bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive utility of serum cytokine levels in patients with metastatic renal cell carcinoma (MRCC) treated with interferon alfa (IFNa)
Authors: Montero A. J. , Diaz-Montero C. , Wang X. , McIntyre B. W. , Tannir N. 
Published: March 2020

14503 Background: IFNa may prolong survival in MRCC patients (pts) due to stimulation of cell-mediated immunity. We hypothesized that IFNa exerts an anti-tumor effect by upregulation of Th1 cytokines and that patients (pts) with elevated serum levels of Th1 cytokines either at baseline (BL) or after treatment with IFNa would have a superior clinical outcome. Methods: Cytokine profiling was performed on 104 pts with MRCC treated in a randomized phase III trial with IFNa 0.5 million units (MU) subcutaneously (SC) twice daily or 5 MU SC daily. Serum samples were collected at BL (n = 104) and after 8 weeks of IFNa therapy (C1) (n = 89). Cytokine concentrations were determined using a 16-plex immunoassay. The linear mixed-effect model was fit to assess the change of cytokine levels from BL to C1. Cox proportional hazards model was fit to evaluate the effect of BL cytokine levels or change of cytokine levels from BL to C1 on the risk of death. Results: Of 16 cytokines evaluated (IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFNa, IFNg, GM-CSF, TNFa, VEGF), lower BL TNFa, IL-8 (Th1), and IL-13 (Th2) levels were associated with clinical benefit (major response or progression-free status at 6 months) (p = 0.01 and 0.03, respectively). By multivariate analysis, only extremely low or high levels of IFNa (p = 0.02) and IL-12 (p = 0.002) at BL were associated with an increased risk of death. IFNa therapy after C1 produced higher levels of several Th1 cytokines (IL-8, IL-12 p40, IL-15) (p < .001) and lower levels of Th2 cytokines (IL-4, IL-13). Unexpectedly, there were significantly lower levels of TNFa and GM-CSF (Th1) and higher levels of IL-10 (Th2) with IFNa. Only an increase of IL-2 levels from BL to C1 (RR 1.45; p = 0.05) correlated with an increased risk of death. Conclusions: Lower BL serum levels of TNFa, IL-8, and IL-13 were associated with clinical benefit to IFNa. Although IFNa therapy favored a shift towards a Th1 response, this effect alone did not correlate with clinical outcome. No significant financial relationships to disclose.
Phase I/II study of docetaxel and atrasentan in men with metastatic hormone-refractory prostate cancer (HRPC)
Authors: Moore C. N. , Creel P. , Petros W. P. , Torain T. , Yenser S. , Gockerman J. , Hurwitz H. , Garcia Turner A. , Sleep D. J. , George D. J. 
Published: March 2020

14504 Background: Docetaxel is first-line standard treatment for metastatic HRPC. New combinations with targeted therapies may improve clinical responses. . Atrasentan is an endothelin receptor A (ETA) inhibitor with an IC50 in the pM range. Clinical studies suggest atrasentan delays time to disease progression, bone turnover markers and PSA kinetics. Methods: We conducted a Phase I/II trial of docetaxel and atrasentan to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and treatment response of this regimen. Patients were treated with docetaxel IV every 3 weeks at doses ranging from 60 to 75 mg/m2. Atrasentan was given orally at 10 mg daily starting on Day 3 and continuously thereafter. Initially, we defined DLT as grade IV neutropenia, but subsequently amended the protocol to redefine DLT as grade IV neutropenia lasting ≥ 7 days. Plasma PK evaluations were conducted for each drug when administered alone (Cycle 1 Day 1, 21) and together (Cycle 2 Day 1). Serial samples were evaluated by LC-MS and data were modeled using a standard, two-stage approach. Results: 18 patients were enrolled over 3 dose levels (9 at 60 mg/m2; 6 at 70 mg/m2 and 3 at 75 mg/m2) in the phase I portion and to date 9 more patients have been enrolled in a dose expansion cohort at a docetaxel dose of 70 mg/m2. Patient demographics include median age 69, PSA level 87.3 ng/ml, hemoglobin 12.7 g/dl, and KPS 90%. DLT, initially any grade IV neutropenia, was seen at every dose level, however no grade IV neutropenia has lasted ≥ 7 days and no MTD has been defined to date. Drug-related grade III/IV toxicities included only neutropenia (42%); grade I-II toxicities included fatigue, peripheral edema, and nausea. To date, 5 of 15 evaluable patients who have been treated with 70–75 mg/m2 of docetaxel and 10 mg of atrasentan demonstrate a sustained PSA response. Preliminary PK data in 11 patients show a mean docetaxel terminal half-life of 46 hr and systemic clearance of 55 L/hr. The median difference in systemic clearance between the cycles was 18% with values increasing in 67% of subjects. Conclusions: The combination of docetaxel and atrasentan appears to be well tolerated to date. The study is ongoing to more accurately determine safety, response and potential pharmacokinetic interactions. [Table: see text]
Tumor location does not impact return of renal function following partial nephrectomy
Authors: Pettus J. , Sharp D. , Ofer Y. , Bach A. , Russo P. 
Published: March 2020

14511 Background: To study the impact of tumor location on the glomerular filtration rate (GFR) changes following partial nephrectomy. Methods: We reviewed our institutional database to identify patients who underwent partial nephrectomy between 1/1995 and 7/2005. Preoperative CT and/or MRI studies were reviewed to characterize tumors as either central or peripheral. Central tumors were defined as those involving the collecting system or renal sinus; all others were categorized as peripheral. We used the Abbreviated Modification of Diet in Renal Disease study equation to estimate GFR preoperatively, in the early postoperative hospital stay, and at 1 and 12 months after surgery. Multivariate models were fit to determine the association of tumor location with changes in GFR at each time period after controlling for age, sex, tumor size, American Society of Anesthesia Score, ischemic time, operative time, and blood loss. Results: A total of 616 patients (265 central and 351 peripheral tumors) were available for analysis. Patients with central tumors were younger compared to those with peripheral tumors (62 vs. 59, p = 0.014), had longer intraoperative renal ischemia (40 vs. 30 min, respectively, p < 0.001), and had longer operations (201 vs. 184 min, respectively, p = 0.01). Although baseline GFR did not differ between the groups, a significantly larger decrease in GFR was found in patients with central compared to peripheral tumors in the early postoperative period (−16 vs. −11 cc/min/1.73 m2, p = 0.013) and 1-month follow-up (−10 vs. −6 cc/min/1.73 m2, p = 0.017). The GFR change was similar at 1-year follow-up, −10 and −11 cc/min/1.73m2 (p = 0.586) for central and peripheral tumors, respectively. On multivariate analysis, tumor location was not significantly associated with the change in GFR at any of the time intervals after adjusting for size, ischemic time, operative time, age, sex and comorbidity. Conclusions: Patients with centrally located tumors have a more pronounced short-term decrease in GFR, which reflects a longer operative time and ischemia duration. Tumor location does not appear to impact the long-term renal function. This suggests that renal sparing surgery should not be withheld from this subset of patients. No significant financial relationships to disclose.
A phase I/II trial of RAD 001 with gefitinib in patients with castrate metastatic prostate cancer and glioblastoma multiforme
Authors: Shaffer D. R. , Abrey L. E. , Beekman K. , Eicher C. , Morris M. , Slovin S. , Feldstein J. , Larson S. , Rosen N. , Scher H. I. 
Published: March 2020

14520 Background: Inactivation of the Pten tumor suppressor gene, leading to constitutive activation of the PI3K/AKT/mTOR pathway, is correlated with resistance to EGFR-targeted therapies. This trial tested the concept that inhibition of mTOR by RAD 001 (NOVARTIS) will restore sensitivity to EGFR inhibition by gefitinib (ASTRA ZENECA), in patients with progressive PC and GBM. Methods: Phase I was designed to determine a safe and tolerable dose and the pharmacokinetics (PK) of RAD (30/ 50/ 70 mg po weekly) with a fixed dose of gefitinib (250 mg po qd) in patients with PC and GBM. Phase II evaluated the proportion of PC patients with no change or a decline in PSA at 12 weeks, without clinical or radiographic progression. FDG PET imaging and immunohistochemistry were included as correlative studies. Results: 12 patients (2 GBM, 10 PC) were treated in Phase I, and 22 of 27 PC patients have been treated in Phase II. (The GBM Phase II results are reported separately). 20/32 (63%) of PC patients had received prior chemotherapy. No dose limiting toxicities were observed in Phase I, and 70 mg of RAD 001 weekly with gefitinib 250 mg qd was studied as the Phase II dose. PK parameters estimated during a 3 week single agent lead-in phase and during subsequent combined therapy suggested no clinically relevant PK interactions between RAD and gefitinib. The most common drug-related grade 3/4 toxicities were lymphopenia (28%) and elevated ALT (7%). Serial FDG PET scans showed > 25% decline in SUV uptake in 9/23 evaluable patients during the first week of treatment; of these, 3 patients showed no progression at 12 weeks. Overall, 5/29 PC patients showed no progression at 12 weeks, 3 (60%) of whom had received prior chemotherapy. Conclusions: Combination therapy with RAD 70 mg weekly and gefitinib 250 mg daily appears to be safe and is associated with modest activity in metastatic prostate cancer. Support: Novartis Pharmaceuticals, Astra Zeneca Pharmaceuticals. [Table: see text]
Matrix metalloproteinase type 2 (MMP2) is selective expressed in adrenocortical carcinoma but not in adrenal adenoma: An immunohistochemical study
Authors: Sperone P. , Volante M. , Berruti A. , Bollito E. , Frangipane E. , Daffara F. , Terzolo M. , Gorzegno G. , Dogliotti L. , Papotti M. 
Published: March 2020

14534 Background: Adrenocortical carcinoma (ACC) is a very rare disease which account for no more than 0.2% of all malignancies, and its differential diagnosis from adrenocortical adenomas (ACA) is based on the application of different scoring systems, which, however, lack a sensitivity and specificity of 100%. Little is known on the mechanisms leading to the malignant phenotype in adrenocortical tumors; among alternative mechanisms, metalloproteinases (MMPs) have been demonstrated in solid tumors, including endocrine ones, to be implicated in malignant progression and metastatization. Our aim was to investigate metalloproteinase 2 (MMP2) expression in adrenocortical tumors. Methods: A series of 33 ACC and 23 ACA was retrospectively collected from a large series of adrenocortical lesions, and the diagnosis was reviewed independently by three investigators (MV, EB, MP) according to the Weiss histological criteria. MMP2 was determined by immunohistochemistry and the results scored by semi-quantitative analysis, based on the intensity of the staining and the percentage of tumor cells positive. Immunohistochemical results were compared to clinico-pathological parameters, such as sex, age, hormonal secretion, and outcome. Results: MMP2 expression was detected in 1/23 ACA (4%), and in 25/33 ACC (76%) (X-square test p < 0.001). MMP2 immunohistochemical pattern in ACC was focal to moderate to strong in 10, 12 and 3 cases, respectively. In addition, moderate to strong MMP2 expression, as compared to low or negative immunostaining, correlated with shorter disease-free survival (p = 0.012) and poor outcome (p = 0.07). No correlation were found comparing MMP2 expression and other clinico-pathological parameters. Conclusions: As reported in a variety of solid tumors, our data indicates a possible role of MMP2 in the malignant evolution of adrenocortical tumors, and its immunohistochemical localization may be a potential useful tool in the differential diagnosis of benign versus malignant adrenocortical lesions. In addition, a strong immunohistochemical MMP2 expression seems to be related to a poor prognosis in ACC. No significant financial relationships to disclose.
Altered expression of β-catenin and UDP-glucose dehydrogenase in normal appearing acini of cancer-bearing prostate glands, detected by quantitative fluorescence imaging analysis
Authors: Huang D. , Casale G. P. , Wehbi N. K. , Tian J. , Hemstreet G. P. 
Published: March 2020

14540 Background: Expression of β-catenin and UDP-glucose dehydrogenase (UGDH) is markedly altered in prostate adenocarcinomas. The objective of this work was to evaluate expression of these proteins in normal appearing acini (NAA) of cancer-bearing prostate glands, as potential biomarkers of PC field disease. Methods: Archived core biopsies of 42 pairs of PC cases and controls were labeled for β-Catenin, and a tissue microarray of 10 prostatectomy specimens of cancer cases and controls were labeled for UGDH. A fluorophore-conjugated secondary antibody was incorporated into the staining protocol. Fluorescence in prostatic acini was measured with an automated Leica microscope and Image Pro Plus software and expressed as mean pixel intensity (MPI) per acinus and average MPI (AMPI) per case or control. Results: Mean AMPI of β-catenin in NAA of 33 cases (545 ± 93) was lower (p < 0.01) than that of normal acini (NA) in age-matched controls (684 ± 90), whereas mean AMPI of NAA in the remaining 9 cases (712 ± 111) was higher (p = 0.003) than that of the matched controls (634 ± 95). Twelve cases under-expressing β-catenin in NAA had AMPIs below the lowest AMPI (506 ± 83) of all controls. Mean AMPI of UGDH in NAA of 7 cases (372 ± 169) was lower (p < 0.05) in comparison to both NA (558 ± 119) and cancerous acini (CA) (645 ± 88). The difference between CA and NA did not achieve statistical significance. Conclusions: Reduced expression of β-catenin is a cancer-associated event in NAA. A cut-off AMPI (506) for β-catenin detected 29% of PC cases with 100% specificity. Altered expression of UGDH in NAA is a potential biomarker of PC. Funded by DoD grant DAMD17–02–1-0121. No significant financial relationships to disclose.
Permanent 125I prostate brachytherapy outcome in patients younger than 60
Authors: Linstadt D. E. , Logsdon M. , Stickney D. , Chabra D. , Russo M. , Workman S. 
Published: March 2020

14553 Background: Permanent 125I prostate brachytherapy (PB) has been shown to be an effective form of treatment for men with clinically localized prostate cancer. However, the efficacy of PB in younger men is not well established, and many urologists and oncologists have been reluctant to recommend PB to younger men, since most reported PB outcome has been based on men implanted in their late 60s and 70s. Methods: Between 1/1/98 and 6/30/01, 100 consecutive men aged 49–59 (median 56) underwent PB. All had either low- or intermediate-risk disease. PB was performed without combined external beam irradiation or post-PB androgen deprivation. The prescribed radiation dose=144–145Gy, the median implant activity=38mCi, median prostate volume=36 ml. Mean day-30 post-PB CT-based implant dosimetry values were V100=94%; V150=60%; D90=160 Gy. The primary endpoint for this analysis was the 5-year biochemical no evidence of disease rate (bNED) defined by the ASTRO consensus definition. Secondary endpoints were disease-specific survival (DSS); freedom from salvage therapy (FSRx), and overall survival (OS). Median PSA followup was 59 months (maximum 93 months). Actuarial results were calculated using the Kaplan-Meier method. Results: The 5-year bNED rate was 92%. 8 patients developed biochemical failure, and 6 went on to salvage treatment with hormonal therapy. There were 2 biopsy-proven local recurrences: one in a patient with previously diagnosed bony metastases, and one with isolated seminal vesicle recurrence (prostate biopsies negative). 3 other patients with biochemical failure had negative re-biopsies at 24, 64, and 66 months post-PB. No patient received local salvage therapy. One patient died from a second malignancy (colon CA diagnosed after PB). The 5-year DSS rate = 100%; FSRx = 93%, and OS = 99%. There were 2 Grade 3 GU complications (urethral strictures) (2%) and one Grade 4 GU complication (TURP) (1%). There were no Grade 3 or 4 GI complications. Conclusions: PB is an effective treatment modality for men younger than 60, with 5 year results comparable to those reported with prostatectomy and external beam irradiation. Given that most men who fail PB do so within 5 years of the implant, there appears to be no compelling scientific reason to advise against PB in men younger than 60 solely based on their age. No significant financial relationships to disclose.
Phase II study of FK228 in patients with hormone refractory prostate cancer (HRPC)
Authors: Molife R. , Patterson S. , Riggs C. , Higano C. , Stadler W. M. , Dearnaley D. , Parker C. , McCulloch W. , Shalaurov A. , De-Bono J. S. 
Published: March 2020

14554 Background: FK228 is a bicyclic depsipeptide that inhibits histone deacetylase (HDAC). HDAC inhibition results in accumulation of hyperacetylated histone proteins resulting in G1 and G2/M arrest, differentiation of transformed cells and apoptosis. FK228 can also inhibit HSP90, ablating androgen receptor expression. Methods: FK228 was administered intravenously at 13mg/m2 on days 1, 8 and 15 of a 28-day schedule for up to 6 cycles. Sixteen patients were treated in stage 1. If ≥ 1 response was seen, an additional 9 patients were to be recruited. Eligibility criteria included: no prior chemotherapy, metastatic disease, ≤3 lines of hormonal therapy, QTcB <500 msec, Karnofsky PS ≥80. The primary endpoint was to measure rate of disease control (complete response [CR], partial response [PR], stable disease [SD] for 6 months). Secondary endpoints were PSA response rate, time to PSA and objective disease progression, safety profile, effect on disease related symptoms and pharmacokinetics (PK) of FK228. Results: Interim results are available after 16 patients were enrolled in stage 1 and 5 patients in stage 2. Median age (n = 21): 65 years (range 43–77). 3 patients have completed 6 cycles of treatment, 4 are ongoing and 14 have discontinued. 16 patients are evaluable for radiological response and 18 for PSA response: 1 has achieved a confirmed radiological PR (6 months [m]), and 6 have confirmed SD (2 for 6m, 1 for 5 m, 1 for 4 m+, 1 for 3 m+). 2 of 18 have had a 50% fall in PSA (6 m, 4 m+) and another a 40% fall (5m). Most common drug related adverse events are (grade [gr],%): fatigue (gr 1–2, 88%), nausea (gr 1–2, 77%; gr 3, 10%), anorexia (gr 1–2, 72%), vomiting (gr 1–2, 55%; gr 3, 10%), non-specific asymptomatic ECG changes (gr 1–3, 44%), diarrhoea (gr 1–2, 38%), thrombocytopaenia (gr 1–2, 33%) and weight loss (gr 1, 20%). Conclusions: Interim results of treatment with FK228 suggest clinically relevant antitumor activity with an 18% disease control rate and a 11% PSA response rate. Toxicity is manageable. Accrual into the study continues. [Table: see text]
Salvage radiotherapy (SR) in patients (pts) with prostate cancer (PC) and rising prostate specific antigen (PSA) after radical prostatectomy (RP): Results from a single-center study
Authors: Wiegel T. , Lohm G. , Hoecht S. , Bottke D. , Neumann K. , Hinkelbein W. 
Published: March 2020

14556 Background: In pts with PC and biochemical relapse after RP SR is well established. However, the significance of pre-radiotherapeutic variables for guidance of treatment decisions is less clear. We analyzed prognostic factors in a large cohort of pts treated with SR after RP. Methods: 163 pts with PC and persisting PSA-levels (n = 60) or PSA-elevation following undetectable PSA-levels (n = 103) after RP received three-dimensional conformal radiotherapy (RT). None received androgen depriving therapy between prostatectomy and start of RT. We evaluated the impact of age, stage, surgical margin status (SMS), Gleason score and PSA-kinetics by survival and regression analysis. Biochemical progression (BP) was defined as PSA-increases at 3 consecutive time points after the post RT nadir. To detect thresholds for significant prognostic variables, we calculated receiver operating characteristic (ROC) curves. Results: Medians for pre-RT variables were: 11.97 ng/ml for pre-prostatectomy PSA (Pre-OP PSA), 5.4 months for PSA doubling time (PSADT) and 0.339 ng/ml for pre-radiotherapy PSA (Pre-RT PSA). Probability for a projected 4-year PFS was 50% (median follow-up: 33.5 months). Logistic regression revealed a significant impact on the probability of BP for Pre-OP PSA (p = 0.036), PSADT (p = 0.024) and tumor-stage (p = 0.043), whereas Pre-RT PSA and SMS had a significant impact on achievement of undetectable post-RT PSA (p = 0.009 and p = 0.028 respectively). Analysis of ROC-curves for Pre-OP PSA, Pre-RT PSA, PSADT revealed an area under the curve not exceeding 0.704 for any of these parameters. Conclusions: By analyzing ROC-curves we could not detect clear thresholds for PSA kinetic variables. In accordance with recently published data we found similar independent significant variables predicting a therapeutic success. However, we observed a lower median Pre-RT PSA and a higher probability of PFS in our patient cohort. This suggests, that early radiotherapeutic intervention improves PFS. No significant financial relationships to disclose.
Diagnosis of local relapse after radical radiotherapy (RRTH) of prostate cancer by biochemical PSA kinetics and transrectal ultrasonography (TRUS) verified by prostate biopsy
Authors: Nietupski K. E. , Demkow T. , Skoneczna I. , Pilichowska M. , Peczkowski P. , Kraszewska E. , Ligaj M. , Poniatowska G. , Sieczych A. , Chaladaj-Kujawska A. , Sikora B. 
Published: March 2020

14631 Background: Patients (pts) with the cancer of the prostate after radical radiotherapy (RRTH) are followed by clinical examination, periodical measurements of PSA level, bone scan, bone x-ray examinations, CT of abdomen and pelvis. The biochemical progression (according ASTRO Consensus Panel) is not always equal the clinical progression. The next step in all cases of rising PSA is to diagnose or to exclude the local progression, which has to be distinguished from systemic progression. Methods: Prospective evaluation of effectiveness of the biochemical indicators as predictors of local relapse after RRTH and probability of positive tru-cut biopsy outcome in case of positive TRUS result. 51 pts with prostatic adenocarcinoma after RRTH, who experienced biochemical (PSA) progression were included. All of them had a negative bone scan results, negative abdomen-pelvis CT scan or ultrasonography and no clinical evidence of distant metastases. All pts underwent a tru-cut biopsy guided by TRUS. Each of them were eligible to local salvage procedures. The TRUS-guided tru-cut biopsy were performed in all pts. Results: The median observation time (between RRTH and biopsy) was 34 mo (11–78). The median PSA level at the biopsy was 2.46 ng/ml (0,69–11,26). TRUS was positive in 20/51 pts. In 31 pts, there was no evidence of local progression in TRUS. TRUS specificity was 62.02% (95% CI 48.75–75.39%) and sensitivity 40.91% (95% CI 27.42%–54.40). The biopsy outcome was positive in 22/51 pts (43%). The biopsy was positive in 58% (25/26) in subgroup with PSA level lower than 2.46 ng/ml and 27% (7/25) in group with PSA upper to this value. There were no significant associations between positive biopsy outcome and PSA velocity. Conclusions: In pts with suspicion of local relapse we observed the low predictive value of PSA level at biopsy (area under ROC curve = 0.6113). There were no associations between positive biopsy outcome and PSADT (PSA doubling time) which could help in better selection for invasive procedure. No significant financial relationships to disclose.