bluuebunny/crossref_metadata_2025 huggingface dataset:
Literacy and race predictors in localized prostate cancer treatment choice
Authors: Wolf M. S. , Zagory J. A. , Chang C. , Knight S. , Ray P. , Kozloff M. , Starr A. , Lyons E. A. , Costello S. , Bennett C. L.
Published: March 2020

14541

Background: Studies have shown that African American populations have low rates of surgery, while similar assessments based on literacy skills have not been reported. Methods: Newly diagnosed prostate cancer patients (n = 311) were approached at 3 hospitals: private, county, and VA. Patients completed demographic and quality of life questionnaires as well as a literacy assessment at baseline, 3 month, and 12 month intervals. Results: Majority (60%) of African American patients were at low functional literacy. In multinomial regression analysis controlling for patient age, clinical stage at presentation, comorbidity, and treatment site, both African American race (RRR 2.4, 95% CI 1.35–5.91) and low literacy (6th grade reading level or below) were significantly and independently associated with a greater likelihood to receive external beam radiation treatment only in relation to other treatment options (AOR 4.26, 95% CI 2.34–7.75). Conclusions: In our inner city population of prostate cancer patients, white patients with high literacy skills opted for radical prostatectomy and persons with low literacy and/or African American race opted for radiation therapy.

No significant financial relationships to disclose.
Activity of the Src-kinase inhibitor AZD0530 in androgen-independent prostate cancer (AIPC): Pre-clinical rationale for a phase II trial
Authors: Evans C. P. , Lara P. N. , Kung H. , Yang J. C.
Published: March 2020

14542

Background: Cells with neuroendocrine (NE) differentiation are found in prostate cancer and may facilitate the transition to AI by supplying alternate growth factors. Androgen deprivation further induces a subgroup of AI NE cells by transdifferentiation. We hypothesized that androgen receptor (AR)- and src kinase-mediated signaling participates in this NE progression, and tested inhibition using the src kinase inhibitor AZD0530. Methods: The neuropeptide gastrin-releasing peptide (GRP) was minimally expressed in androgen-sensitive LNCaP cells. LNCaP-GRP clones demonstrated androgen- and anchorage-independent growth, developed orthotopic tumors in castrated SCID mice & activated PSA with nuclear localization of AR. LNCap-GRP clones & xenografts showed activation of src kinase. Xenografts were recultured (LNCaP-Pro) & grown in androgen-free soft agar or tissue culture either alone, with synthetic androgen R1881 or with inhibitors including: GRP monoclonal antibody 2A11, 10 μM antiandrogen bicalutamide, Src kinase inhibitors AZM475271, AZD0530 (5 μM) and PP2 (10 μM). Mice bearing orthotopic LNCaP-GRP tumors were treated orally with 50 mg/kg AZD0530 daily for 6 weeks. Results: Androgen-depleted soft agar colony counts showed that LNCaP-Pro cell proliferation was not stimulated by R1881 but was partially inhibited by 2A11 antibody or bicalutamide, when compared to controls. A combination of 2A11 & bicalutamide resulted in significant growth reduction (p < 0.05). R1881 mostly reversed the 2A11 inhibition. The Src kinase inhibitors AZM475271 & PP2 showed greatest colony formation inhibition (p < 0.05). AZD0530 inhibited growth in culture (not tested in soft agar) at micromolar concentrations. Testing in vivo inhibited primary tumor growth in 5 of 7 dosed mice (71%), but completely inhibited metastasis in all AZD0530-treated mice (compared with metastasis in 100% of controls). Conclusions: Neuropeptide-mediated AIPC growth is dependent on both GRP and AR. There appears to be a beneficial role for Src kinase inhibition in this model. A CTEP-sponsored phase II trial of the dual Src/Abl kinase inhibitor AZD0530 in AIPC has been initiated. (KO8 DK60748–01, 2RO1 DK/AG52659–04, DOD PC10520, Astra-Zeneca, NO1 CM17101).

[Table: see text]
Effect of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases based on performance status
Authors: Barghout V. , Abetz L. , Arbuckle R. , Bosch V. , Hei Y. , Saad F.
Published: March 2020

14544

Background: Z has demonstrated efficacy in reducing, preventing, delaying the occurrence of an SRE (Skeletal Related Event) including pathologic fractures, severe bone pain requiring radiation therapy, spinal cord compression, surgery to bone and hypercalcemia of malignancy which could lead to a loss of independence. Effects of Z on pain were analyzed in a subgroup of patients based on performance status. Methods: Subjects were randomised to Z 4mg (n = 201) or placebo (n = 201). The short form of the Brief Pain Inventory (BPI) was administered at baseline (visit 2), and visits 3 (weeks 3–4), 4 (weeks 6–8), and then every second visit (every 6 weeks) until study end. Changes in BPI individual item scores and the Pain severity and Pain Interference scale scores were compared between Z and placebo groups. Post baseline missing data were replaced by Last Observation carried forward (LOCF). Changes in scores were examined in the subgroup of patients with ECOG performance status scores of ≥ 1. Results: For patients ECOG score of ≥ 1 at baseline (n = 227), Z was superior to placebo in the BPI items ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the Pain Severity scale at visit 4 (weeks 6–8) and visit 6 (week 12) (p < 0.05). At visit 8 (weeks 18–20) Z was superior to placebo on the ‘pain on average’ item and Pain Severity scale (p < 0.05). For visit 12 (weeks 30–32) and for LOCF Z was superior to placebo for ‘pain at its worst’, ‘pain on average’ and Pain Severity (p < 0.05 for all). For the ‘pain right now’ item there were statistically significant differences at visits 4, 6, 12 and LOCF (p < 0.05). In addition, at visit 6 (week 12), Z was superior to placebo for changes in items assessing interference with: sleep, general activities, mood, walking and enjoyment of life (p < 0.05). Z was also superior to placebo for ‘interference with general activities’ at visits 12 (weeks 30–32), 16 (weeks 42–44) and LOCF (p < 0.05). Conclusion: Results suggest Z provides significant benefit in pain reduction and Z may have an impact on patients’ daily activities which may lead to a preservation of patients’ functionality.

[Table: see text]
Clinical experience with extended lymph node dissection during radical prostatectomy
Authors: Sonpavde G. , Slawin K. , Levitt J. M. , Guariguata L.
Published: March 2020

14545

Background: The value of the extent of lymph node dissection at radical prostatectomy remains controversial. We report our experience with extended lymph node dissection in patients undergoing open radical prostatectomy. Methods: 201 consecutive patients with cT1c-cT3a prostate cancer who underwent open radical prostatectomy with an extended regional lymph node (LN) dissection of up to six packets (iliac, hypogastric, and obturator; right and left) by a single surgeon at The Methodist Hospital between July 2002 and April 2004 were studied. No patient was treated with adjuvant radiation or hormonal therapy before elevated PSA levels were observed. Ultrasensitive PSA (uPSA) using the 3rd generation Immulite assay (DPC) was performed periodically beginning at 6 weeks post operatively. A uPSA level ≥ 0.03 ng/mL and rising on at least one subsequent uPSA obtained at least six weeks later was classified as a biochemical recurrence (BCR). Results: The mean patient age was 59 years at the time of surgery (median, 59; range, 39 to 73 years). Median follow-up after surgery was 21 months (range 1–37 months). Gleason Score was ≤ 6, 7, and 8–10 in 37%, 53% and 10% of patients, respectively. Sixty-two patients had extra prostatic extension and 16 patients had seminal vesicle involvement. A total of 3125 pelvic lymph nodes were removed (per patient: mean, 15.64; median, 15; range 4–42). Of these 22 LN (0.71%) were positive in 11 (5.5%) patients. By specified region, 2/1775 (0.23%) of iliac nodes, 6/642 (0.93%) of hypogastric nodes and 9/708 (1.27%) of obturator nodes were positive. Of the 11 patients with positive LN, 3/11 (27.27%) had positive iliac nodes, 6/11 (54.54%) had positive hypogastric nodes, and 6/11 (54.54%) had positive obturator nodes. Using a very stringent definition of BCR in order to compensate for the relatively short follow-up period, the 2 year progression-free survival (PFS) for patients with at least one positive LN was 37.5%. Conclusions: Extended LN dissection may alter the biology of early nodal metastatic prostate cancer and lead to longterm PFS without additional therapy. A higher percentage of patients and nodes are positive in the hypogastric and obturator regions, supporting the rationale to include these with the iliac nodes when performing LN dissection.

No significant financial relationships to disclose.
A ligand-independent androgen receptor function protects from inositol hexakisphosphate-induced cell death
Authors: Diallo J. , Péant B. , Lessard L. , Delvoye N. , Le Page C. , Mes-Masson A. , Saad F.
Published: March 2020

14566

Background: The androgen receptor (AR) is often aberrantly expressed or activated in hormone-refractory (HR) prostate cancer (PCa). Though it is not clear whether this is directly linked to AR expression, various cell survival pathways are over-activated in HR-PCa, which is characterized by its poor clinical outcome and resistance to available therapies. Inositol hexakisphosphate (IP6) is a phytochemical anti-cancer agent, which we have found to be more effective in PCa cell lines that do not express the AR. Our goal was to address the mechanism of IP6-induced cell death and to evaluate if and how the AR may interfere with its activity. Methods: We used LNCaP, DU145, 22Rv1 as well as wild-type PC3 and AR-expressing PC3 (PC3AR) cell lines to assess the metabolic toxicity of IP6 by WST-1 assay in normal, androgen-supplemented, and androgen-depleted cell culture conditions. A siRNA targeting the androgen receptor (AR) was used to control for genuine AR-mediated effects in the PC3/PC3AR cell lines. Apoptosis was quantified using fluorogenic caspase-3 assays as well as quantitative DNA fragmentation assays. Expression of a variety of genes involved in apoptosis and cell survival pathways was evaluated by real time PCR. Results: While the activity of IP6 was not modulated by the presence of androgens for any cell line, PC3AR cells were significantly more resistant to IP6 than wild-type PC3 cells according to WST-1, caspase-3 and DNA fragmentation assays (p < 0.05). Down-regulation of the AR in the PC3AR cell line resulted in increased metabolic toxicity of IP6 on these cells (p < 10−5). Although treatment with IP6 resulted in the up-regulation of the pro-apoptotic genes Puma, Noxa, as well as of IRF-2 and IkB-αλπηα in PC3 cells, this did not occur in PC3AR cells (p < 0.05). Conclusion: We conclude that, at least in PC3/PC3AR, cells IP6 sensitivity is linked to a ligand-independent function of the AR. To our knowledge, this is the first report of a ligand-independent AR function involved in resistance to a cytotoxic compound. Establishing the molecular details of this novel function is a major part of our ongoing research.

No significant financial relationships to disclose.
Serum pharmacoproteomics of erlotinib-treated advanced prostate cancer patients: A SELDI-TOF mass spectrometry analysis
Authors: Gonçalves A. , Taylor B. , Toiron Y. , Esterni B. , Salem N. , Bladou F. , Viens P. , Gravis G.
Published: March 2020

14603

Background: EGFR (Epidermal Growth Factor Receptor) is a promising target in various epithelial cancers. Erlotinib is an orally active small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, under evaluation in prostate cancer. To identify protein biomarkers associated with EGFR TKI treatment we performed serum protein profiling in advanced prostate cancer patients receiving erlotinib, using Surface Enhanced Laser Desorption/Ionization-Time of Flight Mass Spectrometry (SELDI-TOF MS). Method: Serums from 23 advanced or metastatic prostate cancer patients enrolled in a phase II study of erlotinib as single agent were collected before treatment, on D28 and D56 and kept frozen in liquid nitrogen until analysis. Serum samples from each patients and each time points were first urea treated and then incubated with 3 different ProteinChip arrays (Ciphergen Biosystems): IMAC-Cu, CM10 and H50 using a fully automated platform (Tecan). After adding SPA matrix, arrays were analysed using a PBSIIc ProteinChip reader (Ciphergen Biosystems). After noise reduction, baseline substraction, and data normalisation, protein peaks were detected using the Biomarker Wizard tool integrated to the ProteinChip Software 3.1. Numeric data were then exported to excel files that were used for further biostatistic processing. Results: Combining protein profiles resolved from each experimental condition, several hundreds of protein peaks were obtained. Protein profiles from untreated and D28 and D56-treated patients were compared using non-parametric statistical methods and several protein peaks appeared differentially expressed between pre and post-treatment samples. Supervised methods identified protein peaks correlating with specific erlotinib toxicity on day 28. Since only minimal activity was noted in this trial, no protein profile correlating with anti-tumor effect was identified. Purification and identification of proteins modulated by treatment and associated with toxicity are ongoing. Conclusion: Serum protein profiling using SELDI-TOF MS is a promising method to characterize pharmacoproteomics of innovative compounds under development and to identify protein biomarkers potentially associated with drug effects.

No significant financial relationships to disclose.
ErbB1–4 expression in prostate cancer patients and its correlation to patients’ ethnicity and outcome
Authors: Ben-Yosef R. , Barnea I. , Sarid D. , Vexler A. , Marmor S. , Starr A. , Greif Y. , Inbar M. , Barak N.
Published: March 2020

14615

Background: ErbB family is involved in both cancer progression and treatment response in solid tumors. Few inconclusive studies reported on ErbB over-expression in prostate cancer. We investigated ErbB1–4 expression in prostate cancer patients and its correlation to patients ethnicity and outcome. Methods: ErbB expression was evaluated by immunohistochemistry of prostate cancer specimen using polyclonal antibody (Santa Cruz, CA). The staining was recorded as negative (0/+1), moderately positive (+2) and highly positive (+3). Kattan nomogram was used to predict 5-yr progression-free probability, assuming that all patients received external beam radiation therapy (a total dose of 78 Gy) and hormonal manipulation. Origin was counted in all 43 patients: Ashkenazic patients were defined as those who immigrated from East/West Europe or North America and Sephardic patients - from Middle East and North Africa. Results: ErbB1 (+2/+3) was over-expressed in 12 and 7 patients for a total of 19/43 (44%). ErbB2 over-expression (+2/+3) was not found in all patients. ErbB3 over-expression of +2 was seen in 2 patients and none had +3 (2/43, 5%). ErbB4 over-expression (+2/+3) was seen in 5 and 11 patients for a total of 16/43 (37%). 22 patients were Ashkenazic and 21 - Sephardic. ErbB1 over-expression in Ashkenazic and Sephardic groups was 9/22 (41%) and 10/21 (48%). ErbB4 over-expression in the two groups was 7/22 (32%) and 9/21 (43%). Kattan score of <80 was seen in 20/43 and <60 in 7/43 patients. ErbB1 over-expression was noted in 11/20 and in 4/7 patients. ErbB4 over-expression was seen in 7/20 and in 4/7 patients. In both ErbB1 and ErbB4 over-expression and Kattan nomogram of <80 and <60 the Sephardic ethnicity dominated-7/11 (64%), 3/4 (75%), 5/7 (71%) and 3/4 (75%). Conclusions: ErbB1 and ErbB4 over-expression is presented in 43% and 37% patients while ErbB3 was over-expressed in 5%; no over-expression of ErbB2 was observed. Ashkenazic and Sephardic ethnicity were evenly distributed in the over-expressed ErbB1 and ErbB4 patients. However, a tendency to a worse prognosis, based on Kattan nomogram, was seen in over-expressed ErbB1 and ErbB4 patients from Sephardic ethnicity. Further studies on ethnicity and ErbB prevalence and prognosis are warranted.

No significant financial relationships to disclose.
Retrospective comparison of treatment outcome and cost effective analysis of BEP and VIP for poor-prognosis metastatic germ cell tumors in India
Authors: Dadhich H. K. , Attili S. V. , Saini K. S. , Batra U. , Jacob L. A. , Anupama G. , Singhal N. , Pp B.
Published: March 2020

14638

Purpose: Retrospective comparison of treatment out come and cost effective analysis in two chemotherapeutic regimens (BEP vs. VIP) for poor-prognosis metastatic germ cell tumors in India, a resource poor nation. Methods: All male patients with poor risk germ cell tumors were included in the study between 2001–2003. The patients were stratified into two categories depending on the type of the regimens they received. Results: Finally 36 patients were analyzed with median follow up of 21.8 months. Medical 7.5 for windows was used for the analysis. The baseline characters (age, stage, PS, histology and serum markers) were not different in two treatment arms (P > 0.05). The different treatments (BEP vs. VIP) had no statistically significant influence on the outcome. VIP is less cost effective and more toxic compared to BEP. Conclusion: In view of absence of survival advantage and more toxicities as well as cost of therapy it would be appropriate to still treat the patients of high risk germ cell tumors with the conventional BEP rather than VIP in the Indian setting and keeping the later reserved for the relapse. [Table: see text]

No significant financial relationships to disclose.
A phase II study of ixabepilone (BMS 247550) in metastatic renal cell carcinoma
Authors: Posadas E. M. , Undevia S. , Colevas A. D. , Manchen E. , Vokes E. E. , Stadler W. M.
Published: March 2020

14646

Introduction Ixabepilone (BMS) is a semi-synthetic analog of Epothilone B that functions as a microtubule stabilizer and has anti-cancer effects in several cancers including renal cell carcinoma (RCC) (Zhuang, ASCO 2004). The initial phase II study in RCC utilized a difficult and unconventional dosing schedule (6 mg/m2 IV days 1–5 every 21 days). Hence, this phase II study in RCC was designed to verify previous observations and to test the safety, feasibility, and activity of administering BMS once every 3 weeks- a schedule used in other malignancies. Methods Treatment consists of BMS 40 mg/m2 IV on day 1 every 3 weeks. Eligibility included metastatic RCC with clear or non-clear cell histology, no limits on the number of previous treatments, performance status 0–2, and normal organ function. The primary endpoint is the overall response rate by RECIST criteria on radiologic evaluation conducted every 9 weeks. Accrual to the full planned 41 patients (pts) will proceed provided that 2 or more responses are observed in the first 21 pts. Results Ten pts have enrolled (4 clear cell) with 1 declining participation prior to receiving any treatment. Eight pts have completed at least 3 cycles. Grade 3–4 toxicities include lymphopenia-2, diarrhea-2, alopecia-1, and infection-1. Grade 1–2 toxicities seen in more than 50% of pts include alopecia, neuropathy, nausea, fatigue, anemia, and lymphopenia. We have observed 1 unconfirmed partial response of short duration and 1 pt exhibited stable disease with a minor response but discontinued treatment due to excessive neurotoxicity. Three pts continue on treatment. Conclusions Toxicity at 40 mg/m2 IV on day 1 every 3 weeks is higher than previously reported with the daily x 5 schedule. While lymphopenia, diarrhea, neuropathy, and fatigue are all expected adverse events, the rates of toxicity across all grades is higher than previous reports. VHL mutation analysis is planned and will be correlated with response to therapy. Accrual and pt follow up continue.

No significant financial relationships to disclose.
Prospective evaluation of a “Watchful Waiting” program using initial pathology criteria and PSA-doubling time monitoring for patients with stage T1c prostate cancer
Authors: Kakehi Y. , Kamoto T. , Ogawa O. , Tobisu K. , Saito Y. , Fukuda H. , Kakizoe T.
Published: March 2020

14651

Background: “Watchful waiting (WW)” is becoming a common treatment option for patients (pts) with screening detected prostate cancer. There is, however, no consensus about which pts are suitable for WW and how pts are monitored. Methods: Eligibility criteria: 1) stage T1c prostate cancer pts, 2) age 50–80, 3) serum PSA: 20 ng/ml or less, 4) 1 or 2 positive cores per 6 to 12 systematic core biopsies, 5) Gleason score of 6 or less, 6) 50% or less maximum % cancer occupation in a positive core. The criteria of 4), 5), 6) were confirmed by a central pathologist before pts registration. Registered patients chose either WW or immediate aggressive treatment. In patients who chose WW, serum PSA was monitored every 2 months for 6 months and PSA-doubling time (PSADT) was calculated centrally. Those who showed PSADT 2y and re-biopsy at 13 months fit the initial pathology criteria again. Primary endpoint was “% PSADT > 2 y”, which was defined as proportion of patients who showed PSADT at 6 months > 2 y out of all patients who chose WW. Point estimate of “% PSADT > 2 y” was expected to be higher than 80%. The planned sample size was 100 pts who chose WW, which gives the width of 95% confidence intervals for % PSADT > 2 y within 10%. Results: 134 pts were enrolled from 01/2002 to 12/2003 and 118 pts chose WW while 13 pts chose aggressive treatment (surgery, radiotherapy, hormonal therapy). The initial 6 months’ PSADT could be assessed in 106 patients (measurement point error in 6, early dropout in 6). Of 106 patients, 22 showed PSADT < 2 y (“rapid riser”) while 84 showed PSADT > 2 y. “% PSADT > 2 y” was 71.2% (84/118, 95% CI: 62.1–79.2%). 84 pts have continued WW with median follow-up of 27 months. Neither metastasis nor cancer-death was observed until 06/2005. As to health-related QOL, any domain of SF-36 was not impaired in patients who continued WW at least for 1 year. Conclusion: Our initial selection criteria for WW may include at least 20% of “rapid riser”, hence need further modification. Additionally, it should be confirmed by further follow-up of 84 pts whether eliminating “rapid riser” from WW by initial 6 months’ PSADT is appropriate.

No significant financial relationships to disclose.
Increased cytoplasmic localization of KLF5 in prostate cancer
Authors: Tsai H. T. , Datta M. , Frierson H. , Dong X. , Qiu Y. , Sun S. , Dong J.
Published: March 2020

14652

Background: KLF undergoes genomic deletion, transcriptional downregulation, and excessive protein degradation in prostate cancer cells, but its protein expression has not been examined in prostate cancer specimens. Methods: We performed immunohistochemical staining on a tissue microarray composed of 37 benign prostate tissues, 58 primary prostate cancers, and 9 metastatic tumors. Cultured cells without KLF5 expression and those expressing KLF5 through gene transfection were used as controls. Each sample was scored for presence of staining, nuclear or cytoplasmic localization of staining, and intensity of staining (0, no staining; 1, below counterstain; 2, equal to counterstain; 3, strong staining obscuring counterstain). KLF5 expression was correlated with pathologic characteristics of tumors by performing Chi-square analysis and two tailed t tests. Results: KLF5 staining was noted in all 104 specimens, either as nuclear staining, cytoplasmic staining, or both. While no significant differences were seen in the intensity of the nuclear staining between benign and tumor groups, a significant increase in cytoplasmic staining was seen in tumor specimens (2.24 vs. 1.71, p = 0.0002). In addition, samples with high cytoplasmic and low nuclear KLF5 were more likely to be tumor samples (p = 0.0413). No significant differences were seen between samples with Gleason grades, or between primary tumors and metastases. Conclusions: Increased cytoplasmic localization of KLF5 may impair KLF5’s transcription factor function in the development and/or progression of prostate cancer.

No significant financial relationships to disclose.
Late cardiovascular toxicity of BEP regimen among testicular cancer patients
Authors: Sadowska M. A. , Wiechno P. J. , Greszata L. , Paluchowska B. , Demkow T.
Published: March 2020

14658

Background: Testicular cancer is the most common neoplasm in young men population. Standard chemotherapy for metastatic disease is BEP regimen (cisplatin, bleomycin, etopozyd). Evaluation of some late toxicities regarding cardiovascular system in patients with testicular cancer treated with orchidectomy and standard BEP regimen in comparison with patients treated with orchidectomy alone is presented. Methods: From February 2003 till July 2004, 153 patients (median age 37 year, range: 19–70) were enrolled into the study. The first group consisted of 93 men with metastatic testicular cancer, treated with orchidectomy and standard BEP regimen (3–10 courses, median 4). A control group consisted of 60 patients with stage I testicular cancer, after orchidectomy but without cytotoxic treatment. The patients who failed first line treatment or progressed were excluded from the study. Disease free survival was at least 2 years, median - 74 months (range: 24–327). Authors of the study created an inventory assessing cardiovascular risk factors, which was completed by every patient. Evaluation of the patient consisted of ECG, echocardiography, blood tests, assessment of the Body Mass Index and the risk of cardiac ischaemia incident according to the Polish Society of Cardiology guidelines. Results: Abnormal cardiac rhythm was more frequent among patients after chemotherapy then without cytotoxic treatment (24,8% and 6,7%, retrospectively, p = 0.004). There was also statistically important association between abnormal cardiac rhythm and the number of courses administered (p = 0.008). There were no statistically significant differences in conduction abnormalities (p = 0.218), echocardiography abnormalities (p = 0.72) and dimensions of the heart cavities (p = 0.26). Risk of cardiac ischaemia incident was similar in BEP and control groups (low risk 7.5% vs. 3,3%, moderate 26.9% vs. 16,7%, high 33.3% vs. 45% and very high 24.7% vs. 25%). There were no statistically significant differences between the two groups regarding abnormal BMI or lipidogram. Abnormal blood magnesium levels were more frequent among patients after chemotherapy (p = 0.009). Conclusions: Chemotherapy with BEP regimen increases the risk of rhythm abnormalities and the rate of abnormal blood magnesium level.

No significant financial relationships to disclose.
Initial report of Radiation Therapy Oncology Group (RTOG) 9802: Prospective studies in adult low-grade glioma (LGG)
Authors: Shaw E. G. , Berkey B. , Coons S. W. , Brachman D. , Buckner J. C. , Stelzer K. J. , Barger G. R. , Brown P. D. , Gilbert M. R. , Mehta M.
Published: March 2020

1500

Background: Treatment of adult LGG is controversial. Favorable patients (pts) (age <40 years [yrs] who undergo gross total resection [GTR]) are typically observed. Unfavorable pts (age ≥40 who have subtotal resection [STR] or biopsy [B]) are usually given initial radiation therapy (RT), reserving chemotherapy (historically procarbazine, CCNU and vincristine [PCV]) for recurrence. In 1998, the RTOG, in conjunction with SWOG, NCCTG, and ECOG initiated prospective studies of adult LGG, the results of which are reported herein. Methods: Favorable pts were observed postoperatively in a single arm Phase II study (Arm 1). Unfavorable pts were stratified by age, histology, KPS, and presence/absence of contrast enhancement on preoperative magnetic resonance imaging and randomized to either RT alone (54Gy in 30 fractions to a local treatment field) (Arm 2) or RT followed by 6 cycles of standard dose PCV (Arm 3). Reported results include overall survival (OS) rate, median overall survival time (MOST), progression-free survival (PFS) rate, and median progression-free survival time (MPFST). Survival data are compared using Wilcoxon p-values. Results: A total of 362 eligible/analyzable pts were accrued between 1998 and 2002. Median follow-up time is 4 years. For the 111 favorable pts observed on Arm 1, OS at 2- and 5-yrs is 99% and 94%. PFS at 2- and 5-yrs is 82% and 50%. For the 251 unfavorable pts on Arms 2 (RT alone) and 3 (RT+PCV), there was no difference in OS or PFS. OS at 2- and 5-yrs was 87% and 61% with RT alone versus (vs) 86% and 70% with RT+PCV (p=0.72). MOST was not reached in RT alone pts and was 6.0 yrs in RT+PCV pts. PFS at 2- and 5-yrs was 73% and 39% with RT alone vs 72% and 61% with RT+PCV (p=0.38). MPFST was 4.0 yrs with RT alone vs 6.0 yrs with RT+PCV. Acute grade 3–4 toxicity occurred in 9% of pts who received RT alone, 67% who received RT+PCV (mostly hematologic). There were no treatment deaths on either arm. Conclusions: 5-yr PFS was poor in all three arms ranging from 39% to 61%. Only half of favorable pts were disease-free at 5 yrs. In unfavorable pts, there was no OS advantage with the addition of PCV to RT. Both PFS and MPFST were better with the addition of PCV, but not significantly. Analysis of outcome by 1p19q status is pending.

No significant financial relationships to disclose.
Small cell neuroendocrine carcinoma of uterine cervix: The Scottish experience
Authors: Siva M. , Mahmood R. , Kakumanu S. , Sadozye A. , Reed N.
Published: March 2020

15026

Background: Small cell neuroendocrine carcinoma (SCC) of uterine cervix is a rare sub-type of cervical cancer. We report the results of a retrospective analysis of data from 2 Scottish centres of cases of SCC of cervix. The aim is to examine therapeutic interventions, relapse patterns and survival. Methods: Eligible cases were patients (pts) with cervical SCC presented for management discussion between 1995 and 2005 in the 2 scottish centres. Pathology was reviewed centrally by the network pathologists. We reviewed pts case records for staging information, therapeutic interventions, median time to relapse, salvage therapy and responses and overall survival. Results: A total of 21 pts were eligible for the analysis (Glasgow-13 and Aberdeen-8). The median age of the pts was 33 (Range 22–74). Nine pts were FIGO stage 1B, 3 were 2A and 4 were 2B, 3 were 3B and 2 with metastatic disease. Surgery was done in 13 pts [11-radical hysterectomy/pelvic lymphadenectomy, 1-radical hyseterctomy and 1-total abdominal hysterectomy]. Chemotherapy was given to 16 pts [Neo-adjuvant-6, Adjuvant-9, Concurrent-3]. Fourteen pts received combination chemotherapy containing Platinum and Etoposide [EP-2, CE-8, ICE-1 and ACE-3]. One received non-platinum combination. Fourteen pts received radiotherapy [10-Pelvic radiotherapy and brachytherapy, 3-Pelvic only, 1-Brachytherapy only, 2-PCI]. Two pts died of progressive disease shortly after diagnosis without any specific anti-cancer treatment, two pts were disease free after a follow up of 40 and 53 months respectively and one was lost to follow up 7 yrs after diagnosis. Median relapse free survival (RFS) was 16 months. Two year RFS was 25%. The sites of relapse were as follows: Liver-4, Chest-4, Para-aortic-4, Brain-3, Neck-3, Local-2, Abdomen-1. Twelve pts received salvage therapy after relapse [5-responded, 2-not assessed and 5-progressed]. Seven pts were alive after a median follow up of 40 months [Range 17–90]. Median survival was 28 months and the three year overall survival was 45%. Conclusions: We have shown here that with combination treatment SCC can be effectively managed with occasional durable remissions. The overall survival at 3 years was 45%. We believe this was the result of aggressive combination therapy of surgery, chemo and radiotherapy.

No significant financial relationships to disclose.
High dose rate post-operative brachytherapy and external beam radiotherapy for uterine sarcomas
Authors: Maia M. A. , Novaes P. , Pellizzon A. C. , Ferrigno R.
Published: March 2020

15027

Background: Uteine sarcoma (US) generally needs an aggressive approach with surgical cytoreduction at the time of initial diagnosis with maximum debulking of tumor. This offers the possibility of prolonged survival or cure. The need for adjuvant radiotherapy is not well established for US. Methods: 25 patients presenting completely ressected US were treated from November, 1992 to June, 2003. All the patients had a multidisciplinary approach with surgery, external beam radiation therapy (EBRT) given in a four- fields “box” technique, and high dose rate brachytherapy (HDRB), using either colpostats or vaginal cylinders with diameters ranging from 2.5 to 4 cm. The entire vaginal length treated with HDRB was 2 cm in all cases. Results: The median age of patients was 62 years (range 39–84). The EBRT dose prescription ranged from 40 Gy to 50,4 Gy (median 48 Gy). HDRB was given concurrent to EBRT in 14 patients (56%). The HDRB for the remaining patients started in median interval of 34 days (range 5–99 days) after the completion of EBRT. The median BED for hole treatment was 91.5 Gy10 (range 85.6 Gy10–97.9 Gy10), with a standard deviation of 3.7. The 10- year actuarial disease free and overall survivals were and 42.2% and 63.4%, respectively. On univariate analysis predictive factors for disease free survival (DFS) were age at initial presentation (p = 0.0268), parity (p = 0.0441), tumor grade (p = 0.0095), cervical or vaginal invasion (p = 0.0014) and node dissection at time of surgery (p = 0.0471). On multivariate analysis the only predictive factor was cervical or vaginal invasion (p = 0.048), hazard ratio of 4.7. Conclusion: Our small and heterogeneous group of patients analyzed precludes any definitive conclusions regarding the impact of HDRB combined to EBRT on recurrence or survival of the patients. As US are aggressive tumors, it is quite likely that neither radiotherapy nor chemotherapy alone will appreciably improve survival. If we assume that adjuvant radiation therapy provides better locoregional tumor control, hematogenous metastases probably will assume an even greater proportion of treatment failures.

No significant financial relationships to disclose.
Pilot study of modafinil for treatment of neurobehavioral dysfunction and fatigue in adult patients with brain tumors
Authors: Kaleita T. A. , Wellisch D. K. , Graham C. A. , Steh B. , Nghiemphu P. , Ford J. M. , Lai A. , Peak S. , Cloughesy T. F.
Published: March 2020

1503

Background: Patients with brain cancer develop neurobehavioral dysfunction and fatigue that compromise their performance of daily activities. We report results from evaluating the efficacy and safety of modafinil treatment for tumor/therapy sequelae in this medically fragile patient population. Methods: Patients: 21–65 years old with primary malignant disease or nonmalignant cerebral tumors treated with neurosurgical resection, radiotherapy, and/or chemotherapy. Clinical Global Impression of Severity ratings of mild to severe attention/memory impairment and/or fatigue. Measures: Trail Making (TM) A and B, Symbol Digit Modalities (SDM), Verbal Fluency (VF), Hamilton Depression Scale (HAM-D), Fatigue Severity Scale (FSS), Visual Analogue Fatigue Scale (VAFS), Modified Fatigue Impact Scale (MFIS). Design: Double-blind dose-controlled randomization (200 or 400 mg/day modafinil in divided doses) 3 wks; Washout 1wk; Open label extension 8 wks. Statistical analyses: Changes from baseline at scheduled visits (1, 3, 4, 8, 12 wks) using paired t-tests or Wilcoxon Signed Rank tests as appropriate. Results: Thirty patients, 63% male, mean age (SD) = 45.3 (11.7) yrs were accrued from 6/03–10/05. Illness severity: moderate 3 (10%), marked 13 (43%), severe 14 (47%). Tumor histology: glioblastoma multiforme 8 (27%), anaplastic glioma 10 (33%), low grade glioma 10 (33%), meningioma 1 (3%), CNS lymphoma 1 (3%). Treatment: neurosurgical resection 93%, radiotherapy 87%, chemotherapy 70%. The table shows relationships of nine variables at baseline and 8 and 12 weeks after initiation of modafinil. Adverse events reported by ≥4 patients: headache 13 (42%); insomnia 8 (26%); dizziness 7 (23%); dry mouth 7 (23%); depressed consciousness 5 (16%); nausea 4 (13%). Conclusions: Results show improvement across cognitive, mood, and fatigue outcome measures. Modafinil was generally well tolerated, with a low incidence of adverse events. Greatest improvements in outcomes were observed 8 wks after baseline.

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A pilot study to assess the tolerability and efficacy of RAD-001 (everolimus) with gefitinib in patients with recurrent glioblastoma multiforme (GBM)
Authors: Nguyen T. D. , Lassman A. B. , Lis E. , Rosen N. , Shaffer D. R. , Scher H. I. , Deangelis L. M. , Abrey L. E.
Published: March 2020

1507

Background: The majority of GBMs overexpress EGFR and have PTEN loss leading to activation of AKT signaling. mTOR is a downstream target which is blocked by RAD-001. The addition of an mTOR inhibitor to EGFR blockade by gefitinib may augment downregulation of AKT. Methods: Nineteen patients with GBM were enrolled in a phase I/II protocol open to patients with either hormone refractory prostate cancer or recurrent GBM. Patients on enzyme inducing anti-epileptic drugs (EIAEDs) were excluded, but prior treatment with an EGFR inhibitor was allowed. All patients received gefitinib 250 mg daily. Two patients enrolled in a dose escalation arm received RAD-001 30 mg or 50 mg weekly; 17 patients received the maximum tolerated dose of RAD-001 70 mg weekly. Baseline and follow-up MRIs were reviewed by a neuro-radiologist. Primary endpoints were radiographic response and progression-free survival (PFS). Results: There were 11 men and 8 women with a median age of 53 years (range 22–72) and median KPS of 80 (range 70–100). Seventeen patients (89%) were treated at their second or greater recurrence. The most frequent grade 1 and 2 toxicities were thrombocytopenia, elevated ALT, rash, anemia, leukopenia, and diarrhea. Grade 3 lymphopenia occurred in 8 patients (42%); two patients (11%) had grade 4 seizures unrelated to the study drugs. Five patients (26%) had a partial radiographic response, including one treated at 3rd recurrence, 2 treated at 4th recurrence, and one who had progressed through prior gefitinib therapy. Two additional patients (11%) had disease stabilization for greater than 4 months. Median PFS was 2.6 months. Median overall survival has not been reached, with a median follow up of 5.4 months for surviving patients. Conclusions: The combination of RAD-001 and gefitinib demonstrated activity in 37% of patients with GBM (26% responded, 11% achieved stable disease). Most subjects were heavily pre-treated and expected to have resistant disease. Because disease control was not durable, alternate dosing, or treatment earlier in the course of disease should be considered in further studying this promising combination.

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Immunological evaluation of personalized peptide vaccination for patients with malignant glioma: The results of a clinical phase I trial
Authors: Yamanaka R. , Yajima N. , Mine T. , Yamada A. , Shigemor M. , Ito K.
Published: March 2020

1524

Purpose: To investigate the safety and immunological responses of personalized peptide vaccination in patients with malignant glioma. Patients and Methods: Twenty-six patients with recurrent malignant glioma entered in the phase I clinical study of personalized peptide vaccination. Peripheral blood mononuclear cells (PBMCs) and plasma prior to vaccination were provided for cellular and humoral responses in vitro to each of 31 or 36 peptides in cases of HLA-A24+ or HLA-A2+ patients, respectively, and then only the reactive peptides (maximum: 4) were allowed to in vivo administration. Post-vaccination PBMCs and plasma, and also pre-and post-vaccination cerebrospinal fluid, were provided for their reactivity to the vaccinated peptides. Expression of class 1 molecule on glioma cell was evaluated using EMR 8–5 antibody by immunohistochemical analysis. Results: The protocol was generally well tolerated, although the majority of patients developed grade 1 or 2 local redness and swelling at the injection site. Increase in cellular and humoral responses specific to at least one of the vaccinated peptides was observed in the post vaccination (6th)-PBMCs and -plasma from 62%, 73% respectively. More importantly, peptide-specific IgG were found in the post-vaccination cerebrospinal fluid of tumor sites. Clinical responses were 4 partial response, 8 stable disease, and 8 progressive disease. The clinical response was correlated to the expression of MHC class 1 on the glioma cell. The median overall survival for patients with recurrent glioblastoma multiforme in this study was 622 days. Conclusion: Personalized peptide vaccination is well tolerated and has ability to induce immune responses to the majority of malignant glioma patients along with several cases of major tumor regression. These results would encourage the phase II clinical study of personalized peptide vaccination to patients with recurrent malignant glioma.

No significant financial relationships to disclose.
Brain metastases in HER2-overexpressing metastatic breast cancer: Comparative analysis of trastuzumab levels in serum and cerebrospinal fluid
Authors: Stemmler J. , Schmitt M. , Willems A. , Bernhard H. , Harbeck N. , Heinemann V.
Published: March 2020

1525

Purpose: Patients receiving trastuzumab for HER2-overexpressing MBC suffer from an increased risk to develop BM despite responsive visceral disease. The present pilot study was conducted to explore trastuzumab levels in S and CSF of MBC patients afflicted with BM, and to evaluate whether radiotherapy will lead to impairment the blood-brain barrier (BBB) to allow penetration of trastuzumab into CSF. Methods: Patients with BM from HER2-overexpressing MBC (IHC; DAKO Hercep Test) were included. Trastuzumab levels in S and CSF were determined at different time points by a newly developed immunoenzymatic test for functional, reactive trastuzumab. Results: Six out of 8 eligible patients were evaluable. Prior to whole-brain radiotherapy (WBRT), the median trastuzumab serum level was 52,054 ng/ml compared to a median CSF level of 124 ng/ml (ratio 420:1). After completion of WBRT, the median level of trastuzumab was 20,185 ng/ml in serum and 226 ng/ml in CSF (ratio 76:1). In two cases of concomitant meningeal carcinomatosis, the median serum level of trastuzumab after WBRT was 17,431 ng/ml and 356 ng/ml in CSF (ratio 49:1). Conclusion: These data indicate that the BBB prevent trastuzumab to reach adequate concentrations in CSF. These levels are increased under conditions of an impaired BBB, as is known for meningeal carcinomatosis and for patients receiving WBRT. The new test system in this pilot study provides the basis for the evaluation of radiotherapeutic strategies which allow most favorable penetration of trastuzumab into the CNS in patients receiving concomitant trastuzumab for HER2-overexpressing metastatic breast cancer.

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Primary intraocular lymphoma (PIOL): An International Primary CNS Lymphoma Collaborative group report
Authors: Grimm S. , Pulido J. , Jahnke K. , Schiff D. , Hall A. , Shenkier T. , Siegal T. , Nancy D. , Batchelor T. , Abrey L.
Published: March 2020

1534

Background: PIOL is a hemopoietic tumor that arises in the retina, vitreous or optic nerve head, and carries a high risk of ocular and CNS relapse. The natural history and optimal management are unknown. Methods: A retrospective series of 81 patients with PIOL was assembled from 15 centers in 7 countries. Only patients with isolated ocular lymphoma were included; none had brain, spinal cord, or systemic lymphoma at diagnosis. Results: The median age at diagnosis was 65 (24–85). 58% were women. The median ECOG performance status was 0, and only three had a score > 1. The median latency from symptom onset to diagnosis was 6 months (0– 36). Slit lamp exam was positive in 51, negative in 6, and not reported in 24. Vitrectomy was positive in 72 and negative in 2. 6 had a positive choroidal or retinal biopsy and 1 had no ocular surgery. CSF cytology was positive in 10 (17%), negative in 48, and unknown in 23. 21 received local therapy at diagnosis: 6 intra-ocular methotrexate (400 ug), 14 ocular radiation (median 3600 cGy), and 1 both modalities. 52 received more extensive therapy including systemic chemotherapy alone in 20 and a combination of chemotherapy and radiotherapy in 32. 5 received no treatment and details are unknown in 3. 47 patients (58%) relapsed a median of 19 months (0.5–180) after initial therapy. Sites of relapse included brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Patients treated with ocular therapy alone did not have an increased risk of failing in the brain (p = 0.6). Progression free survival (PFS) and overall survival (OS) were 29.6 and 57 months respectively and were unaffected by the choice of therapy. CNS disease was the cause of death in 19/33 (58%). Conclusions: In this series, treatment type did not affect sites of relapse, PFS or OS in patients with PIOL. To minimize toxicity, the best initial therapy should be limited to intraocular chemotherapy or focal radiotherapy. Prospective clinical trials are needed to improve our understanding and treatment of this disease.

No significant financial relationships to disclose.
Phase II study of concurrent temozolomide and whole brain radiation therapy in patients with brain metastasis
Authors: Dawood S. , Ragaz J. , Navaratnam S. , Mihalcioiu C.
Published: March 2020

1540

Background: 30% of patients (pts) with lung cancer develop brain metastases, with XRT representing the conventional treatment of multiple BM. Methods: Pts with lung cancer, Brain metastases (BM) and performance status of 0–2 were enrolled. TMZ (75mg/m2 day 1–14) given on cycle 1 with XRT (3000cGy in 10 fractions) followed by cycles 2–4 TMZ (200mg/m2 day 1–5, q 4 weeks). Pts with active systemic disease received also chemotherapy (cisplatin or docetaxel or paclitaxel) during TMZ cycles 2–4. Primary end points: 1. Radiological response of BM assessed after 4–6 weeks from the end of XRT, 2. Treatment related toxicity, 3.Functional Scale score(FSS)(1 best, 3 worst, based on interaction of WHO performance status, score 0–4, with the neurological status score 1–3). FSS was assessed at baseline, and during the follow up visits. Secondary end points: time to progression and overall survival. Results: 22 patients enrolled, 8 pts received TMZ alone and 14 pts had additional chemotherapy. CR was documented in 2 pts, PR in 6 pts, SD in 5 pts, 4 pts progressed on treatment; 5 pts were not evaluable (death from other causes within 2 months from diagnoses). FSS at baseline was available on 19/22 patients. Of those, thirteen, four and two pts had a FSS of 1, 2 and 3, respectively. Fifteen of the 19 pts maintained their FSS at the end of Tx, with 3 pts exhibiting deterioration, and one patient improved. Post treatment FSS remained stable in 16 patients up to one month prior to death. The median survival (22 pts) from the time of diagnosis of BM was 9 months with average TTP of 3.5 months. Except for moderate nausea and vomiting there was no significant toxicity by combining TMZ with XRT. The addition of single agent chemotherapy to TMZ was well tolerated but two patients who required GCSF support. Conclusion: Adding TMZ to XRT for the treatment of BM from in lung cancer patients showed a response in 13 out of 17 assessable patients with a median survival of 9 months which is above the mean 3 to 6 months survival reported in the literature with XRT alone. More importantly, the majority of patients maintained a stable FSS up to one month prior to death suggesting a quality of life benefit during most of their life span. TMZ can be safely administered concomitantly with either XRT or with other single agent chemotherapy.

No significant financial relationships to disclose.