bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduction of circulating regulatory T cell (Treg) by intravenous high-dose interferon (HDI) treatment in melanoma patients
Authors: Ascierto P. A. , Napolitano M. , Celentano E. , Simeone E. , Gentilcore G. , Capone M. , Ciccarelli L. , Palmieri G. , Castello G. , Mozzillo N. 
Published: August 2020

9040 Background: T regulatory (Treg) cells are an immunoregulatory cell type which express high levels of surface CD25, CTLA-4, and GITR. Tregs have been shown to be present in tumor and tumor-draining lymph nodes, acting as an inhibitory population blocking effector cell function. Depletion or blockade of Tregs might be able to enhance antitumor immunity. Recent evidence has been reported about the possibility of High Dose Interferon (HDI) to act through an indirect immunomodulatory mechanism (Gogas, NEJM 2006; Moschos JCO 2006). We started a study to verify if iv HDI treatment in melanoma patients could be able to reduce the number of Treg cells in peripheral blood. Methods: Analysis was performed on melanoma pts referring to the National Cancer Institute of Naples since July 2006 and who addressed to Neoadjuvant or Adjuvant treatment with iv HDI (20 MUI/m2, 5 days per week) for 4 wks. Peripheral blood mononuclear cells (PBMC) were obtained from 22 consecutive melanoma pts. Blood draw was performed at days 0, 8, 15, 22 and 29. PBMC were thawed and labeled with anti-CD4 and anti-CD25hi (BD, San Diego, CA) and anti-FoxP3 (eBioscience, San Diego, CA). Labeled cells were analyzed using a FACScalibur (Becton Dickinson). Results: Fifteen (68.2%) out of 22 pts showed a decrease of Treg cells in peripheral blood. The average value at day 0 for circulating Treg (cTreg) was 2.7%. The average percentage at day 29 was 1.4%. The average reduction was 1,4 (50% reduction in the average value of cTreg). Statistical analysis showed an average decrease of 0.29% per week of treatment. Despite of this clear trend in reducing cTreg by HDI, statistical significance was not reached (probably due to the power of the study). Moreover, it has been observed great differences between the disease status, the prognosis (recurred/not recurred pts, alive/deceased) and an increased basal percentage of cTreg. Our preliminary data are consistent for an effect of HDI on reducing cTreg, although no conclusion about the role of such reduction in terms of response to treatment or as prognostic markers of better/worse disease can be inferred. Further data are awaited in order to verify if the Treg reduction after a HDI treatment may indeed contribute to the antitumor response. [Table: see text]
Association between HU177 serum level and prognosis in patients with primary melanoma
Authors: Hamilton H. , Krich D. , Christos P. J. , Shapiro R. L. , Berman R. S. , Pavlick A. C. , Polsky D. , Liebes L. , Brooks P. C. , Osman I. 
Published: August 2020

9044 Background: Cleavage of type IV collagen during extracellular matrix (ECM) remodeling leads to exposure of cryptic regulatory sites within the ECM shown to be involved in tumor angiogenesis. Increased levels of a soluble form of the cryptic epitope HU177 in sera of melanoma patients have been shown to be associated with greater tumor thickness and nodular histological subtype. In this study, we investigate the association between HU177 serum levels and melanoma patients' clinical outcomes. Methods: Sera from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (85 females, 124 males, mean age=58, mean thickness=2.09 mm, Stage I n=140, Stage II n=40, Stage III n=29) were analyzed for HU177 level. HU177 serum levels at the time of diagnosis were then correlated with disease-free survival (DFS) and overall survival (OS). Results: Median follow-up time for survivors was 54.9 months (range 2–81 months). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. HU177 sera levels ranged from 0–139.9 ng/ml (mean=6.2 ng/ml; median=3.7 ng/ml). Because the distribution of HU177 levels was positively skewed, we analyzed the data using the median in addition to the mean. HU177 level > 3.7 ng/ml (the median) was associated with a higher rate of melanoma recurrence (p=0.04) and increasing mortality (p=0.01) in a Kaplan Meier analysis. HU177 remained an independent prognostic factor for DFS and OS when controlling for tumor thickness and histological subtype in multivariate Cox proportional hazards regression models. In the DFS hazard model controlling for tumor thickness and histology, the hazard ratio for HU177 >3.7 ng/ml (the median) was 2.01 (95% CI= 1.002, 4.04; p=0.049). In the OS hazard model controlling for tumor thickness and histology, the hazard ratio for HU177 >3.7 ng/ml (the median) was 2.23 (95% CI=1.06, 4.70; p=0.03). Conclusions: Increased serum level of HU177 identifies a subset of primary melanoma patients with worse prognosis and suggests that anti-angiogenic therapy in the adjuvant setting may be a rational approach. [Table: see text]
The prognostic significance of lymphatic invasion in primary melanoma
Authors: Xu X. , Chen L. , Hwang W. , Dawson P. , Guerry D. , VanBelle P. , Elder D. , Schuchter L. , Gimotty P. 
Published: August 2020

9050 Background: Lymphatic invasion (LI) is an under-observed phenomenon in primary malignancies that can be better detected by immunostaining and that may associate with prognosis. In this study we sought to test the hypothesis that LI was associated with melanoma-specific survival (MSS) and was an independent prognostic factor. Methods: This study included 277 patients with stage I/II melanomas in vertical growth phase (VGP) who had at least 10 years of follow up. The log-rank test was used to test the study hypothesis - 72 melanoma-specific deaths were needed for 80% power to detect an odds ratio of 2.1. Paraffin sections were stained with antibodies to podoplanin (lymphatic vessels) and S-100 (melanoma cells) to identify LI. Univariate and multivariate Cox models were used to evaluate the prognostic significance of LI. An independent cohort of 106 similar patients was used for validation of the 10-year MSS rates. Results: LI was observed in 44.5% (95% CI: 38.6% - 50.4%) of the melanomas and its presence was significantly associated with thickness, mitotic rate, gender, age, and ulceration (U). The Kaplan-Meier survival curves for those with and without LI were significantly different (log-rank test p=0.022). The final multivariate model for time to MSD identified 4 independent prognostic factors: thickness (HR=1.5, p<0.001), U (HR=2.2 p=0.013), site (HR=3.9, p<0.001) and LI (HR=1.9, p=0.015). These factors were used to define a prognostic tree with 5 risk groups defined by melanomas that were thin (≤1.0mm) with no LI or U; thin with LI but no U; 1–3mm with no U; 1–3mm with U; and >3mm. Respectively, MSS rates were 100%, 88.6%, 77%, 48% and 42%. In the validation set, observed 10-year MSS rates in each risk group were not significantly different from those predicted from the survival curves for the tree-based risk groups. Conclusions: LI is an independent prognostic factor for MSS. Among patients with thin melanomas without U the 10-year MSS was lower for those patients with LI (89%, 95% CI=78% - 99%; n=41) compared to those without (100%, n=78). LI is an important prognostic factor that needs further validation in a population of patients from the sentinel node biopsy era. No significant financial relationships to disclose.
Plitidepsin alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM)
Authors: Plummer R. , Hayward L. , Lorigan P. , Soriano V. , Moiseyenko V. , Szyldergemajn S. , Prados R. , Smyth J. , Calvert H. 
Published: August 2020

9059 Background: AUM remains incurable in most patients (pts). DTIC alone had a 8–15% response rate (RR), while plitidepsin (Aplidin [APL]) showed a 6% RR and a 14% stable disease (SD) in a Phase (Ph) II study in 35 relapsed/refractory pts after DTIC failure. Furthermore, APL + DTIC has additive activity in preclinical models. Methods: This multicenter Ph Ib study aim to determine the safe recommended dose (RD) of APL on days 1, 8 & 15 + DTIC only day 1 q4wk. RD was defined as the highest dose with >5 days G4 neutropenia or G4 thrombocytopenia (TC) and/or febrile neutropenia (FN); any drug-related ≥ G3 toxicity (except nausea/vomiting or hypersensitivity reaction) in cycle 1. Results: Of 28pts with AUM, 23 were evaluable for DLT; 57% were males, median (med) age was 48 y (20–77), med ECOG 0 (0–2) and med LDH was 226 IU/l (126–983). Most pts (96%) had metastasis with a median of 2 sites involved (1–5). Dose levels of APL + DICT (mg/m2), were: DL1 (1.8 + 800), 7 pts; DL2 (2.4 + 800), 8 pts; DL 2b (2.4 + 1000), 5 pts; DL3 (3.0 + 800), 8 pts. Pts received 4 (2–6), 2 (2–5), 2 (1–2), 2 (1–8) median cycles respectively. The number of DLTs were 1/6, 1/7, 2/4, 2/6, respectively. DLTs were G3 ALT in 4 pts and FN + TC in 1 pt. The MTD was at DL 2B and the RD was at DL 2. There were 3 partial responses (PR, 14%) and 4 SD > 3 months (19%); all PR at DL2/3. Five pts were not evaluable, 2 pts had G3 hypersensitivity reactions related to Cremophor oil (APL formulation) and 1 pt had a idiosyncratic reaction to DTIC with prolonged pancytopenia. One pt had a wrong diagnosis and 1 pt had early progressive disease (PD). Conclusions: APL + DTIC can be safely combined at ≥ 70% of their respective single- agent RD in AUM. Main DLTs were asymptomatic, transient and reversible ALT elevations. Ph Ib showed 14 % PR and 19% clinically meaningful SD. A randomised Ph II study of DTIC + APL vs APL alone is ongoing. [Table: see text]
Pharmacokinetics (PK) of CR011-vcMMAE, an antibody-drug conjugate (ADC), in a phase (Ph) I study of patients (pts) with advanced melanoma
Authors: Sznol M. , Hamid O. , Hwu P. , Kluger H. , Hawthorne T. , Crowley E. , Simantov R. , Pavlick A. 
Published: August 2020

9063 Background: CR011-vcMMAE, an ADC of fully-human monoclonal anti-GPNMB antibody (Ab) with monomethylauristatin E (MMAE), is in Ph I/II trials in pts with melanoma and breast cancer. We report PK and toxicity data from a Ph I study in melanoma pts treated every (q) 3 weeks (w), qw, or 2 of 3w. Methods: Enzyme-linked immunosorbent assays were used to measure ADC, total Ab (TA), soluble GPNMB (sGPNMB), and anti-ADC Ab in pt samples. Free MMAE was measured by liquid chromatography/mass spectrometry. Results: Initially, 32 pts were treated in 9 cohorts of 0.03 to 2.63 mg/kg iv q3w using standard 3+3 dose escalation. Noncompartmental PK analysis showed dose-proportional TA, ADC and free MMAE levels. As previously reported, maximum tolerated dose (MTD) was 1.88 mg/kg iv q3w; dose limiting toxicity (DLT) was rash. At MTD (n=15), terminal phase half life (T½) of TA was 41 ± 25h and T½ of ADC was 29 ± 13h. Mean maximum plasma concentrations of free MMAE was 1.3–2.9% of TA concentration across all doses. Mean sGPNMB at baseline was 12 ng/ml (range 1.3–32 ng/ml), corresponding to 0.024 % of TA concentration at MTD. Anti-ADC Ab were detectible in 8/240 (3.3%) samples (n=54). Based on the T½, two additional dose schedules (qw and 2 out of 3w) were initiated (n=14). Pts received 0.75 mg/kg (n=3) and 1.0 mg/kg (n=5) in the qw schedule and 1.25 mg/kg (n=3) and 1.5 mg/kg (n=3) in 2 of 3w. The most common adverse events (AEs) were rash (n=6), pruritus (n=5) and fatigue (n=4). 1 DLT (Gr 3 rash) was observed at 1.0 mg/kg qw. Enrollment is ongoing in both schedules. Conclusions: The relatively short T½ of CR011-vcMMAE (∼40h) does not appear to be due to immunogenicity or sGPNMB-mediated clearance. Preliminary data suggest that weekly dosing is tolerated at higher per-cycle cumulative doses than the q3w schedule. [Table: see text]
Tailoring end-of-life discussions to advanced cancer patients’ state of grief
Authors: Prigerson H. G. , Wright A. A. , Block S. D. , Maciejewski P. K. 
Published: August 2020

9500 Background: Prior research has shown end-of-life (EOL) discussions are not associated with significant psychological distress, but are associated with earlier referrals to hospice and lower rates of intensive care. Nevertheless, associations between EOL discussions and care received may vary depending on patients’ state of grief over their cancer diagnosis. The aim of this study was to determine how Kubler-Ross’ proposed 5 states of grief –numbness, anger, bargaining, depression, and acceptance –modify the effects of EOL discussions on EOL care received. We hypothesized that the early grief state of numbness would interfere with patients’ processing of an EOL discussion, thereby, reducing its association with care received. Methods: Coping with Cancer is an NCI/NIMH-funded, multi-site prospective, longitudinal cohort study of patients with advanced cancer, conducted from September 2002-February 2008. Analyses were based upon 316 deceased patients who were interviewed at baseline and followed until death 4.4 months later. Patients were assessed at baseline on 5 grief states in response to their cancer diagnosis (i.e., numbness, anger, bargaining, depression, and acceptance) and whether an EOL discussion with their physician had occurred. Information on medical care received in the last week of life was obtained from chart review, and regressed on the interaction between each of the 5 grief states and the patient's report of an EOL discussion. Results: Of the 5 grief states, only numbness significantly moderated the effect of EOL discussions on medical care received. For patients with higher than average numbness (i.e., ≥ 1 on the 0–4 numbness score continuum), the effect of EOL discussions on ventilation or resuscitation in the last week of life was significantly reduced by a factor of 10 [OR=9.96, 95% CI (1.21–82.2)]; the effect of EOL discussions on death in the ICU was significantly reduced by a factor of three [OR=2.98, 95% CI (1.01–8.78)]. Conclusions: Associations between EOL discussions and care received are much reduced among patients who are high on numbness (i.e., those who have not resolved the 1st grief state). Physicians should consider their patients’ grief state (i.e., numbness) when deciding whether to engage in EOL discussions. No significant financial relationships to disclose.
Geriatric medication management: Evaluation of pharmacist interventions and potentially inappropriate medication (PIM) use in older (≥65 years) cancer patients
Authors: Lichtman S. M. , Boparai M. K. 
Published: August 2020

9507 Background: Polypharmacy and inappropriate drug use are risk factors for adverse drug reactions (ADR) and poor compliance in older cancer patients. Drug evaluations in the past have not focused on this group. An evaluation of the prevalence of PIMs, pharmacist interventions, and the number and type of medications was performed. An educational component helped patients with drug management to increase adherence, avoid drug-drug and drug-disease interactions. Methods: A geriatric clinical pharmacist reviewed patient's medications, assessed understanding of their drugs, evaluated adherence, reviewed for PIMs (Beer's criteria), identified possible ADR and side effects, and provided detailed instructions. The pharmacist collaborated with the oncologist to determine appropriate therapy for the patient. Only patients over the age of 65 were eligible for this clinic. Consults were performed from March 2008 to June 2008, this includes new and follow up visits. An additional retrospective chart review was performed on 100 patients ≥ 65 years of age seen from July 2007 to November 2007. Results: There were 154 patients who underwent a prospective consultations; 74 yrs (65–91; 58% female). The interventions were: an alternative agent was recommended (31pts/20%), drug - drug interactions identified (15/10%), problems with adherence (58/37%), drugs discontinued (54/35%), additional medication (64/42%), dose change (17/11%), pain management (28/18%) and cost issues (19/12%). More then one issue was addressed during visits. In the retrospective study, median age 72 (65 - 90), 48% were females; medications: median 8 (range 0–23). Most common classes of medications were anti-hypertensives (52%), vitamins/herbals (46%), proton pump inhibitors (32%) and lipid lowering agents (29%). The prevalence of PIMs was 11%. The most common were propoxyphene, high doses of long-acting benzodiazepines and diphenhydramine. Conclusions: A geriatric medication management evaluation resulted in 50% of patients requiring specific interventions and identification of PIMs in 11% of patients. This type of intervention can optimize care by increasing adherence and avoiding adverse drug events and their serious sequelae. No significant financial relationships to disclose.
Use of age and BMD to predict fracture risk in men on androgen deprivation therapy
Authors: Lin D. , Smith M. R. , Morton R. A. , Steiner M. S. 
Published: August 2020

9517 Background: Androgen deprivation therapy (ADT) decreases bone mineral density by reducing estrogens to castrate levels and, as a result, increases fracture risk. We recently completed a two-year trial in 1382 men in which we examined the ability of toremifene to reduce fracture risk in men on ADT. Herein we describe analyses of the placebo group to assess the baseline characteristics associated with new fractures. Methods: We conducted a randomized double blind placebo controlled trial in 1382 men with histologically confirmed prostate cancer on ADT. Entry criteria included age ≥ 50 years, continous ADT for 6 months or longer or intermittent ADT for 12 months or longer. Subjects on intermittent ADT at enrollment had to remain on continuous ADT for their duration on study. Subjects were randomized to receive either 80mg toremifene citrate daily or matching placebo. The primary end point was the incidence of new morphometric vertebral fractures. Secondary endpoints included bone mineral density, clinical fragility fractures, bone turnover markers, lipid profile, hot flashes, and gynecomastia. Results: The modified intent to treat (MITT) population included subjects who took study medication and had an on-study radiograph. There were 467 subjects in the placebo MITT population. To identify factors associated with fracture risk in men on ADT we compared placebo subjects who suffered a fracture or during the first year on study suffered 7% or greater bone loss with those placebo subjects who did not. Baseline characteristics included: BMD (spine, hip, femoral neck), Age, history of fracture, ADT duration, bone turnover markers, and race. Logistic regression models of the probability of fracture/bone loss as a function of country showed that each of BMD at all sites, age, race, CTX, and history of previous fracture independently predicted fracture/7% bone loss. When all characteristics were analyzed in a multivariable model lower spine BMD (p=0.006) and older age (p=0.018) were significantly associated with incident fractures. Conclusions: In prostate cancer patients on ADT older age and lower baseline spine BMD were associated with a greater risk of fracture in untreated patients. [Table: see text]
A retrospective database analysis to assess the impact of zoledronic acid (ZOL) on skeletal-related events (SREs) in solid tumor cancer and multiple myeloma (MM) patients (pts)
Authors: Thayer S. , Cooke J. , Kaura S. 
Published: August 2020

9518 Background: For cancer pts with malignant bone lesions (BM), SREs including pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and radiotherapy and/or surgery to bone are associated with significant morbidity and mortality and reduced quality of life. ZOL is an IV bisphosphonate (BP) proven to reduce and delay incidence of SREs in several tumor types. This study was designed to assess the benefit of long-term ZOL use in a real-life setting. Methods: Claims-based analysis of commercial and Medicare data from a large US managed care plan and a 45 health-plan database was used to evaluate mortality rates, SRE rates, and time from BM to SREs in pts treated with ZOL, pamidronate (PAM), or no IV BP therapy. Pts older than 18 years with solid tumors (breast, prostate, lung, bladder, or renal cell cancers) or MM and BM diagnosed between Jan 2001 and Dec 2006 were included. Continuous enrollment in the health plan for 6 months before the index date and no prior evidence of BM or IV BP use were required. Pts were followed until they left the care plan, switched therapy, or completed the study period. SRE and mortality rates were assessed. Results: The study sample included 28,415 pts with a mean age of 62.5 ± 12.24 years; approx. 25% were treated with ZOL, 8% with PAM, and 67% with no IV BP. Incidences of first and subsequent SREs were higher in the no IV BP group (incidence rate ratio [IRR] = 2.27; 95% CI = 2.03, 2.53 and IRR = 1.3; 95% CI = 1.24, 1.37, respectively) vs the ZOL/PAM groups. Time to first SRE was delayed by approx. 153 days for ZOL vs no IV BP pts. Overall, pts who had greater persistency with ZOL had lower risks of first SRE compared with no IV BP, the greatest risk reduction being observed in the 12- to 18-month persistency cohort, which experienced > 5-fold risk reduction (IRR = 0.19; 95% CI = 0.11, 0.31). The same persistency cohort also had a 27% lower risk of developing a second SRE (IRR = 0.73; 95% CI = 0.62, 0.86) compared with no IV BP. Conclusions: This study showed that in cancer pts with BM, persistence with ZOL resulted in reduced risk of developing first and subsequent SREs. Pts with longer persistence with ZOL achieved better outcomes. [Table: see text]
Scintigraphic evaluation of mandibular bone turnover inhibition by bisphosphonates in patients with solid tumors
Authors: Van den Wyngaert T. , Huizing M. T. , Fossion E. , Vermorken J. B. 
Published: August 2020

9519 Background: Bisphosphonates (BP) have been associated with the occurrence of osteonecrosis of the jaw (ONJ), possibly by causing an excessive inhibition of local bone turnover. However, little in vivo evidence currently exists to support this theory. Methods: Whole-body scintigrams acquired after administration of 99mTc labeled medronate of 120 patients were studied. Patients with skeletal metastases from a solid tumor (n=40) were individually matched with cancer patients without BP exposure (n=40) and controls with neither a malignancy nor BP use (n=40). Controls were matched for age, gender, malignancy, steroid and hormonal therapy use, where appropriate. Patients with established ONJ or intense focal abnormalities in the studied regions were excluded. Mandibular bone turnover (MBT) was quantified relative to the femurs by defining regions-of-interest on the scintigrams with correction for background activity. The study had a power of 90% to detect a 10% reduction in MBT after BP use. Results were analyzed using a repeated-measures ANOVA with a two-sided significance level of p<0.05. Results: The patients with BP exposure (34 female, 6 male) had a median age of 62 years (range 25–80) and received a median number of 11 zoledronic acid administrations (range 1–48). Malignancies included: breast (n=30), prostate (n=4), colon (n=2) and bladder cancer (n=2); and neuroendocrine carcinoma (n=2). The mean MBT was significantly lower in BP using cancer patients (2.59) compared with matched controls from oncological patients without BP use 3.01 (difference 0.42; 95% CI 0.13 - 0.72; p=0.006), or patients without cancer or BP exposure 3.09 (difference 0.50; 95% CI 0.21 - 0.78; p=0.001). In contrast, there was no significant difference in MBT between non-BP users (difference 0.08; 95% CI -0.31 - 0.46; p=0.7). Likewise, no correlation between MBT and the number of BP administrations could be demonstrated (r2=0.01; p=0.4), suggesting a stochastic rather than a deterministic effect. Conclusions: This in vivo data suggests that BP cause a higher inhibition of bone turnover in the mandible relative to the femur, which strengthens the hypothesis that the inhibition of bone turnover may be important in the pathophysiology of ONJ. [Table: see text]