bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cumulative corticosteroid exposure in patients experiencing checkpoint inhibitor toxicity.
Authors: Mir Romaana , Shaw Heather May , Kuhan Hariharan , Bataille Veronique , Vergis Roy , Corner Carie , Nathan Paul D. 
Published: September 2018

e21010 Background: Despite significant gains from systemic immunotherapy, prompt recognition and management of immune related adverse events (irAEs) remains key to minimising acute and chronic morbidity, and can sometimes allow treatment to be re-initiated. Active management of irAEs is corticosteroid based, with additional immunosuppressants used for steroid-refractory toxicity. Although the majority of irAEs resolve promptly, prolonged steroid exposure is required to maintain irAE control. Patients are therefore frequently exposed to cumulative high doses of steroids that in turn can be associated with significant long-term morbidity. Methods: Melanoma patients treated at Mount Vernon Cancer Centre (UK) with ipilimumab, pembrolizumab or combination ipilimumab and nivolumab; who were managed for checkpoint inhibitor-induced colitis had their corticosteroid exposure calculated. Data was collected on patient characteristics, onset of colitis and the subsequent use of corticosteroids, immunosuppressant and anti-TNFα agents until complete resolution of symptoms. Results: Of 137 patients, 18 (13.1%) had grade 3-4 colitis. Median time to onset of colitic symptoms was 13 days (IQR 7-20) with 8 (44%) requiring intravenous corticosteroid. Median time from commencement of steroid treatment to grade 1 colitis was 11.5 days (IQR 6.75-25.25), with resolution of symptoms seen at a median of 43 days. Median total corticosteroid exposure was 3000mg oral prednisolone equivalent (range 540-7580mg) with median duration of corticosteroid exposure being 103.5 days (IQR 67-136). 8 patients experienced flare of colitis during corticosteroid dose reduction. In all cases of colitis flare, the anti-TNFα agent infliximab resulted in improvement to grade 1 toxicity within 48 hours. Conclusions: Patients requiring treatment with corticosteroids for checkpoint inhibitor induced colitis are exposed to high doses of corticosteroids for prolonged periods of time, with the potential for significant steroid-associated sequelae. Alternative steroid-sparing regimens to manage checkpoint inhibitor induced autoimmune toxicities are required.
Real world treatment patterns of first-line combination therapies among patients with metastatic melanoma and BRAF mutation.
Authors: Qiu Ying , Li Zhiyi , Tang Jackson , Atanasov Pavel , Mahmood Syed , Grzegorzewski Kris , Chen Lei , Chen Joyce S 
Published: September 2018

e21011 Background: First line (1L) systemic combination (combo) therapies for treatment of metastatic melanoma (MM) include targeted combo therapies such as dabrafenib+trametinib (D+T) or vemurafenib+cobimetinib for patients (pts) with BRAF mutation (BRAF+), or immunotherapy combo ipilimumab+nivolumab (I+N) for pts irrespective of BRAF status. The objective of this study was to describe real world characteristics and treatment patterns among BRAF+ mm pts who were treated with either D+T or I+N as 1L therapy. Methods: This retrospective observational study utilized Flatiron Health’s electronic health record (EHR) data from Jan 2013 to Jul 2016. Pts were aged ≥18 years with a mm diagnosis, and treated with either D+T (N = 86) or I+N (N = 61) as 1L therapy. Prior to therapy initiation, 86/86 of D+T pts were tested BRAF+. 55/61 of I+N pts completed BRAF testing and 19/61 were BRAF+. All analyses focused on BRAF+ pts who were treated with either D+T or I+N as 1L therapy. Baseline characteristics, treatment patterns and data on therapy discontinuation were collected from structured data in patient records and unstructured data in physician notes, and were descriptively assessed. Statistical inferences were not drawn due to sample size limitations. Results: At baseline, 35% of D+T pts vs 32% of I+N pts had brain metastasis, 29% of D+T pts vs 11% of I+N pts had high LDH levels, and 20% of D+T pts vs 42% of I+N pts reported ECOG = 0 status. The median follow-up time was 219 days for the D+T pts vs 150 days for the I+N pts. The 3 and 6 month discontinuation rates were 9% and 24% for the D+T pts vs 21% and 47% for the I+N pts. 13% of D+T pts vs 26% of I+N pts discontinued treatment citing toxicity in physician notes. Among pts with brain metastasis, the 3 and 6 month discontinuation rates were 3% and 20% for D+T pts vs 33% and 50% for I+N pts. Conclusions: Among BRAF+ mm pts who were treated with either D+T or I+N as 1L therapy, D+T pts were more likely to have advanced disease such as brain metastasis and high LDH levels than I+N pts. Compared with 1L D+T pts, 1L I+N pts had higher discontinuation rates due to toxicity, even with a shorter median follow-up time. 1L I+N pts with brain metastasis also had higher discontinuation rates.
Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.
Authors: de Moraes Rafael Vanin , Salgado Boneti Bianca , De Barros E. Silva Milton Jose , Cordeiro De Lima Vladmir Claudio 
Published: September 2018

e21022 Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected Results: 54 patients with histologiacally confirmed mm were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being < or > the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or > 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT > 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT > 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH > ULN and pooled TBT > 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or > 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.
Gene-signature based prediction of relapse-free survival in melanoma patients with known sentinel lymph node status.
Authors: Gambichler Thilo , Reinhold Uwe , Tsagoudis Konstantinos , Bierhoff Erhard , Dirschka Thomas , Sülberg Heiko , Borowski Matthias , Hinke Axel , Brunner Georg , Stockfleth Eggert 
Published: September 2018

e21037 Background: Staging of cutaneous melanoma (CM), as defined by the American Joint Committee on Cancer (AJCC), includes determination of the sentinel lymph node (SLN) status as a major prognostic factor. We have previously identified and validated a gene expression risk score (GRS) in primary CM and adjacent stroma, consisting of 7 protective genes and 1 risk-associated gene, which predicts patient survival, independently of AJCC stage. This external validation study evaluated single and combined performance of GRS and SLN in predicting relapse-free survival (RFS). Methods: The study cohort included 203 formalin-fixed, paraffin-embedded (FFPE) -primary CMs (AJCC stages IA-IIIC, n=31 RFS events). Tissue samples and clinical data were provided by two centers, and gene expression was determined externally using real-time RT-PCR (double-blind study). External prospective data analysis followed a pre-specified protocol. Results: Integration Discrimination Improvement (IDI) analysis demonstrated non-inferiority of GRS vs. SLN status in predicting RFS (IDI estimate=-0.8%, p=0.040). In univariate Cox regression analysis, GRS and SLN status predicted RFS (GRS: p=0.011, HR=2.44 [1.2-4.95]; SLN: p=0.038, HR=2.12 [1.03-4.38]). Multivariate Cox regression demonstrated independent contribution of prognostic information by both parameters (GRS: p=0.015, HR=2.40 [1.18-4.89]; SLN: p=0.046, HR=2.11 [1.02-4.37]. IDI analysis demonstrated that combining GRS and SLN status improved prognostic performance, as compared to SLN status alone (IDI estimate=3.2%, p=0.044). When complementing SLN status with GRS (SLN positive or high GRS), sensitivity of relapse detection increased from 38.7% for SLN alone to 67.7%. Conclusions: GRS is a non-invasive predictor of RFS, complementary to SLN analysis. Combining GRS and SLN status significantly improves accuracy of melanoma prognosis and, therefore, may guide follow-up care as well as treatment decisions regarding new adjuvant therapies, e.g. of SLN positive patients with high GRS. [Table: see text]
Risk factors of fast growing melanomas in a French prospective cohort.
Authors: Gaudy Marqueste Caroline , Troin Laura , Malissen Nausicaa , Loundou Anderson , Monestier Sandrine , Mallet Stéphanie , Hesse Sylvie , Magis Quentin , Richard Marie-Aleth , Grange Florent , Grob Jean-Jacques 
Published: September 2018

e21042 Background: Rate of growth (ROG) of the primary tumor is a known prognostic factor in melanoma (MM). Fast growing melanomas (FGMM) could account for an important part of the thick tumors which still exist despite earlier and earlier detection. Methods: All patients referred for a primary mm to two French Dermatology Department from the period 2012-2016 were prospectively enrolled in an observational case control study. ROG was calculated as the ratio of Breslow thickness to time to mm development according to patient, following a well-established process. FGMM were defined as those with a ROG > 0.5 mm/month and MMs with a ROG ≤05mm/month were used as controls. Differences in epidemiological, clinical and pathological features were evaluated with univariate and multivariate analysis. Results: 464 patients were enrolled. 149 mm (32.1%) were FGMM. Factors associated with FGMM in univariate analysis were age > 70 years (p = 0.006), tumor location (p = 0.032), histological subtype (p = 0.021), median thickness (p < 0.001), ulceration (p < 0.001), high mitotic rate ( > 1/mm2 )(p = 0.002), sentinel node involvement (p = 0.008), hair color at the age of 20 (p = 0.011), lower NSAIDS consumption (p = 0.012) and lower number of sunburns (p = 0.002). Age > 70 years (OR 1.88 95%CI 1.19-2.98, p = 0.007), ulceration (OR 3.70 95%CI 2.05-6.61) p < 0.001), sentinel node involvement (OR 1.93 95%CI 1.01-3.69 p = 0.046), regression (OR 0.37 95%CI 0.15-0.94) p = 0.037) and NSAIDS exposure (OR 0.29 95%CI 0.11-0.78, p = 0.014) remained associated with FGMM in multivariate analysis. OS and PFS were significantly lower in the FGMM group (HR 1.98 (95%CI 1.11-3.54, p = 0.02) and HR 1.79 (95%CI 1.17-2.73, p = 0.007), respectively). Conclusions: Fast growth characterizes a subset of primary mm which are intrinsically more aggressive and have different risk factors than other MM, namely more frequent in the elderly and with no association with skin type, nevus count or sun exposure. Association with ulceration could reflect a specific immune context. Negative association with NSAIDS exposure warrants more investigation, since it may have therapeutic implications.
Genomic profiling of melanomas of unknown primary.
Authors: Wells Keith Ryan , Hintzsche Jennifer , Amato Carol M , Robinson William 
Published: September 2018

e21048 Background: Approximately 2-10% of metastatic melanoma patients present without an identifiable primary melanocytic lesion. These melanomas of unknown primary (MUP) are clinically classified into stage III or stage IV based upon extent of spread of metastatic disease. Previous studies, evaluating MUP using a limited sequencing of BRAF, NRAS, and KIT, have shown a similar frequency of mutations as cutaneous samples. Methods: We identified and performed retrospective chart review on 43 patients treated at the University of Colorado who presented with a melanoma of unknown primary. We excluded patient who presented with a preceding pigmented lesion treated with excision or cryotherapy without a histological diagnosis. After informed consent, DNA was extracted from the tumor samples of these 43 patients. Whole exome sequencing (WES) was performed with exome capture on an Illumina HiSeq sequencer. Results: Our cohort showed a male predominance at 58.1%. The median age at diagnosis was 50.6 years. In our cohort, 93% were Caucasian, while 4.7% were Hispanic and 2.3% were of unknown ethnic origin. 9.3% of patient had a family history of melanoma. Sun exposure was documented in 39.5% of patients and its presence was associated with an increased survival (Median OS of 3.7 vs 1.3 years, p = 0.026). Patients with stage III melanoma had an increased survival (Median OS of 6.8 vs 1.3 years, p = 0.013). Genomic analysis showed mutational pattern similar to cutaneous melanoma with 50% harboring a BRAF mutation, 12% with an NRAS mutation, and 19% carrying an NF1 variant. We found mutational signatures for each tumor and classified each against a larger cohort of cutaneous, mucosal and acral melanomas. Conclusions: We present the genomic data of a large cohort of MUP. The mutational profile of MUP is consistent with other cutaneous melanomas.
Photoacoustic detection of circulating melanoma cells as a predictor of metastasis in stage III patients.
Authors: Viator John Andrew , Sanders Martin , Tarhini Ahmad A. , Sander Cindy , Edgar Robert Hugh , Goldschmidt Benjamin ,   Viator
Published: September 2018

e21053 Background: Circulating tumor cells have been correlated with disease state and distant metastatic spread in cancer patients. We postulated that enumerating circulating melanoma cells (CMCs) may predict the onset of distant metastasis in Stage III patients. We detected CMCs using our photoacoustic flow cytometer, in which we irradiated enriched blood samples with nanosecond pulsed laser light. While there is no effect on non-optically active leukocytes, absorption of laser light by pigmented melanoma cells resulted in robust ultrasonic waves that indicated CMCs in the sample. Methods: We tested 32 archived samples from 9 Stage III melanoma patients using our photoacoustic flow cytometer. Each patient had between 2 and 6 serial blood samples. We used a pulsed Nd:YAG laser to irradiate mononuclear cells in suspension and under flow. The number of CMCs detected after testing was recorded, indicating the time sequence of circulating tumor cell activity. Results: The numbers of CTCs for each sample is shown in the table below. The ultimate disease state, whether the patient became metastatic or not, was blinded to the investigators who performed the photoacoustic tests. One sample for patient 3 indicated 63 CMCs, though this test was known to be contaminated and had an unknown number of false detections. Conclusions: We found that patients who had a series of more than 4 CMCs were more likely to become metastatic than those patients who tested for 4 CMCs for fewer, indicating that a sequence of CMC detections in serial blood draws provides a potentially strong predictor of metastasis in Stage III melanoma patients warranting further investigation at this and lower stages of melanoma. We are developing a more rigorous model based on time series analysis of CMCs for prediction of metastasis. [Table: see text]
Assessment of treatment response to immunotherapy in melanoma patients with pathogenic mutations of NRAS, BRAF, CDKN2A and P53.
Authors: DeLeon Thomas , Kipp Benjamin , Langlais Blake , Flotte Thomas , Winters Jennifer , Kosiorek Heidi E. , Joseph Richard Wayne , Markovic Svetomir , Dronca Roxana Stefania , Block Matthew Stephen , McWilliams Robert R. , Kottschade Lisa A. , Borad Mitesh J. , Rumilla Kandelaria M. , Voss Jesse S , Bryce Alan H. 
Published: September 2018

e21057 Background: BRAF, NRAS, CDKN2A and P53 mutations are commonly observed pathogenic mutations in cutaneous melanoma. The influence of mutations such as BRAF, NRAS, CDKN2A and P53 on treatment response in the PD1 inhibitor era has not been well defined. Methods: This study included patients with melanoma with a cutaneous or unknown primary. All patients had genomic profiling with the Mayo Clinic 50-gene solid tumor mutation panel. Treatment response to first line immunotherapy with PD1, CTLA-4, or combination PD1/CTLA-4 inhibitors were assessed by response rate and time-to-progression (TTP) rate at 12 months. Each patient outcome was stratified by non-mutually exclusive gene mutation status into BRAF, NRAS, P53, CDKN2A, or quadruple negative (N4) groups. Results: Genomic profiling was performed on 208 patients, of whom 102 received first line immunotherapy. Most patients received a PD1 inhibitor (n = 62), followed by CTLA-4 inhibitor (n = 34), and combination therapy (n = 6). A trend towards improved outcomes was observed in CDKN2A and BRAF mutated patients with worse outcomes noted in P53, N4, and NRAS patients. The percent without progression at 12 months were BRAF 52.2%, CDKN2A 58.2%, NRAS 30.5%, P53 37.7%, and N4 26.7% (see table below). Response rates were BRAF 46.4%, CDKN2A 38.5%, NRAS 22.2%, P53 40.0%, and N4 33.3%. Conclusions: There is a trend towards improved outcomes with immunotherapy in BRAF and CDKN2A mutated patients while P53, NRAS and N4 patients have inferior outcomes. [Table: see text]
Burden of Merkel cell carcinoma: A targeted literature review.
Authors: Narayanan Siva , Gala Smeet 
Published: September 2018

e21073 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer characterized by high incidence of local recurrences, regional nodal metastases, distant metastases, and high mortality rates. It has no approved drug therapies and limited treatment options, especially to manage the metastatic disease. Our objective was to conduct a comprehensive review of MCC disease burden. Methods: We conducted a targeted literature review of studies published from 2010 to 2016 to assess epidemiology, patient burden, and unmet needs associated with MCC. An article was retrieved for full review if the abstract met each of the following criteria: reported incidence, natural morbidity or mortality of MCC; derived from a peer-reviewed journal; and reported in English-language published since January 2010. Results: The incidence of MCC (per 100,000 persons per year) is reported highest in Australia (0.82-1.60), followed by the US (0.6), Netherlands (0.35), Sweden (0.18-0.33), Finland (0.24-0.25), Spain (0.28), Denmark (0.22), South East Scotland (0.133), France (0.13). Inadequate data available from countries like Canada, UK, Germany and most part of Asia-Pacific. Typically, stage I-II MCC is observed in approximately 60% - 75% patients, stage III in 10% - 30% patients, and stage IV (metastatic) in 2% - 16% patients. The 5-year and 10-year survival is 0% - 68%, and 21% - 65% respectively, based on factors such as disease stage and gender. Although less than 20% patients progress to advanced metastatic stage IV MCC, they experience the highest unmet need due to lack of effective therapeutic options. Data on economic burden and humanistic burden (e.g., impact on patient quality of life) is not available. Conclusions: Epidemiological review indicates an increasing incidence of MCC; however, available estimates are at least 5 years old. Epidemiological data as well as data on clinical, economic and humanistic burden of MCC is lacking from several parts of the world. Further research is warranted to adequately quantify the burden-of-illness of MCC and assess comparative effectiveness of evolving treatment options to better inform patients, prescribers and payer organizations concerning optimal cost-effective modalities of disease management.
End-of-life chemotherapy and adherence to ASCO’s Top Five List recommendations: A single-center retrospective review.
Authors: Tancredi Richard , Stefani Sara , Gervaso Lorenzo , Fregoni Vittorio , Poojary Priti , Cefalì Marco , Piacentini Giulia , Riccardi Alberto 
Published: September 2018

e21509 Background: End-of-life palliative chemotherapy does not improve quality of life nor does it prolong survival of terminal cancer patients. On the contrary, it is related not only to increased health costs, but also to severe therapy related side effects and to patient and caregiver distress. The first point of the ASCO’s Top Five List, released in 2012, tried to address the issue of chemotherapy overuse near the end of life. We tried to determine the aggressiveness of end of life care at our Institute by evaluating the number of patients who received end-of-life chemotherapy. We also aimed to verify whether the recent ASCO recommendations were followed or not. Methods: Electronic medical records were examined to identify patients who received at least one cycle of palliative chemotherapy and who died either in the Oncology or in the Palliative Care unit of the ICS Maugeri hospital between January 2014 and December 2015. Results: 181 patients were included in the study. 22% (40 patients) of these received chemotherapy in the last 4 weeks, and 6% (10 patients) in the last 2 weeks of life. 45% (18) of patients who were actively treated in the last month of life began a new chemotherapeutic regimen within the same period of time. Recently diagnosed patients were more likely to be treated aggressively in their last weeks of life (chi-square test, p value = 0.007). 12% of patients (7 patients) who started a new chemotherapeutic regimen within 90 days of death had already received 3 or more previous regimens. Futhermore, 16% of them (19 patients) had an ECOG PS of 3 or 4 at the beginning of the last regimen. The median survival since the beginning of the last chemotherapeutic regimen was 63 days for patients with a PS of 1 or 2 and 32 days for patients with a PS of 3 or 4 (Logrank test, p = 0.005). Conclusions: Almost 1 patient out of 4 receives end-of-life chemotherapy at our institute. About 30% of our patients began a new chemotherapeutic regimen even though they were in compromised clinical conditions or did not respond to 3 or more previous regimens. Our data highlight a relevant abuse of active anticancer treatments; efforts should be done to reduce these figures and to focus on supportive care near the end of life.