative to pancytokeratins, CD34, Desmin, and SMA. Conclusions: Given the features of the patient’s pathology and resected metastatic disease, he was administered adjuvant alpha interferon therapy.
Acral melanoma in the Asian/Pacific Islander population: Analysis of +8q and 8q24 chromosomal aberrations.
Authors: Morita Shane Young , Kim Iris H. , Lum Christopher A.
Published: March 2020

e20029

Background: Acral melanoma (AM) is a distinct subtype of melanoma that displays a higher proclivity in the minority population. AM is associated with a worse outcome in comparison to conventional cutaneous melanoma (CM). Asian/Pacific Islanders with AM in particular, exhibit the poorest survival amongst all ethnic groups. Recent studies have profiled the importance of +8q and 8q24 as markers for an adverse prognosis in CM. However, a focused chromosomal analysis of minority patients with AM at this locus has not been previously described. Methods: IRB approval was obtained for this retrospective analysis. From 2004 to 2012, 14 Asian/Pacific Islander patients histologically confirmed to have invasive AM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, ulceration, and mitoses per mm squared were compiled. In situ hybridization was performed targeting the centromeric region of chromosome 8 (Vysis CEP 8-FITC) and the myelocytomatosis viral oncogene homolog locus (MYC; 8q24.12 q24.13, Vysis LSI-Spectrum Orange). The overall ratio of signals and individual spot counts for CEP8 and 8q24 was recorded. Results: Our findings demonstrated that +8q chromosomal aberrations were highly prevalent (8/14; 57%). The majority of our entire cohort (7/14; 50%) exhibited thick primary lesions (>4.0 mm) with a high propensity for ulceration. There were no copy number gains in 8q24. Demographics of the Asian/Pacific Islander cohort included mean age of 67.4 years old (range 43-86) and male gender 9/14 (64%). Tumor location principally involved the foot 11/14 (79%); mean Breslow thickness was 4.6 mm (range 0.9-11.0), ulceration 7/14 (50%), and mean mitoses per mm squared was 3.4 (range 0-9). Conclusions: Asian/Pacific Islanders with AM were found to have a high frequency of +8q chromosomal alterations. There appeared to be an association with a thicker Breslow and presence of ulceration. This is the first study to our knowledge that has examined chromosomal aberrations of +8q and 8q24 in a non-Caucasian population of AM patients. This is compelling data that may be applied to future prognostic classifications.
Association of increased body height with BRAF mutations in male melanoma patients.
Authors: Maubec Eve , Geay Maria , Regnier-Rosencher Elodie , Fite Charlotte , Boitier Francoise , Kramkimel Nora , Chrisment Di Lucca Julie , Carlotti Agnes , Deschamps Lydia , Marinho Eduardo , Couturaud Benoit , Albert Sebastien , Kalampokas Athanasios , Sastre Xavier , Rouleau Etienne , North Marie- Odile , Lamoril Jerome , Crickx Beatrice , Dupin Nicolas , Avril Marie-Françoise
Published: March 2020

e20032

Background: Somatic BRAF mutations occur in approximately 40-50% of patients (pts) with unresectable cutaneous melanoma (CM) and are more common in young pts. The objective of this study was to determine if body height and body mass index (BMI) are associated with BRAF mutation status. Methods: 212 consecutive BRAF-tested patients with unresectable stage IIIC or IV CM were analysed. Tumor samples from two departments of dermatology were screened by high-resolution melt curve analysis of BRAF exon 15; abnormal results were confirmed by DNA sequencing. Associations between BRAF mutation status and height, BMI and age of pts were examined using univariate and multivariate logistic regression analyses in the whole sample and according to sex. Results: The BRAF mutation frequency was 42%. On univariate analysis in the whole sample, BRAF mutated status was not associated to BMI (p=0.9) but was associated to age and height (p≤0.027). The BRAF mutation frequency was higher in taller pts reaching 59% in pts > 180 cm (p=0.003, χ² test). According to sex, this association was significant in males (p=0.004) but not in females (p=0.39). Size did not differ significantly in the 4 quartiles groups of age (<50, 50-62, 62-72 and >72 years; p >0.07). On multivariate analysis, in the whole sample, only age was associated to mutated BRAF status (p<0.001); but in the male subgroup, age and height were independent factors predicting BRAF mutations (p<0.04). Conclusions: Tallness was significantly associated with BRAF mutations in male melanoma pts. This is in agreement with published data for colorectal carcinoma. This study might suggest a genetic susceptibility to somatic BRAF mutations, increased height and melanoma. [Table: see text]
Impact of survival on health care charges during melanoma treatment.
Authors: Brixner Diana I. , Bellows Brandon Kyle , Dahal Arati , Stenehjem David D.
Published: March 2020

e20043

Background: Treatment charges increase during the last year of life in patients with melanoma, but it remains unknown if charges differ between patients who die during treatment and survivors. The objective of this study was to examine annualized mean charges by melanoma survival status. Methods: The University of Utah Enterprise Data Warehouse was used to analyze patients ≥18 years with a diagnosis of melanoma identified by ICD-9 code (first diagnosis defined as index date) treated at the Huntsman Cancer institute (HCI) from 2002-2010. The HCI tumor registry was used to determine stage at diagnosis and other cancer diagnoses. Cause and date of death was captured from the Utah Population Database. Cancer-related (CR) and non-CR charges were assessed by ICD-9 codes from index date until death or end of the follow-up period, were weighted by the inverse probability of survival, and annualized. Generalized linear models (GLM) with gamma distribution and log link function were used to examine charges by survival status, adjusting for baseline characteristics including demographics, disease stage, and comorbidities. Results: A total of 1205 patients were included, of which 218 (18%) died. Compared to alive patients, deceased patients were older (60 vs. 56), more female (40% vs. 28%), more were diagnosed with stage IV disease (19% vs. 3%), and less with stage I disease (26% vs. 66%) (all p≤0.001). Mean unadjusted annualized charges were not significantly different between the two groups for CR charges (deceased $15,109 vs. alive $14,519; p=0.89), but non-CR charges were higher for deceased patients ($77,390 vs. $18,719; p<0.001). GLM results indicated deceased patients, relative to survivors, had 59% higher annualized CR charges (p<0.001) overall, with higher CR charges at stages I and II (86% and 76%, respectively; both p<0.001), and lower CR charges at stage IV (-127%; p<0.001). Death was associated with 154% higher annualized non-CR charges (p<0.001) at stages I, II, III, and IV (210%, 167%, 119%, and 73%, respectively; all p<0.05). Conclusions: When adjusting for confounders, deceased melanoma patients had higher charges overall compared to melanoma survivors. The exception was for decreased CR charges in stage IV, most likely related to earlier death.
Something to sing about: A global choir of cancer survivors—Building bridges.
Authors: Donnellan Paul P. , Gill Donal , Hynes Deanna , Gallagher Olive , Leonard Seamus
Published: March 2020

e20505

Background: 68% of cancer patients live at least 5 years after diagnosis and many are cured. Cancer survivors continue to need support. Music is energising, affirming and therapeutic. More funds are needed for cancer research so that more patients become long-term survivors. In 2012 Galway University Hospital founded 'Something To Sing About' (STSA.ie), a not-for-profit organisation to support cancer survivors and cancer research. Methods: Local publicity brings small bands of cancer survivors together rehearsing the same music at the same time every week (Wednesday 7pm) in a local hall, hospital or hotel, each with its own local musical director. The music is selected by a representative music committee and music therapist. Musical instruction is disseminated by the chief musical director via website and social media. A plenary rehearsal takes place every 3 months. All profits from events and music sales are allocated to cancer research projects through an open peer-reviewed grant-application process. Results: In 6 months STSA has grown from concept to network of 20 centres with total membership of 251 cancer-survivors. Immediate feedback has been extremely positive as assessed by personal communication and facebook activity (currently 1,025 ‘likes'). Over 100 singing-survivors participated in the first plenary rehearsal. All commercial venues have donated their meeting rooms gratis. Internationally there is one participating centre in Brisbane, Australia, with others signalling their intention to join in 2013 including: Memorial Sloan Kettering Cancer Center, New York; 14 breast cancer support centres in UK; and one centre in the Czech Republic (updated at meeting). STSA members are particularly keen on establishing links with other cancer patients abroad. Professional musicians are pledging support and suggesting fund-raising collaborations. Conclusions: Cancer survivors continue to need ongoing support and find the music therapy and group therapy provided by STSA most beneficial. Cancer survivors are very interested in supporting cancer research. STSA has the potential to become a major international cancer support network and cancer research foundation.
Denosumab for the treatment of bisphosphonate-refractory hypercalcemia of malignancy (HCM).
Authors: Hu Mimi I-Nan , Glezerman Ilya , Leboulleux Sophie , Insogna Karl L. , Gucalp Rasim A. , Misiorowski Waldemar , Yu Bennett Winston , Zorsky Paul , Tosi Diego , Bessudo Alberto , Jaccard Arnaud , Tonini Giuseppe , Wang Huei , Braun Ada , Jain Rajul K.
Published: March 2020

e20512

Background: HCM, caused primarily by tumor-induced bone resorption, is treated with intravenous (IV) bisphosphonates (BisP), but patients (pts) can relapse or become refractory. Denosumab binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption. Methods: In this single-arm, open-label, proof-of-concept study, pts with HCM (corrected serum calcium [CSC] >12.5 mg/dL [CTCAE grade ≥3]) despite IV BisP treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 28, then every 4 weeks. The primary endpoint was the proportion of pts with CSC ≤11.5 mg/dL (CTCAE grade ≤1) within 10 days of denosumab initiation. Results: The study enrolled33 pts (64% men; mean age 60 years; 76% with advanced solid tumors, 39% with bone metastases [BM]), with a median (25th, 75th percentile [Q1, Q3]) follow-up of 56 (18, 79) days. Median (Q1, Q3) baseline CSC was 13.7 (13.2, 14.2) mg/dL; 19 pts (58%) had HCM symptoms. Median (Q1, Q3) time from last BisP treatment to first dose was 17 (13, 22) days. At day 10, 21 pts (64%) reached CSC ≤11.5 mg/dL, including 54% of pts with BM and 70% without BM. Over the course of the study, 23 pts (70%) reached CSC ≤11.5 mg/dL, by a median (95% confidence interval [CI]) of 9 (5–19) days. A complete response (CSC ≤10.8 mg/dL, as defined by previous studies) occurred in 12 pts (36%) at day 10, and in 21 pts (64%) during the study, by a median (95% CI) of 23 (11–43) days. Among pts who reached CSC ≤11.5 mg/dL, the median (95% CI) duration of response was 104 (9–not estimable) days. The most frequently reported serious adverse events were worsening of HCM (5 pts, 15%) and dyspnea (3 pts, 9%). Two pts had isolated episodes of CSC levels ≤8.0 mg/dL (CTCAE grade 2); no pts had CSC <7.0 mg/dL (grade 3). No osteonecrosis of the jaw was reported. Conclusions: In this study of pts with HCM despite recent IV BisP treatment, denosumab effectively lowered serum calcium to grade ≤1 in 64% of pts within 10 days, and induced durable responses. These findings are particularly meaningful given that pts entered this study with grade ≥3 HCM within a median 17 days after receiving IV BisP. No unexpected safety findings were identified. Denosumab may offer a new treatment option for HCM in these pts. Clinical trial information: NCT00896454.
Follow-up study of a randomized clinical trial with quality of life diagnosis and therapy: Long-term quality of life of breast cancer survivors.
Authors: Klinkhammer-Schalke Monika , Lindberg Patricia , Steinger Brunhilde , Koller Michael , Wyatt Jeremy , Hofstädter Ferdinand , Lorenz Wilfried
Published: March 2020

e20517

Background: To improve breast cancer patients` quality of life (QoL) as second relevant outcome of care, a clinical pathway with diagnosis and therapy of diseased QoL has been developed, implemented and tested in a randomized trial (RCT) as part of a complex intervention. More than 6 years after RCT, long-term QoL of survivors was assessed and separately analyzed in 2 cohorts: QoL-intervention + guideline treatment in the first postoperative year (GC+) and guideline treatment alone (GC). Methods: Both cohorts were part of a randomized trial with 2 x 100 primary breast cancer patients, surgically treated between 2004 - 2006, with QoL measurement every 3 months during the first year (EORTC QLQ-C30, BR23). In GC+ cohort, QoL was presented to coordinating physicians in a QoL-profile, including recommendations for treatment of diseased QoL (cutoff <50 points on scale 0 = bad, 100 = good) in 10 dimensions (global QoL, physical, role, emotional, cognitive, social functioning, arm symptoms, body image, pain, fatigue) and up to 5 targeted therapies to improve QoL. GC was treated according to S3 guideline. At follow-up >6 years after diagnosis (range of months since surgery: GC+ 74-94; GC 74-96), rates of diseased QoL in both cohorts were analyzed and compared with QoL 12 months postoperatively. Results: Long-term QoL was assessed in 66 patients of GC+ (mean age 64.7 (±10.9)) and 67 of GC (mean age 63.7 (±10.9)) (death GC+=13, GC=18; response rate 79%). In GC+, 48% of patients reported at least 1 QoL deficit at 12 months compared with 52% at 6-year follow-up, while in GC rate of diseased QoL increased from 53% to 62%. Regarding single dimensions, in GC+ rates of diseased QoL increased from 12 months to 6 years (except global QoL), reaching significance for arm symptoms (9% vs 29%) and body image (3% vs 16%) (p<.01, McNemar`s test). In GC no dimension changed significantly, but rates of diseased QoL for arm symptoms (26% vs 31%) and body image (9% vs 17%) were already rather high at 12 months. Conclusions: Breast cancer patients need tailored QoL therapy, exceeding the first postoperative year. Similar to traditional medical care, QoL needs to be considered continuously by anchoring it in follow-up care.
Pharmacokinetics (PK), tolerability, and efficacy of APF530 in patients receiving moderately (MEC) and highly (HEC) emetogenic chemotherapy: Phase II trial results.
Authors: Gabrail Nashat Y. , Yanagihara Ronald H. , Cooper William , O'Boyle Erin , Smith Carrie L. , Spaczynski Marek
Published: March 2020

e20518

Background: Up to 30% of patients continue to have chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 PK, tolerability, and efficacy were studied in two open-label, single-dose trials (1 US, 1 EU) in patients receiving MEC or HEC. Methods: In the US study, 45 patients received 250, 500, or 750 mg APF530 SC (5, 10, or 15 mg granisetron, respectively). In the EU study, 35 patients were randomized to 250 or 500 mg APF530 SC. Injections were given 30 to 60 minutes before single-day MEC or HEC. Plasma granisetron was measured from pre-dose to 168 hours. Safety, tolerability, and efficacy were also evaluated. Results: APF530 PK was dose proportional with slow absorption and elimination of granisetron after a single SC dose. Median tmax, exposure, and t1/2were similar for 250 and 500 mg APF530 in both trials, with no differences between MEC and HEC groups. Adverse events in both trials were as expected for granisetron; injection-site reactions (eg, erythema, induration), predominantly mild, were seen in ≤ 20% of patients. Complete responses (no emesis, no rescue medication) were obtained in ≥ 80% and ≥ 75% of patients in both trials with the 250- and 500-mg doses, respectively. Conclusions: APF530 showed dose-proportional PK and sustained concentrations of granisetron over 168 hours. The 250- and 500-mg doses were carried into phase III; both were well tolerated, and maintained therapeutic granisetron levels for ≥ 5 days. Clinical trial information: 2007-005068-29. [Table: see text]
Phase II randomized, placebo-controlled trial of phytotherapeutic product Catuama for breast cancer women undergoing adjuvant radiation therapy.
Authors: Cruz Felipe Melo , Cubero Daniel de Iracema Gomes , Santi Patricia Xavier , Landeiro Luciana Garcia , Tamashiro Andressa Sayuri , Ribeiro Larisse Soares , Del Giglio Auro
Published: March 2020

e20524

Background: Fatigue and Depression are common in patients undergoing Breast Cancer (BC) treatment. Catuama is a registered phytotherapic that contains 4 brazilian herbs per capsule: Trichilia catigua (87.5mg), Ptychopetalum olacoides (87.5mg), Paullinia cupana (125 mg) and Zingiber officinale (10mg). Objectives: Since one of its constituents is Guarana (Paulinia cupana) which we already reported to have anti-fatigue effects, we decided to test Catuama potential anti-fatigue effects in BC women undergoing adjuvant 4 weeks of Radiation Therapy (RxT). Methods: This is a double blinded, randomized, placebo-controlled, Phase II cross-over trial. Patients with histologically proven BC with the indication of adjuvant RxT, non-pregnant nor breastfeeding, older than 18 years of age, with ECOG PS 0 or 1, without a history of cardiac, renal, hepatic or psychiatric decompensation, received Catuama 1 capsule twice daily versus a matching placebo for the first 2 weeks of RxT treatment, followed by a week of wash out, followed by an additional two weeks of treatment with crossover of experimental arms. Patients were evaluated on days 1, 15 and 36 with the Brief Fatigue Inventory (BFI), Hospital Anxiety and Depression Scale (HADS), Quality of Life FACIT-F, FACIT-ES questionnaires, and Chalder Fatigue scale. Results: We enrolled 90 patients with a median age of 53 years (26 – 80). We saw no statistically significant differences of FACIT ES, FACIT F, HADS, Chalder or BFI scores treated with Catuama or Placebo when we considered all included patients. When we selected only patients with a BFI score above 30, Catuama significantly decreased BFI scores as compared to baseline (p<0.0001). We observed one instance of grade 3 hypermagnesemia in the Catuama arm and one patient had hyperglicemia grade 3 both in the Catuama and in the placebo arm. No grade 4 toxicities were seen. Conclusions: Catuama may help selected patients who already start RxT with evidence of fatigue.