bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of cytokine-induced plasticity in melanoma on invasive, therapy-resistant cells that express EMT-related genes and pathways.
Authors: Cebon Jonathan S. , Anaka Matthew , Hudson Christopher , Lo Pu-Han , Davis Ian D. , Vella Laura J , Jayachandran Aparna , Behren Andreas
Published: March 2020

8542

Background: The acquisition of new mutations can explain resistance to targeted therapies; however resistance also develops without demonstrable new mutations. To better understand potential mechanisms for treatment failure we studied subpopulations of chemo-resistant cells that can be identified in early passage cell lines and the cellular plasticity that yields these. Methods: Melanoma subpopulations were identified and sorted on the basis of functional assays. Gene expression was evaluated with Illumina HT12 arrays and qPCR to identify potential mechanisms and targets. Sorted cells were evaluated in vitro for the induction of phenotype switching and effects of target inhibition. Results: A subset of slow proliferating label-retaining cells (LRC) was identified using a membrane dye. Direct isolation of LRC from a pt showed these were not an in vitro artefact. LRC isolated from multiple cell lines comprised the majority of cells that resisted cytotoxic drugs and could invade through an artificial extracellular membrane. Gene expression profiling identified a network of over-expressed genes related to epithelial-to-mesenchymal transition (EMT) notable for the expression of Thrombospondin-1 (TSP-1), Transforming-Growth Factor, Beta Induced, (TGFBI) and other extracellular matrix molecules. Initial studies show that LRC shared gene expression characteristics with PLX4032-resistant cells. Although interrogating LRC by qPCR showed up-regulation of the putative melanoma stem cell marker ABCB5 and the lysine specific demethylase Jarid1B, cell sorting and serial re-labelling experiments revealed a dynamic and interchangeable phenotype for these cells, challenging the hierarchical stem cell model for melanoma. The observed slow-cycling and chemo-resistant phenotype could be induced in vitro through TGF beta-mediated phenotype switching and cellular invasion was blocked using an antibody against TSP-1. Conclusions: Cytokine-induced plasticity in melanoma yields invasive, therapy-resistant cells which express EMT-related genes and pathways. We hypothesize that these cells are a source of treatment resistance in vivo and blocking their emergence may prevent treatment failure.
Ipilimumab in the treatment of uveal melanoma: The Memorial Sloan-Kettering Cancer Center experience.
Authors: Khan Shaheer A. , Callahan Margaret , Postow Michael Andrew , Chapman Paul B. , Schwartz Gary K. , Dickson Mark Andrew , D'Angelo Sandra P. , Luke Jason John , Bluth Mark J. , Roman Ruth Ann , Montefusco Mary , Barker Christopher Andrew , Abramson David H. , Wolchok Jedd D. , Carvajal Richard D.
Published: March 2020

8549

Background: Ipilimumab (ipi) is an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) and improves overall survival in patients (pts) with metastatic melanoma. Uveal melanoma (UM) is a rare and biologically unique disease subtype with no known effective systemic therapy. Ipi has proven efficacy in cutaneous melanoma (CM), but limited data exists regarding its activity in UM. We reviewed our single-institutional experience with ipi in advanced UM. Methods: After IRB approval, the MSKCC melanoma database was queried for patients with metastatic UM treated with ipi between 03/08-01/12. Radiographic response by RECIST and immune-related response criteria (irRC) was assessed by a single radiologist blinded to clinical outcomes. Immune-related adverse events (irAEs), survival and absolute lymphocyte count (ALC) were also evaluated. Results: 20 pts were identified: the median age was 61yrs (range 46-83), 55% were male, 85% had liver metastases, 60% had elevated LDH, and pts reported a median of 1 prior therapies (range 0-5). Pts received a median of 4 doses (range 1-16) of ipi. Response rates (RR) by irRC at 12 and 24 wks are listed below. Among pts with stable disease (SD) at 12 wks, the median time to progression was 30.6 wks (range 19.6-83), with one partial response (PR) occurring after 24 wks (overall RR 10%). Responses were observed in lung, liver and peritoneal metastases. Pts with an ALC ≥ 1.0 at 7 wks had a trend toward a higher clinical benefit (CB= CR + PR + SD) than pts with ALC < 1.0 (5/12 [42%] vs 0/5 [0%]; p= .09), consistent with prior studies in CM. To date, median survival for the group is 8.6 mos (95% CI, 3.5-NR), with two ongoing PRs (3+ yrs and 24+ wks). Reported irAEs include rash/pruritis (10/20), hepatitis (1/20), colitis (1/20), pancreatitis (1/20) and uveitis (1/20). Conclusions: Ipi has potential for benefit in pts with advanced UM; RR and irAE rates are similar to those observed in pts with advanced CM. Further evaluation of ipi in the treatment of UM, including identification of potential biomarkers of CB, is warranted. [Table: see text]
Randomized, double-blind, and multicenter phase II trial of rh-endostatin plus dacarbazine versus dacarbazine alone as first-line therapy for the patients with advanced melanoma.
Authors: Guo Jun , Cui Chuan Liang , GU Kangsheng , Tao Min , Xin Song , Lin Tongyu , Ren Xiu Bao , Qin Shukui
Published: March 2020

8554

Background: rh-endostatin (Endostar, water-soluble, rES) is an inhibitor of angiogenesis, which is effective as single agent or in combination with chemotherapy for non-small cell lung cancer in phase I/II clinical trials. This study (NCT00813449) was a randomized, double-blind and placebo-controlled phase II trial, aimed to observe the efficacy and safety of rES with dacarbazine (DTIC) as the 1st line therapy for patients (pts) with advanced melanoma. Methods: Untreated pts with ECOG 0/1 and unresectable stage IIIC or IV melanoma (confirmed by histopathology) were enrolled, and randomized (1:1) into Arm A (DTIC 250 mg/m2 d1-5 + placebo d1-14) or Arm B (DTIC 250 mg/m2 d1-5 + rES 7.5 mg/m2 d1-14). Treatment was continued in 21-day cycle until progression or intolerable toxicity occurs. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR) and safety, evaluated every 2 cycles. Results: From Dec. 2008, 120 pts were enrolled and 110 pts evaluable. 30.9% of them were in M1a, 39.1% in M1b, and 29.1% in M1c. Mean treatment cycles were 3.2 (range: 1-10) in Arm A and 4.0 (range: 1-12) in Arm B. Until the last follow-up in Nov. 2011, 27 pts were still alive. The median PFS was 1.5 months (95% CI: 1.35-1.65) in Arm A and 5.0 months in Arm B (95% CI: 2.45-7.55, P=0.004, log-rank test). The median OS was 7.0 months in Arm A (95% CI: 4.41-9.59) versus 16.0 months in Arm B (95% CI: 10.46-21.54, P=0.003, Breslow test). 1-year survival rate was 22.2% versus 51.0%, and 2-year survival rate 8.9% vs.10.2%. No statistical significance was found for both ORR and toxicities. The most common toxicities were increased transaminase (28.9% in Arm A versus 56.1% in Arm B) and leucopenia (14.4% versus 13.4%). The incidence of grade 3-4 toxicity (increased transaminase and thrombocytopenia) was only 1.7% in Arm B. Conclusions: rES plus DTIC may obviously improve mPFS and mOS versus DTIC alone as the 1st line therapy for advanced melanoma. That combining therapy was well tolerated and could be recommended as a new, safe and effective regimen for untreated pts with advanced melanoma.
Adjuvant sunitinib in high-risk patients with uveal melanoma: A pilot study.
Authors: Valsecchi Matias Emanuel , Shockley Nancy , Summers Deborah , Shields Carol L , Shields Jerry A , Mastrangelo Michael J. , Sato Takami
Published: March 2020

8560

Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite the successful treatments for primary tumors, up to 50% of the patients later die of distant metastases. Currently no effective adjuvant treatment is available for these patients. Our group previously reported that sunitinib stabilized systemic metastases in 65% of uveal melanoma patients who failed prior treatments. In this pilot study, we tested sunitinib in an adjuvant setting in high-risk patients with primary uveal melanoma. Methods: Patients with estimated metastatic death rate ≥ 50% based on the following criteria were eligible: (1) monosomy 3 and 8q amplification; (2) large tumor (≥ 15 mm in diameter and ≥7 mm in thickness); (3) monosomy 3 and other risk factors (large tumor, epithelioid dominant cell type, local recurrence, or extra-scleral extension). Sunitinib was given at 25 mg PO daily for at least 6 months. Primary endpoint was disease-free survival (DFS) and overall survival (OS), estimated with Kaplan-Meier analysis (SPSS 17.0). Secondary endpoint was safety. Results: A total of 23 Caucasian patients (median, 54 years; range: 25 – 77) were enrolled. All patients received sunitinib for at least 6 months (range: 6 – 12). Eighteen patients had confirmed monosomy 3, from whom 13 (72%) also showed 8q amplification. The median follow-up was 24 months (range 12 – 54 months). Only one patient died of unknown cause (OS: 30.4 months). A total of seven patients (30%) developed systemic metastases, all of which were liver metastases. The DFS and OS rates at 2 years were 70% (95% CI: 47 – 86%) and 100%, respectively. The OS rate at 2 years was better than historical control with monosomy 3 patients (51%, 95% CI: 31 – 71%) (Invest Ophthalmol Vis Sci 2003; 44:1008). In those patients who relapsed, the median time to progression after finishing sunitinib was 2 months (range: 0 – 8). The most common adverse events were: diarrhea (47%), fatigue (39%), dermatitis (30%), stomatitis (13%), leucopenia (8%), and nausea (4%). Most were grade 1 or 2 (88%) and only one was considered grade 4 (diarrhea). Conclusions: In high-risk uveal melanoma patients with estimated metastatic death rate of ≥ 50%, adjuvant sunitinib showed promising results and deserves further investigation.
A single-arm, open-label, U.S. expanded access study of vemurafenib in patients with metastatic melanoma.
Authors: Schuchter Lynn Mara , Flaherty Lawrence E. , Hamid Omid , Linette Gerald P. , Hallmeyer Sigrun , Gonzalez Rene , Cowey Charles Lance , Pavlick Anna C. , Kudrik Fred J. , Lawson David H. , Margolin Kim Allyson , Ribas Antoni , McDermott David F. , Khatcheressian James L. , Flaherty Keith T. , Day Bann-Mo , Linke Rolf Gerhard , Hainsworth John D.
Published: March 2020

8567

Background: Vemurafenib (vem) has been FDA approved for the treatment of unresectable or metastatic BRAFV600E mutated melanoma since August 2011 based on results of a randomized phase III study (treatment-naive) and a single arm phase II study (previously treated). We report results of an expanded access study that allowed appropriate patients (pts) to receive vem until the drug was approved. Methods: Eligible pts had metastatic melanoma with a BRAFV600E mutation as detected by the cobas 4800 BRAFV600 Mutation Test. Enrolled pts received oral vem 960 mg b.i.d. Adverse events (AEs) were evaluated for vem-related toxicities; tumor responses were assessed using RECIST 1.1. Results: 29 US sites screened 745 pts and enrolled 374 from December 2010 until October 2011. The following results are based on a median follow up time and treatment duration of 2 months. At baseline, mean age of pts was 54 y with 22% of pts ≥65 y; 75% had stage M1c disease; 29% had received radiotherapy for brain metastases. 19% of pts were ECOG PS 2 or 3; 71% of pts had prior systemic therapy for metastatic melanoma (21% 1 regimen; 50% ≥2 regimens). 50 pts had prior adjuvant treatment. At data cut-off, 243 pts had sufficient follow-up time for tumor assessment. In this group, the unconfirmed overall response rate was 52% (95% CI, 46 to 59). The median time to response was 1.8 months. Based on 240 pts with available ECOG PS status at time of analysis, response rate was 53% for pts with ECOG PS 0 or 1 (n=209), and 45% for pts with ECOG PS 2 or 3 (n=31). 370 pts were evaluable for safety analysis. The most common vem-related AEs were rash (36%), arthralgia (33%) and fatigue (21%) with the majority (~90%) of grade 1 or 2. 25 vem-related serious AEs were reported in 5.4% of pts with a slightly higher rate of pts with ECOG PS 2 or 3 (8.7%) compared to ECOG PS 0 or 1 (4.7%). 18% of pts missed at least one dose and 11% of pts required dose reduction of at least one level due to AEs. Conclusions: This expanded access study, with its limited follow-up time, confirms the established rapid and high tumor response rate with vem. No new safety signals were detected. Compared to the overall population, pts with an ECOG PS 2 or 3 demonstrated a similar benefit.
Development of a melanoma risk prediction model incorporating MC1R genotype and indoor tanning exposure.
Authors: Smith Lauren A , Qian Meng , Ng Elise , Shao Yongzhao , Berwick Marianne , Lazovich DeAnn , Polsky David
Published: March 2020

8574

Background: Invasive melanoma is the second most common cancer in young adults, yet they exhibit poor skin-protective behavior. We previously demonstrated a significant association between melanoma risk, melanocortin receptor (MC1R) polymorphisms, and indoor ultraviolet light (UV) exposure. As existing melanoma risk models do not take these factors into account, we investigated whether these variables would improve the predictive ability of a clinical risk model, especially in a younger population. Methods: We determined MC1R genotype and collected self-reported phenotypic and UV (indoor and outdoor) exposure variables from 923 melanoma cases and 813 healthy controls between ages 25 – 59 from the Minnesota Skin Health Study. These data were initially used to develop a clinical melanoma risk model (Model A) with conventional risk factors (i.e. age; gender; hair, skin, and eye color; mole count, freckling, and family melanoma history). We then developed a second model (Model B) combining outdoor UV, indoor UV, and MC1R genotype variables with those in Model A to determine if the model’s predictive ability improved. Finally, we assessed the predictive ability of both models when confined to younger subjects (ages 25-35). Results: The clinical model, combining conventional melanoma risk factors (Model A), yielded an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.70 – 0.75). Incorporating outdoor UV, indoor UV, and MC1R genotype variables (Model B) increased the AUC to 0.75 (p=0.001, 0.72 – 0.77). Confining the analyses to younger subjects substantially increased the AUC of Model A to 0.78 (0.72 – 0.84) and Model B to 0.83 (p=0.007, 0.78-0.88). Conclusions: This preliminary risk model is the first in melanoma to demonstrate that the addition of genotypic data and indoor UV exposure results in a measurable increase in predictive ability when compared to models comprised only of clinical and outdoor UV exposure variables. The enhanced predictive ability of the model (AUC>0.80) when limited to younger individuals suggests the potential for developing tools to facilitate targeted screening and prevention strategies in melanoma.
Diagnosis of melanoma: Importance of comparative analysis and “ugly duckling” sign.
Authors: Grob Jean Jacques , Wazaefi Yanal , Bruneu Yvane , Gaudy-Marqueste Caroline , Monestier Sandrine , Thomas Luc , Avril Marie-Françoise , Triller Raoul , Pellacani Giovanni , Malvehy Joseph , Fertil Bernard
Published: March 2020

8578

Background: “Ugly duckling” (UD) sign is widely admitted as a major sign for melanoma (MM) detection. UD is based on the concept of intra-individual comparative analysis, which has never been validated. It is assumed that, in a given individual, variability of nevi is limited and represented by a few similarity clusters (SC) grouping all nevi sharing the same pattern, and that a nevus is suspicious when it does not fit with the SCs of this individual (UD). Objective: To validate the concept of UD and SC. Methods: 9 international experts (dermatologists) and 9 novices (untrained individuals) were blindly tested, using digital images of the nevi at clinical and dermoscospic scale successively in 80 patients, (2,089 nevi and 7 MM). Concordance was assessed by kappa statistics for UDs, and B-cubed metrics for SCs. Results: At clinical scale, experts had a better concordance for UDs (kappa= 0.53, [0.33 - 0.87]) and SCs (B-cubed = 0.65, [0.55, 0.73]), than novices (0.31, [0.03, 0.51] and 0.56 [0.49, 0.64], respectively). Experts identified a mean number of 1 UD and 2.7 SCs per patient, and agreed on consensual UD and SCs, whatever their natural propensity to see a high or a low number of UDs and SCs: among the 254 nevi considered as UDs by at least 1 expert, 54 were considered as such by at least 5, and from them, 20 by all 9 experts. The 20 consensual UDs included all the MMs (7/7) (sensitivity for MM: 100%). At dermoscopic scale, concordance tended to be lower for SCs than at clinical scale. Conclusions: We demonstrated the limited variability of nevi patterns in each patient, the consistency in the recognition of UD, and its clinical relevance, supporting evidence that it is useful for experts and to a lesser degree to general population to spot the skin lesions with the highest probability of being MM.
Molecular profiling and comparative genomic hybridization analysis in human melanoma cell lines and identification of BRAF amplification in a PLX4032 acquired resistance cell line.
Authors: Von Euw Erika Maria , Dering Judy , Anderson Lee , Ginther Charles , Cheng Hsiao-Wang , Gong Ke-Wei , Konkankit Veerauo V , Finn Richard S. , Slamon Dennis J.
Published: March 2020

8592

Background: Melanoma is the most aggressive form of skin cancer. Its management is evolving rapidly due to an improved understanding of the molecular heterogeneity and the development of effective, personalized targeted therapies. PLX4032 is a BRAF inhibitor that induces tumor response in patients with BRAF mutation whose response is limited due to acquired resistance. We used comprehensive microarray and genomic analysis to molecularly characterize a panel of melanoma cell lines with the goal of identifying new molecular subgroups. To better understand the mechanisms of acquired resistance to PLX4032, we included two cell lines that were conditioned in vitro to acquire resistance. Methods: Using microarray, we studied 52 melanoma cell lines for mRNA expression and performed array CGH using genome microarrays. Data analysis was done using Rosetta Resolver and Agilent Analytics 4.0 software. Results: Microarray analysis suggests melanoma is comprised of at least two distinct molecular groups. One group has a differentiated melanocyte phenotype and the other has an expression signature characteristic of progenitor-like cells. The progenitor-like group expresses SOX9, WNT5A and WNT5B and also has the lowest relative expression of MITF. The most differentiated group had the highest MITF and SOX5 levels, while the progenitor-like cell lines have decreased expression. MITF appears to be a strong candidate marker for this group. Positive correlation exists between MITF expression levels and gene copy number, as almost all of the MITF samples amplified by CHG analysis are also overexpressed. A third group shows strong expression of SOX5, SOX10 and Nestin. One of the most important findings is M14-R cell line, conditioned to acquire PLX4032 resistance, has a focal, high level amplification of BRAF (Log2 ratio = 3, 8-fold amplification) when compared with the parental cell line, which is extremely sensitive to PLX4032. Conclusions: These results afford new insight into the potential pathogenesis and classification and provide a greater understanding of melanoma. BRAF amplification could be a novel mechanism of resistance to PLX4032.
Parenteral hydration (PH) in advanced cancer patients: A multi-center, double-blind, placebo-controlled randomized trial.
Authors: Dalal Shalini , Hui David , Torres-Vigil Isabel , Palmer J. Lynn , Allo Julio , Frisbee-Hume Susan , Tarleton Kenneth , Bruera Eduardo
Published: March 2020

9025

Background: The vast majority of cancer patients at the end of life receive PH in hospitals and no PH in hospice. There is limited evidence supporting either practice. Our preliminary study suggested that PH (1L/day) improved dehydration symptoms (Bruera et al. JCO 2005). In this randomized controlled trial, we determined the effect of PH on symptoms associated with dehydration, quality of life and survival for patients with advanced cancer. Methods: We randomly assigned 129 cancer patients from 6 hospices to receive subcutaneous PH (normal saline 1 L/day) or placebo (normal saline 100 mL/day) daily over 4 hours. The primary outcome was change in the sum of 4 dehydration symptoms (fatigue, myoclonus, sedation and hallucinations, 0=best and 40=worst possible) between day 4 and baseline. Secondary outcomes included Edmonton Symptom Assessment Scale (ESAS), Memorial delirium assessment scale [MDAS], Nursing delirium screening scale [NuDESC], unified myoclonus rating scale [UMRS], FACIT-F, creatinine, urea, and overall survival. Intention-to-treat analysis was conducted to examine the change in each variable between baseline and day 4 or day 7. Log rank test was used for survival analysis. Results: Mean age was 67 (range 43-92), female 61%, Caucasians 60%, gastrointestinal, genitourinary and lung cancers 70%, performance status 3-4 113 (88%), with no baseline differences between the hydration (N=63) and placebo (N=66) groups. No significant differences were found between the hydration and placebo groups for the sum of 4 dehydration symptoms (-3.3 v. -2.8, p=0.77), ESAS (all non-significant), MDAS (1 vs. 3.5, p=0.084), NuDESC (0 v. 0, p=0.13) and UMRS (0 vs. 0, p=0.54). We also did not identify any group differences for day 7, except for a decrease in urea level in the hydration group (-2 vs. 2, P=0.02). Median overall survival was 21 days for PH and 15 days for placebo (p=0.83). Conclusions: PH at 1 L/day did not improve symptoms, quality of life or survival compared to placebo. Further studies are required to determine if any subgroups would benefit from PH.
Association of screening for psychosocial distress in patients with newly diagnosed stage IV NSCLC and survival.
Authors: Pirl William F. , Greer Joseph A. , Gallagher Emily R. , Temel Jennifer S. , Traeger Lara , Lennes Inga Tolin
Published: March 2020

9030

Background: While screening for psychosocial distress has become an ASCO QOPI indicator of quality cancer care, data has yet to show an association with improved cancer outcomes. We examined the relationship between adherence to the QOPI measure for assessment of emotional well-being and survival in a sample of patients with newly diagnosed stage IV NSCLC. Methods: From 8/07 to 9/10, we recruited consecutive new patients in a multidisciplinary thoracic oncology clinic to participate in a research database for which patients completed self-report instruments for depression (PHQ-9) and anxiety (GAD-7) at their first oncology visit. We then performed a QOPI chart audit for patients with stage IV NSCLC who received care at our institution. To adhere to the QOPI measure, oncologists were required to document their own assessment of patient emotional well-being (without access to patient self-report data) within one month of the first office visit. Survival was calculated from first oncology visit to death. Cox proportional hazards models were used to test associations with survival. Results: 243 patients completed baseline assessments and had follow up. Emotional well-being was assessed in 90 (37%). Median survival of those with an emotional assessment was 12 months vs. 10 months for those without (p=.03). Yet, emotional assessment was associated with younger age (p=.01) and higher depression (p=.05) and anxiety scores (p=.03). Controlling for age, sex, performance status, smoking, primary oncology provider, PHQ-9, and GAD-7, having an assessment of emotional well-being was associated with improved survival (HR .68, 95% CI .49-.93, p=.02). Although higher PHQ-9 scores were independently associated with worse survival (HR 1.05, 95% CI 1.02-1.08, p=.004), neither depression nor anxiety moderated the relationship between clinician screening and survival. Conclusions: In this large prospective study of patients with newly diagnosed stage IV NSCLC, adherence to the QOPI measure for assessment of emotional well-being was associated with a survival benefit. This benefit appears to extend to all patients, not just those with depression and anxiety. Randomized trials are needed to confirm these findings.
Difficult conversations with terminal patients: Palliative care and death at home.
Authors: Morgenfeld Eduardo L. , Martin Reinas Gaston , Gercovich Daniela , Gil Deza Ernesto , Rivarola Edgardo G. J. , Gercovich Felipe G.
Published: March 2020

9038

Background: More than half the total number of oncological patients may die due to the disease’s progression, and at some point in time the oncologist must communicate that the disease is terminal. This is the hardest conversation (HC) of a clinical oncologist. The following paper’s objective is to determine whether or not the treatments applied to patients, and their evolution, are affected by having had the HC. Methods: All patients who died due to progression of the disease in 2011 were selected for this study. Both medical histories and applied treatments were evaluated. All doctors were interviewed to establish when the HC had taken place. The distribution of variables was analyzed and both populations compared. Results: Between January 2011 and December 2011, 110 patients who met the previous criteria were studied. Population characteristics: Sex (Female: 52 pts; Male: 58 pts). Median age at the time of death: 61 years (Range: 27-88). Patients were divided in two groups: A (terminal status of the disease had been discussed; 70 pts) and B (terminal status of the disease had not been discussed; 40 pts). Both groups were similar in diagnosis, age and previous treatments. During the post HC evolution, three elements were categorized according to the table below. Conclusions: 1 – The conviction, ethical sense and strength of will of the doctor are determining factors when related to his or her capacity to talk with the patient about the terminal aspect of the disease. 2 – The chemotherapy treatments applied during the last two months of life are similar in both groups. 3 – The percentage of patients that died at their homes under palliative care was remarkably higher amongst those who had been informed than those who had not been informed. [Table: see text]
Feasibility and acceptability of patient-reported outcomes data collection for clinical care following breast reconstruction.
Authors: Pusic Andrea , Klassen Anne , Scott Amie , Cano Stefan , Shouery Marwan , Basch Ethan M.
Published: March 2020

9042

Background: To date, systematic measurement of patient-reported outcomes (PROs) has played an important role in cancer research, but not in routine clinical care. Our objective was to evaluate the feasibility of developing and piloting an electronic PRO data collection in clinical care among breast reconstruction patients using the BREAST-Q, a previously developed condition-specific PRO measure for breast surgery patients that measures quality of life (e.g. psychosocial, physical and sexual well-being) as well as patient satisfaction (e.g. satisfaction with breasts, with information, with surgeon). Methods: The BREAST-Q was loaded to the MSKCC WebCore, a generic electronic patient-reporting platform adhering to strict privacy and security standards. Patients attending visits at the MSKCC Breast Reconstruction Clinic were asked to complete the BREAST-Q electronically prior to scheduled visits. For patients with email addresses, a reminder with web-link to the questionnaire was emailed automatically prior to the visit. Results: Over a 9 month start-up period, BREAST-Q surveys were completed by 1442 patients. Patients completed the questionnaire at set time points before and after surgery. A total of 2340 BREAST-Q surveys were completed overall. Mean completion time was 5:53 minutes. Acceptability was high with both patients and clinical staff contributing positive comments along with suggestions for improvement via email. Conclusions: This pilot experience suggests that ePRO data can be efficiently collected among outpatient breast surgery patients with high acceptability. In the next phase of this project, we will introduce real-time individual patient reports to the clinical team and evaluate the impact of this information on clinical care and quality improvement.
A positron emission tomography (PET) study to assess the degree of neurokinin-1 (NK1) receptor occupancy in the human brain after single doses of netupitant to healthy male subjects.
Authors: Rossi Giorgia , Olivari Tilola Silvia , Rudengren Cecilia
Published: March 2020

9054

Background: Netupitant (NETU) is a highly selective neurokinin 1 (NK1) receptor antagonist for the prevention of nausea and vomiting associated with emetogenic chemotherapy. In this study, PET imaging with the NK1 receptor-binding–selective tracer 11C-GR205171 was used to determine the levels and the duration of central NK1 receptor occupancy (RO) achieved by therapeutic doses of NETU. Methods: This was a single dose, randomized, open-label, PET study investigating the degree of NK1 RO in human brain after single oral doses of NETU (100, 300 or 450 mg) in 6 healthy male subjects. PET scans and blood samples for NETU determination were obtained up to 96 hrs post dose. The Patlak model was used to define the net uptake rate of 11C-GR205171 in the brain regions of interest while the percent of NK1 RO was calculated as the relative difference between the uptake rate at baseline and post-treatment administration. Results: NETU plasma concentrations over the 100 mg to 450 mg dose range were comparable with those obtained in previous single dose studies. A NK1 RO of 90% or higher was achieved with all tested single oral doses in the majority of the outlined brain regions 6 hrs after dosing (corresponding to netupitant Cmax). All doses had a long duration of blockade of NK1 receptors with the 300 mg dose showing moderate (62%) to high (94%) NK1 RO for all investigated brain regions at 96 hrs post dose. The relationship between NETU concentration and NK1 RO, assessed using a sigmoid Emax model, indicated that in the striatum, the reference brain area with the highest NK1 receptor expression, a concentration of 225 μg/L of NETU corresponded to an NK1 RO of 90%. This data suggests that a single oral dose between 100 and 300 mg NETU would be needed to reach 90% NK1 RO levels in human brain. Conclusions: PET results demonstrate that NETU is a potent agent targeting NK1 receptors with a high degree of occupancy for a long duration. NETU, given as single doses of 100 to 450 mg was well tolerated.
Prevention of palmoplantar erythrodysesthesia (PPE) with an antiperspirant in breast cancer patients treated with pegylated liposomal doxorubicin (PLD), a placebo-controlled, double blinded, phase lll trial (SAKK 92/08).
Authors: Ruhstaller Thomas , Ribi Karin , Sun Hong , Schmitz Shu-Fang , Borner Markus , Winkler Annette , Mueller Andreas , von Rohr Lukas , Winterhalder Ralph C. , Rochlitz Christoph , Von Moos Roger , Anchisi Sandro , Caspar Clemens B. , Zaman Khalil , Bodmer Alexandre , Beyeler Michael , Berardi Simona , Thurlimann Beat J. K. , Templeton Arnoud
Published: March 2020

9059

Background: PPE, also known as hand-foot syndrome, is a distinctive adverse drug reaction of PLD treatment. PLD has been detected in elevated concentrations in eccrine sweat glands in palms and soles. We postulated that prophylactic administration of an antiperspirant (F511 cream) prior and during treatment with PLD could decrease the incidence of PPE. Methods: Patients (pts) with metastatic breast cancer treated with PLD monotherapy ≥10mg/m2 per week applied an antiperspirant to the left or right hand and foot and a corresponding placebo to the opposite site with double-blinding for the content of the cream applied to either side (intra-patient randomization). The creams were applied once daily during the first week, then three times per week. The primary endpoint was the rate of PPE grade (G) ≥ 2 in the antiperspirant or placebo treated side. Pts were evaluable if they developed PPE G ≥ 2 or had received cumulatively at least 160mg/m2 PLD. Patient-reported extent of symptom burden was a secondary endpoint. Using McNemar’s matched pairs design 53 pts were needed to detect a difference of 20% between the sides with a significance level of 5% and power of 90%. Results: 52 of 90 pts from 11 Swiss centers included were evaluable. Median age was 64.5 years; median duration of PLD treatment was 12 weeks. 30 pts developed PPE G ≥ 2. In 3 pts PPE G ≥ 2 occurred on the placebo side but not on the antiperspirant side (p=0.097; table). PPE G ≥ 2 was borderline significantly more frequent in placebo foot than antiperspirant foot (p=0.048). Patient-reported extent of symptom burden showed a trend in favor of the antiperspirant side for skin problems (peeling, blistering, bleeding) in the group of pts with PPE G ≥ 2 (p=0.051). Conclusions: In this double-blind trial with intra-patient randomization we observed a trend towards less PPE G ≥ 2 with application of the antiperspirant cream F511 in pts treated with PLD as determined by the treating physician and reported by the pts. [Table: see text]
Clinical needs of patients referred early to supportive and palliative care.
Authors: Kwon Jung Hye , Hui David , Ha Caroline Ann , Chisholm Gary B. , Yennurajalingam Sriram , Kang Jung Hun , Bruera Eduardo
Published: March 2020

9065

Background: Palliative care is evolving from delivering care to patients at the end-of-life to those earlier in the disease trajectory. We evaluated the differences in clinical characteristics, symptoms burdens, and service utilization between traditional palliative care patients (late referrals, LR) and the new patients group who are in earlier in their course of disease (early referrals, ER). Methods: We reviewed consecutive cancer patients referred to the Supportive Care Clinic with follow up visit within 30 days between August 2008 and October 2010. Patients were divided into two groups: ER (defined as patients with expected survival ≥ 2 years or receiving treatment for curative intent) and LR (all others). We compared clinical characteristics, symptoms and service utilization between both groups using chi-square test and Wilcoxon rank sum test. Results: 58% (695/1208) patients had a 2nd visit within 30 days. Among them, 100 patients were classified as ER (14.4%) and 100/595 LR were randomly selected as the comparison group. ER patients were younger (median age 54 years vs 60 years, p=0.009), more likely to have head and neck cancer (67% vs 6%, p<0.001) and to have a shorter interval between cancer diagnosis and palliative care consultation (3.8 m vs 16.2 m, <0.001). ER patients were also more likely to be CAGE positive (15% vs 4%, p=.014), referred from radiation oncology (49% vs 3%, p<0.001), referred for treatment related side effects (70% vs 9%, p<0.001), and receiving active anti-cancer treatment at the time of consultation (74% vs 48%, p=0.0002). Baseline symptoms (Edmonton Symptom Assessment Scale) were similar between ER and LR except for insomnia (1.8 vs 2, p=0.004). LR patients experienced greater improvement in the symptom distress score (-5.5 vs -3, p=0.007). Overall median number of medical visits was 24 for ER vs 10.5 for LR (p<0.001); however, median visit per month was 4.3 for LR and 2.1 for ER (p<0.001). Conclusions: ER was associated with different patient characteristics; patients have similar distress but different needs and outcomes as compared to traditional LR patients.
Efficacy and safety of rolapitant, a novel NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting in subjects receiving highly emetogenic chemotherapy.
Authors: Fein Luis Enrique , Poma Allen , Hedley Mary Lynne
Published: March 2020

9077

Background: Management of chemotherapy-induced nausea and vomiting (CINV) improves quality of life and increases the likelihood that patients will continue to receive appropriate treatment. The objective of this dose finding study was to evaluate rolapitant for the prevention of CINV in subjects receiving highly emetogenic chemotherapy (HEC). Methods: A phase II, double blind study in which 454 subjects receiving HEC (≥70mg/m2 cisplatin-based chemotherapy) were randomized in equal fashion prior to chemotherapy to receive ondansetron + dexamethasone + either placebo or 10, 25, 100 or 200mg of rolapitant. Subjects recorded episodes of emesis, severity of nausea, and use of rescue medication(s) daily within a subject diary from Days 1 through 6 of Cycle 1. Results: The rolapitant 200mg group had significantly greater complete response rates (no emesis and no use of rescue medication) in the overall (0 to 120 hours), acute (0 to ≤24 hours) and delayed (>24 to 120 hours) phases compared to the placebo group (62.5% vs. 46.7%, p=0.032; 87.6% vs. 66.7%, p=0.001 and 63.6% vs. 48.9%, p=0.045, respectively). Moreover, the 200mg group had significantly greater rates of no emesis and no significant nausea in the overall, acute, and delayed phases and achieved statistically significant better QoL scores (FLIE questionnaire) compared to the placebo group. Rates for no emesis and no significant nausea for the 200mg dose group in Cycles 2 to 6 continued to demonstrate superior treatment effect vs. placebo. Treatment-related adverse events were mild and included constipation, headache, fatigue and dizziness. Overall, serious adverse events (SAEs) occurred with similar incidences across all treatment groups (9% - 14%). Most common SAEs were febrile neutropenia, neutropenia, vomiting, dehydration, nausea and pneumonia and were considered related to chemotherapy or underlying cancer and not to rolapitant. Conclusions: Administration of rolapitant 200mg with ondansetron and dexamethasone is safe and effective at preventing CINV in subjects receiving HEC.
Longitudinal relationship between inflammatory markers and patient-reported symptom severity during induction therapy for multiple myeloma.
Authors: Sailors Mary H , Wang Xin Shelley , Liu Ping , Johnson Valen E. , Reuben James M. , Cohen Evan N. , Williams Loretta A. , Mendoza Tito R. , Cleeland Charles S.
Published: March 2020

9083

Background: Multiple myeloma (MM) patients undergoing induction therapy experience both disease- and therapy-related symptoms. We investigated the association between the trajectory of symptom severity and changes in levels of inflammatory markers. Methods: MM patients (N=62) rated symptoms via the M. D. Anderson Symptom Inventory (MDASI) twice a week during induction therapy. Patients contributed serum samples before the start of every chemotherapy cycle. A panel of pro- and anti-inflammatory cytokines and markers was evaluated by Luminex. Ordinal regression analyses were used to describe the relationship between cytokines and symptom outcomes across time. These analyses were adjusted for patient and clinical factors (age, sex, diabetes diagnosis, anemia, BMI, comorbidity, staging, ECOG PS, prior treatment status, tumor response, opioid use, and chemo regimen). Results: Bortezomib-based induction therapy was received by 89% of the sample. Fatigue was persistently the most severe symptom during induction therapy, followed by disturbed sleep, muscle weakness, pain, drowsiness, and bone aches. Numbness, which is representative of chemotherapy-induced peripheral neuropathy, significantly worsened from baseline (p=0.01). We observed significant longitudinal associations between sIL-1R1 and distress and sadness (both p=0.02); between sIL-6R and disturbed sleep (p=0.001), poor appetite (p=0.04), and sore mouth (p=0.006). IL-6 was significantly associated with pain, fatigue, nausea, and sore mouth (all p<.05). A negative association between sTNF-RII and pain, sleep, distress, remembering, poor appetite, and nausea (all p<0.05) was also observed. MCP-1 was positively associated with numbness (p=0.04); while MIP-1α was negatively associated with sleep, numbness, constipation, poor attention (all p<0.01), and bone aches (p=0.0006). IL-10 was negatively associated with mood interference (p=0.04). Conclusions: Frequent assessment can document the longitudinal course of multiple symptoms during induction and provides opportunity to evaluate systemic inflammation as a potential source of symptom burden during induction therapy for MM.
Risk of skin rash with the proteasome inhibitor bortezomib: Updated systematic review and meta-analysis.
Authors: Case Emily Christine , Wu Shenhong , Gerecitano John F. , Lacouture Mario E.
Published: March 2020

9092

Background: Rash is a common, adverse event to the novel proteasome inhibitor bortezomib (Velcade). Indicated for the treatment of multiple myeloma and mantle cell lymphoma, bortezomib is the first proteasome inhibitor approved by regulatory agencies. Because the incidence of bortezomib-induced skin rash varies widely in published manuscripts, we performed a systematic literature review and meta-analysis to determine the incidence and overall risk. Methods: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology and The American Society of Hematology annual meetings (1998 to July 2011) to identify relevant clinical studies. Eligible studies included prospective clinical phase II and phase III trials, with data on the incidence of rash in patients taking 1.3mg/m2, 1.5mg/m2, or 1.6 mg/m2 of bortezomib intravenously either weekly or twice weekly. The incidence of rash and relative risk (RR) were calculated using random-effects or fixed-effects model, depending on the heterogeneity of included studies. Results: A total of 2,616 patients with various hematologic and solid malignancies from 35 clinical trials were included for analysis. Among patients receiving twice weekly bortezomib, the summary incidence of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant increase in all grade rash incidence with higher doses of bortezomib: 19.3 % (95% CI: 15% to 24.5%) and 20.8% (95% CI: 11.6% to 34.4%) for doses of 1.3 mg/m2 and 1.5 mg/m2, respectively. In addition, bortezomib was associated with an increased risk in both all grade (RR: 19.70, 95% CI: 8.73 to 44.44, p<0.001) and high-grade rash (RR: 5.35, 95% CI: 2.16 to 13.29, p<0.001), compared to controls. Weekly bortezomib is associated with lower risk of rash compared to twice weekly dosing (incidence 3.9% versus 18.8%, p=0.001). Conclusions: Bortezomib is associated with a significant risk of developing rash with a higher risk among patients receiving twice weekly dosage. Management of rash to bortezomib is critical to prevent a negative effect on quality of life and dose modifications, both of which affect clinical outcome.
Early outpatient palliative care in patients with metastatic NSCLC: A qualitative study.
Authors: Yoong Jaclyn , Park Elyse R. , Greer Joseph A. , Jackson Vicki A. , Gallagher Emily R. , Pirl William F. , Back Anthony , Temel Jennifer S.
Published: March 2020

9101

Background: Early outpatient palliative care (PC) is an emerging practice and its key components have not been defined. We conducted a qualitative analysis of data from a randomized controlled trial which demonstrated improved quality of life, mood and survival in outpatients who received early PC integrated with standard oncologic care versus standard oncologic care alone. Our objectives were to 1) identify the content and key components of early PC clinic visits, 2) explore timing of key components, and 3) compare the content of PC and oncology visit notes at the critical time points of clinical deterioration and radiographic disease progression. Methods: We chose a random selection of 20 patients with newly diagnosed metastatic NSCLC who received early PC who survived within 4 time frames: less than 3 months (n=5), 3 to 6 months (n=5), 6 to 12 months (n=5) and 12 to 24 months (n=5). We performed content analysis on PC and oncology electronic health record notes of these patients using NVivo 9 software. Results: Addressing symptoms and coping ability were the most prevalent components of the PC clinic visits. The content of initial visits focused on building relationships and rapport with patients and their families and illness understanding. Discussions about prognostic awareness occurred during earlier visits while goals of care and hospice discussions occurred in later visits. The frequency of addressing these components was similar regardless of patients’ length of life. Comparing PC and oncology visits around critical time points, both included discussions about current illness status and goals of care; however PC visits emphasized symptoms, coping, and implications of anti-cancer treatments, while oncology visits focused on medical discussions about treatment plans. Conclusions: Early PC clinic visits emphasize managing symptoms, strengthening coping, and cultivating illness understanding and prognostic awareness in a structured, responsive and time-sensitive model. Around critical clinical time points PC and oncology visits have distinct features that suggest a key role for PC involvement while enabling oncologists to focus on anti-cancer management.
Treatment and mortality rates of older cancer patients with a body mass index <20: Results from the IN-GHO registry.
Authors: Honecker Friedemann , Wedding Ulrich , Rettig Klaus , Huschens Susanne , Bokemeyer Carsten ,   on behalf of the IN-GHO Advisory Board
Published: March 2020

9114

Background: Older cancer patients (pts) compose a heterogeneous population. Data from clinical trials are limited, and little is known about treatment decisions and outcomes. The internet based IN-GHO registry prospectively collects data of cancer pts ≥ 70 years from >100 centers in Germany and Austria. Methods: Data from 1.563 cancer pts were analysed, comparing results between pts with a body mass index (BMI) <20 versus (vs) BMI ≥20 by Chi-square or Mann-Whitney U test. Analyses included results from a comprehensive geriatric assessment, physicians’ rating (fit vs compromised vs frail) and pts’ self rating of fitness for treatment (Likert scale 1= very fit to 6 = very unfit), type (combination vs. monotherapy vs no) and dosage of treatment (full vs adapted), as well as mortality within 5-7 months. Results: Mean BMI of the total cohort was 25.6. 119 (7.6%) pts had a BMI <20. Low BMI showed a positive association with female sex, small height, higher age (classified), adapted dosage of treatment, lower number of comedication, lower ADL, IADL, and Karnofsky index scores, reduced mobility, and a lower mean MMSE score. More pts with BMI <20 were judged compromised or frail, both by physicians’ or pts’ assessment (p<0.001 and p=0.038, respectively). The risk of early mortality was 1.5 fold increased in pts with low BMI compared to pts with BMI ≥20 (35.3% vs 22.3%, p=0.002). Interestingly, none of the following showed an association with lower BMI: comorbidity, type (hematologic vs solid neoplasia), stage (metastatic vs non-metastatic), time since first diagnosis, decision to apply chemotherapy, and curative vs palliative intention of treatment. Conclusions: The internet based registry is useful to gain data on prognostic factors, treatment, and outcome in older cancer pts. Significant differences regarding dosage of treatment and incidence of early mortality were found between pts with BMI <20 and pts with BMI ≥20. Elderly cancer pts with BMI <20 should be considered a high risk population.