bluuebunny/crossref_metadata_2025 huggingface dataset:
Is local lymph node involvement a prognostic factor in paediatric renal cell carcinoma?
Authors: Indolfi P. , Bisogno G. , Cecchetto G. , Ferrari A. , Piva L. , Carli M. , Donofrio V. , Schiavetti A. , De Salvo G. , Donfrancesco A.
Published: March 2020

20014

Background: RCC in childhood is rare. Children with RCC tend to have a similar overall prognosis when compared with adults, where prognosis worsens with increasing stage, although direct comparisons of adult and paediatric data isn’t easy. The aim of our study is to identify the prognostic significance of local lymph node involvement in children with Renal Cell Carcinoma (RCC). Methods: On the basis of a retrospective study, the recently founded Italian Association for Paediatric Hematology and Oncology-Rare Tumors Paediatric Age (AIEOP-TREP) identified 16 patients (9 females) with RCC and local lymph node involvement at 10 of these centers. The cases were observed among 59 paediatric RCC, corresponding to 27.1% of RCC presenting in Italy from January 1973 to May 2006. Results: Overall, 9 patients were alive and disease free at last follow-up: eight patients had regional lymph node dissection (RLND) from the diaphragm at the aortic bifurcation, and one had the para-aortic lymph nodes removal. Six patients died: one had RLND (died from progression of disease), three had the renal hilum lymph nodes removal, and two the para-aortic lymph nodes dissection. One patient was lost to follow-up after relapse: this patient had para-aortic lymph node removal at diagnosis. Estimated 25-year DFS and OS rates for all patients were 64.2% and 50.5%, respectively. Given the small number of patients, little can be said about the value, if any, of adjuvant immunotherapy in this group of RCC. Conclusions: Children with lymph node positive RCC had a relatively unfavourable long- term prognosis. In our experience the RLND improves the prognosis. Further investigation of the biologic differences is warranted. Because of the very low incidence of paediatric RCC, an international clinical trial will be required to establish optimal therapy for children with RCC.

No significant financial relationships to disclose.
Concordance and evaluation among IGCCCG and POG staging systems in pediatric germ cell tumors
Authors: Robles-Castro J. , Rivera-Luna R. , Calderon-Elvir C. , Leal-Leal C. A.
Published: March 2020

20019

Background: The knowledge regarding treatment and prognosis of pediatric germ cell tumors has been taken from the development of these in the adult population. The object of this work was to compare the International Classification (IGCCCG) used in adults versus the POG classification used traditionally in a pediatric population. Methods: We reviewed clinical records from March 1994 through June 2003 with the diagnosis of malignant germ cell tumor of testis, retroperitoneal and mediastinum. All patients completed the treatment proposed initially with a follow up of more than 24 months. They were staged with the POG classification at diagnosis and with the International Classification for this study. Results: We obtained 61 patients with a 4 year follow up. They were all male, with germ cell tumor of testis or mediastinum. There were no retroperitoneal primary tumors. The age range was from 4 months to 188 months with an average of 48.7 months. Prognosis and treatment with the POG and the IGCCCG classifications had concordance of 0.0004 and 0.0371 respectively. Conclusions: We found limitations such as diverse chemotherapy protocols used in patients within the same risk group. Biological tumor Markers sampling play an important role in the the initial approach to allocate staging and risk based treatment protocols. It is necessary to carry out new studies with a homogeneous based population with similar diagnosis, treatment protocols and staging system to corroborate the utility and implementation of the International Classification in order to ameliorate morbidity and mortality of our pediatric patients.

[Table: see text]

No significant financial relationships to disclose.
Phase IIa trial of cilengitide (EMD121974) single-agent therapy in patients (pts) with recurrent glioblastoma (GBM): EMD 121974-009
Authors: Reardon D. , Fink K. , Nabors B. , Cloughesy T. , Plotkin S. , Schiff D. , Raizer J. , Krueger S. , Picard M. , Mikkelsen T.
Published: March 2020

2002

Background: Our phase IIa study evaluated the safety, toxicity, and clinical activity of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, as a single agent at doses of 500 and 2000 mg in pts with recurrent GBM. Methods: In this multicenter, open-label, randomized, uncontrolled study, pts with GBM and measurable disease that had relapsed after previous temozolomide and radiotherapy were randomized to receive cilengitide at either 500 mg or 2000 mg i.v., 2x/week, until progression. Neurologic exams were performed after every cycle (4 weeks) and MRIs were performed every other cycle. Central, blinded pathology and radiology reviews were performed. The primary endpoint was Progression Free Survival (PFS) at 6 months (6-mth PFS). Secondary endpoints included response, survival, time to disease progression, safety, tolerability and pharmacokinetics (PK). Results: 81 pts accrued (median Karnofsky Performance Status 80%; median age 57 yrs) at 15 sites including 41 at the 500 mg and 40 at the 2000 mg dose levels. Demographic and pretreatment variables were comparable between dose level cohorts. The median number of infusions was 16 [range, 4–179]. PK studies revealed significantly greater exposures among the 2000 mg cohort. Treatment related NCI CTC grade 3 adverse events (AEs) included elevated transaminases (at 500 mg), arthralgia/ myalgia (at 500 mg), and weight increase/ edema (at 2000 mg) in 1 patient, respectively. No grade 4 therapy related AEs were reported. One CTC grade 2 cerebral hemorrhage was reported in a pt at progression. The 6- mth PFS was 16.1% (n=13/81 pts). 10 pts (12.3 %, n=4 with 500 mg, n=6 with 2000 mg) received 12 or more cycles. Six pts (7.4%) remain progression-free and on treatment. Median Overall Survival (mOS) was 6.5 mths [95% CI: 5.2–9.3 mths] in the 500 mg arm and 9.9 mths [95% CI, 6.3–15.7 mths] in the 2000 mg arm. Although not statistically significant, there was a trend towards better tumor control in pts receiving 2000 mg 2x/week. Conclusions: Cilengitide was well tolerated and demonstrated single agent activity in recurrent GBM, with long term disease stabilization in a subset of pts.

[Table: see text]
Imatinib mesylate in the treatment of paediatric chronic myeloid leukaemia (CML): A study of 30 cases from a regional cancer centre in western India
Authors: Parikh AP S. K. , Shukla S. N. , Shah P. M. , Patel K. M. , Parikh B. J. , Addl A. S. Anand , Asso S. S. Talati , Shah S. A. , Panchal H. P. , Patel A. A.
Published: March 2020

20021

Background: CML is a very rare disease in childhood. There are scant data available concerning the use of Imatinib in the paediatric patients. Methods: Thirty cases of paediatric CML (25 males, 5 females; median age-11, range: 4–14 years, 23 Interferon naive, 1 interferon resistant) during the period of September 2003 to October 2006 were analyzed. Results: There were 28 patients in chronic phase (CP), 1 accelerated phase (AP) and 1 with blast crisis (BC). All patients were Philadelphia positive (Ph+) (20 by G-banding, 10 by fluorescence in situ hybridization [FISH]) and treated with imatinib using 260 mg/m2 daily for CP and 340 mg/m2 for AP/BC. The median time from diagnosis to imatinib therapy was 4 months (range: 0.5–91 months). Twenty-five (92.5%) of 27 evaluable patients achieved complete haematological remission (CHR) (World literature 95% in adult) at a median duration of 60 days (range: 25–150 days). Two patients did not respond; one of them with BC died due to progressive disease and three patients were not evaluable (2 patients loss to follow up and in 1 patient imatinib started recently). Complete cytogenetic response (CyGR) was achieved in 7 of 15 patients studied; 2 patients had partial CyGR while 4 had no CyGR while in 2 patients result was inconclusive. In 2 patients molecular remission was studied with RT-PCR, had attained it at 12 months. Overall, the drug was well tolerated and none of the patients had to permanently discontinue the drug. There were no treatment related deaths. The common adverse events were thrombocytopenia (6.6%), neutropenia (16.6%), skin rash (6.6%), anaemia (3.3%), superficial oedema (6.6%), weight gain (6.6%) and muscle cramps (3.3%). Severe (grade III-IV) events were infrequent except 1 patient with grade IV febrile neutropenia. At median follow up of 24 months (range: 1–35 months, 11 patients followed >24 months), one patient has haematological relapse while one patient has disease progression in form of myeloblastic crisis. Conclusions: The Imatinib mesylate treatment is safe and it achieves rapid and higher CHR in paediatric CML.

No significant financial relationships to disclose.
Identification of novel candidate genes for ependymoma progression in chromosomal regions over-represented at recurrence and detected by CGH array
Authors: Puget S. , Valent A. , Bieche I. , Dessen P. , Kauffmann A. , Peyre M. , Dirven C. , Sainte-Rose C. , Vassal G. , Grill J.
Published: March 2020

2008

Background: The biology and genetics of ependymomas remain poorly understood. As opposed to other pediatric tumors, few recurrent chromosomal abnormalities or relevant pathways have been identified. Method: In order to gain new insight into the molecular mechanisms involved in ependymoma progression, we performed BAC array-based comparative genomic hybridization (aCGH) in a series of 59 tumors at diagnosis and at relapse (42 posterior fossa and 17 supratentorial). Specific chromosomal imbalances were confirmed by FISH. Expression of candidate genes was evaluated by RT-PCR and immunohistochemistry. Results: As compared to CGH (Cancer Genet Cytogenet 2002), aCGH detected more abnormalities since 18/33 samples at diagnosis and 22/26 at recurrence showed chromosomal imbalances. Three distinct patterns were observed : no imbalance (15 at diagnosis, 4 at relapse), large and numerous imbalances (7 at diagnosis, 12 at relapse) and small and rare imbalances (11 at diagnosis, 10 at relapse). At diagnosis, absence of chromosomal imbalance was correlated with young age (p=0.034) and shorter progression-free survival (p=0.014). At relapse, patients with large and numerous imbalances had a shorter survival (p=0.026). Specific chromosomal imbalances were significantly more frequent at recurrence: 9 qter gain (54% vs 21%), 1q gain (12% vs 0%) and 6q loss (27% vs 6%). Samples were available both at diagnosis and relapse for 16 patients. Whole genome changes were towards increase of genomic abnormalities (n=10) but also simplification (n=6), the former being associated with a higher risk of death from disease (Fisher exact, p=0.03). A candidate gene strategy was focussed on the frequently gained 9qter locus. Significant overexpression compared to normal brain was identified for Tenascin-C (median 35 fold, max 220 fold, p<0.0001) and Notch1 (median 6 fold, max 45 fold, p<0.0001). Notch pathway analysis by RT-PCR revealed potential regulatory loops between JAG1/2 or DLL1/3 and Notch1/2. Conclusion: aCGH pattern may identify subgroups of ependymomas with respect to prognosis. Notch pathway and Tenascin-C are important regulatory genes in ependymoma progression and may represent interesting new targets for therapy.

No significant financial relationships to disclose.
F-18-labeled fluorodeoxyglucose positron emission tomography for evaluation of disease extent, response to treatment and follow-up in primary CNS lymphoma
Authors: Kiewe P. M. , Maza S. , Munz D. , Korfel A. , Thiel E.
Published: March 2020

2015

Background: Fluorine-18-labeled (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) has demonstrated remarkable sensitivity in the detection and follow-up of malignant lymphoma. The aim of this study was the prospective evaluation of potential benefits of FDG-PET including whole-body PET for evaluation of disease extent, response to treatment and follow-up of patients with primary CNS lymphoma (PCNSL). Methods: Extent of disease and response to therapy were evaluated using homologous scans of MR imaging and a total number of 36 18F-FDG-PET examinations in 10 immunocompetent patients with newly diagnosed or recurrent PCNSL before and repeatedly during treatment and follow-up. Results: In 4 of 10 patients before treatment, MRI findings lacked a PET correlative, and in two patients each one additional lesion not visualized by MRI was detected by PET. Additional systemic spots of activity in whole-body PET were found in two patients and confirmed as asymptomatic lymphoma manifestations by computed tomography (CT) in one patient. Under treatment, tumor response was congruent on PET and MRI in 4 of 6 patients. In two patients, however, PET indicated complete disappearance of vital tumor while findings persisted on MRI. During follow-up in a series of 5 patients, pathologic FDG-uptake had been found in one patient on PET 34 weeks after therapy and 9 weeks before relapse was diagnosed on MRI. In another patient, relapse was suspected on PET 76 weeks after therapy without a correlative on MRI performed 2 and 6 weeks thereafter. Conclusions: In PCNSL, FDG-PET may contribute additional information regarding the extent of disease and response to treatment. Relapse can probably be detected earlier than with MRI.

No significant financial relationships to disclose.
Leptomeningeal disease from oligodendroglioma: Clinical and molecular analysis
Authors: Roldán G. B. , Scott J. , George D. , Easaw J. , Yan E. , Parney I. , Cairncross G. , Forsyth P.
Published: March 2020

2019

Background: Leptomeningeal disease (LMD) is a late complication of malignant glioma, mostly of glioblastoma, that usually responds poorly to treatment and is rapidly fatal. A long surviving case led us to review our experience with LMD in patients with oligodendrogliomas. Methods: A 10-year retrospective chart review was performed. Patients with both oligodendroglial tumors and LMD were identified. A single neuro-pathologist reviewed all histological sections, a single neuro-radiologist reviewed all available images and 1p/19q status was assessed. Results: Seven patients with an oligodendroglioma and LMD were identified. Six were male. Median age at tumor diagnosis was 41 years (range, 28–50). None had radiographic or pathological evidence of leptomeningeal or subependymal tumor at initial diagnosis. Most patients had pure anaplastic oligodendrogliomas (4/7); 6/7 had 1p/19q co-deletion. The median time to first relapse was 41 months (range, 19–127). LMD was diagnosed at first relapse in one case and subsequently in six. The median time to LMD was 76 months (range, 19–151) from initial diagnosis and 28 months (range, 0–36) from first relapse, respectively. LMD treatments included spinal radiation and intrathecal and systemic chemotherapy. After progression, some patients with LMD remained stable clinically. The median survival from initial diagnosis was 104 months (range, 19–183) and from LMD diagnosis was 32 months (range, 2–43). Conclusions: LMD is a complication of oligodendroglioma that may occur preferentially in long surviving patients with 1p/19q co-deletion. LMD in patients with oligodendrogliomas appears to be relatively indolent which may have implications for their treatment and be related to 1p/19q status.

No significant financial relationships to disclose.
Leptomeningeal metastases: Results of different therapeutic approaches
Authors: de Wit M. , Lange-Brock V. , Kruell A. , Bokemeyer C.
Published: March 2020

2047

Background: The aim of this study was to compare different treatment options for patients with leptomeningeal metastases (LM). Method: In this retrospective single center study all patients (n=135) between 1985 and 2005 diagnosed with leptomeningeal metastases (LM) showing malignant cells in the cerebrospinal fluid (CSF) were evaluated. Results: 135 patients, 80 females and 55 males, were treated for LM, 73 patients with solid tumors and 62 patients with hematological malignancies. Of the total 135 patients 28% received combined chemotherapy and intrathecal chemotherapy (ITC), 22% only ITC, 3% received only systemic chemotherapy, 28.5% radiochemotherapy and 1.5% radiotherapy only. 13% patients were treated with supportive therapy only and in 4% therapy could not be evaluated. Median overall survival (OS) was 2.5 months (3 days- 58.2 months). According to univariate analysis age > 50 years and Karnofsky status < 80 were predictors of poor survival. Response to therapy and application of systemic therapy were correlated with longer survival. In this study, time of survival varied considerably depending on the type of primary tumor. Univariate analysis of Kaplan-Meier plots revealed age >50 years and Karnofsky performance status <80 as therapy-independent predictors of poor survival. Positive prognostic factors were response to therapy as measured by malignant cell count in the CSF, and application of systemic chemotherapy alone or in combination with other therapy-modalities in the entire cohort. Difference through systemic therapy was extremely relevant for the two entities NHL (n=37) and breast cancer (BC) (n=35). The median OS was 4.4 months for NHL and 7.0 months for BC following systemic therapy compared to 1.8 months for NHL and 1.4 months for BC without systemic treatment thus demonstrating a significant better OS using systemic therapy. Conclusion: The results suggest that systemic chemotherapy has the main impact on improved survival in patients with LM and chemosensitive disease. Still the prognosis for patients with LM is poor and treatment is aimed at palliation of symptoms and preservation of neurologic function. Future randomized studies of therapies should include quality-of-life assessment and provide additional data on this important outcome.

No significant financial relationships to disclose.
A phase III trial of topotecan and whole brain radiation (WBRT) therapy for patients with CNS metastases due to lung cancer
Authors: Ko Y. , Neuhaus T. , Müller R. , Grabenbauer G. , Hedde J. , Schüller H. , Kocher M. , Stier S. , Ullrich R. , Fietkau R.
Published: March 2020

2049

Background: Brain metastases represent an important cause of morbidity in patients (pts) with lung cancer and are associated with a mean survival of less than 6 months. Thus studies to improve outcome are urgently needed. Methods: Based on promising data raised in a phase I/II trial, in which WBRT was combined with topotecan (ASCO #444, 2003), we initiated an open, randomized, prospective, multicentric phase III trial, comparing WBRT (20 x 2 Gy; arm A) alone with WBRT + topotecan (0.4 mg/m2/d x 20; arm B). 320 pts with CNS-metastases due to SCLC or NSCLC were projected. Primary endpoint was overall survival (OS), secondary endpoints were local response and progression-free survival (PFS). However, since until the cut off date of study completion (i.e. a study duration of 34 months) only a total of 96 (A: 49, B: 47) pts have been recruited, an interim analysis was performed at that time point. Results: The demographic data (ø age 59 (34–75), 64% male, 66% NSCLC, mainly (64%) ECOG 0–1, extracerebral metastases in 75% and more than 4 cerebral lesions in 26% of pts) were evenly distributed in the two groups. Also the rate of grade 3/4 toxicities (besides alopecia 115 non-hematological (A/B: 60/55) and 43 hematological events (18/25)) did not differ remarkably between the arms. Early deaths (within 6 weeks after recruitment) occurred in 24% of the patients (A/B: 30%/18%), mainly due to tumor progression. Local response, evaluated 2 weeks after treatment, was assessable in 44 (A/B: 21/23) pts, showing CR in 8 (5/3), PR in 17 (6/11), SD in 14 (6/8) and PD in 5 (4/1) pts (all differences n.s.). Neither PFS (median A/B; days: 76/97, range, 24–251/20–428) nor OS (median A/B; days: 95/87, range 4–433/3–752) differed significantly (Cox-Mantel test; p=0.82 and 0.43, respectively). Conclusions: The available data, gained from the only phase III trial regarding concurrent WBRT and topotecan, show no significant advantage for concurrent radiochemotherapy for patients with lung cancer, however due to the limited number of recruited patients a possible small advantage of a combined treatment could not be demonstrated. Based on these results and the slow recruitment a continuation of the study did not seem reasonable.

No significant financial relationships to disclose.
Can we predict therapy outcome in patients with high risk soft tissue sarcoma using positron emission tomography?
Authors: Kasper B. , Dimitrakopoulou-Strauss A. , Wuchter P. , Egerer G. , Ho A. D.
Published: March 2020

20511

Background: We used 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG) studies to evaluate the FDG metabolism kinetics in patients (pts.) with high risk soft tissue sarcomas receiving an induction or neoadjuvant chemotherapy. The treatment effect was assessed with regard to the prediction of therapy outcome. Methods: The ongoing evaluation includes 25 pts. with high grade soft tissue sarcoma with different histologies: 14 pts. received an induction chemotherapy consisting of adriamycin 75 mg/m2/day 1 and ifosfamide 1500 mg/m2/day 1–4 (AI-G regimen, six cycles) prior to peripheral blood stem cell transplantation, and 11 pts. were treated with pre-operative chemotherapy consisting of etoposide 125 mg/m2/day 1+4, ifosfamide 1500 mg/m2/day 1–4 and doxorubicin 50 mg/m2/day 1 (EIA regimen, 4 cycles). Pts. were examined prior to onset of therapy and after completion of the first cycle of AI-G and after two cycles of EIA chemotherapy, respectively. The restaging data of 21 patients (11 pts with AI-G and 10 patients with EIA treatment) served for reference. Restaging was performed using computed tomography and magnetic resonance tomography after six cycles of AI-G or four cycles of EIA chemotherapy. Results: 21 pts. were evaluable by the time of data evaluation. According to RECIST criteria, clinical outcome was as follows: 3 pts. showed no evidence of disease (NED), 6 partial remissions (PR), 5 stable diseases (SD), and 7 pts. with progressive disease (PD). Due to the small number of pts., we dichotomized the data in pts. with NED/PR (n = 9) and pts. with SD/PD (n = 12). Median average standard uptake value (SUV) prior therapy was 5.4 in comparison to 4.1 after chemotherapy. Median maximum SUV was 8.3 prior to chemotherapy in comparison to 6.6 following therapy. We used discriminant analysis and four predictor variables, namely the average and maximum SUV of both the baseline and the follow-up study to classify the pts. into responders and non-responders. Discriminant analysis revealed a correct classification rate of 70 %. Conclusions: On the basis of these data, prediction of chemo-sensitivity of the tumor and moreover of the therapy outcome might be possible.

No significant financial relationships to disclose.
A case of synchronous relapse of breast cancer and uterine mullerian adenosarcoma after adjuvant tamoxifen in a pre-menopausal woman
Authors: Farhat F. S. , Fakhredin N. A. , Sraj A. A.
Published: March 2020

20533

Background: Uterine müllerian adenosarcoma is a rare tumor of postmenopausal women. An increase in its incidence with the use of tamoxifen therapy for breast carcinoma is reported in several studies. Methods: We report a case of 42 years multigravida, premenopaused woman with breast carcinoma, who presented - after four years of use of adjuvant tamoxifen - a synchronous liver, bone, and lung metastasis of breast cancer with müllerian adenosarcoma. Results: Immunohistochemical stains on uterine tumor for estrogen and progesterone receptors showed positivity for both epithelial and stromal cells, actin, desmin and proliferative index (MIB-1) showed positivity for stromal cells only. The patient underwent a hysterectomy followed by palliative chemotherapy. The patient deceased at 14 months after her relapse because of progressive disease (cerebral, bone, liver and lung metastasis). Conclusion: Our case is the only one reported in the literature with synchronous relapse of the breast adenocarcinoma and a Müllerian adenosarcoma. Also it's of the rare cases occurring in a pre-menopaused woman since all except two cases were postmenopausal.

[Table: see text]

No significant financial relationships to disclose.
Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression
Authors: Viola F. S. , Katz A. , Arantes A. , Gaiger A. , Vasconcellos C. , Passos V. , Barrios C. H.
Published: March 2020

2056

Background: GBM are the most common primary brain tumors in adults. Despite available treatment they carry a poor prognosis with recurrences in most patients (pts) after initial therapy. PDGF signaling has been postulated to play a role in GBM transformation. We have demonstrated that PDGFRβ is expressed in tumor cells in 50% and in peritumoral endothelial cells in 65% of GBM (Barrios et al, abstract 11518, Proc ASCO 2006). Imatinib, an inhibitor of PDGFRa/β kinase activity could have therapeutic activity in these cases. Methods: We evaluated Imatinib in pts with recurrent GBM (previous radiation and chemotherapy) selected by PDGFR expression. Analysis of PDGFRa/β was performed by standard IHC. Positivity was considered in case of any qualitative expression. Pts were treated with 800 mg/day of Imatinib until tumor progression. All were on steroids and taking enzyme inducing antiepileptic drugs. Response was determined by MRI with spectroscopy and perfusion every 8 weeks according to RECIST criteria. Results: Twenty pts were enrolled (18 GBM, 2 AA). Median age: 51 (21–74), 7 were females. ECOG-PS at inclusion: 0 (3), 1 (10), 2 (7). All pts had expression of PDGFRa and 55% expressed PDGFRβ. Response data are available for all 20 pts. Main adverse events (all grade 1–2) were: edema (55%), nausea (50%), diarrhea and fatigue (35% each). We did not observe any PR but 13 pts (65%) showed disease stabilization. Median progression-free survival was 7.8 months with 60.8% of pts alive at 6 months; 6 months PFS was 52.2%. Conclusions: Imatinib was well tolerated in this group of poor prognosis highly pre-treated GBM pts demonstrating disease stabilization in a significant proportion of cases. These results, in a limited sample, compare favorably with historical data in similar populations. Selection of pts according to the specific molecular expression of their tumor may lead to better therapeutic results.

No significant financial relationships to disclose.
Final results of a phase I trial with the novel anthracycline derivative RTA 744 in patients with primary brain tumors
Authors: Conrad C. A. , Maher E. , Cloughesy T. , Groves M. , Gilbert M. , Madden T. , Levin V. , Priebe W. , Meyer C. , Yung W.
Published: March 2020

2062

Background: RTA 744 is an anthracycline derivative that was shown preclinically to cross the blood-brain barrier, not be a substrate for P-gp or MRP, and improve survival in an orthotopic murine model of glioblastoma. A trial of RTA 744 was conducted in patients with progressive high-grade gliomas. Methods: RTA 744 was administered as a 2-hour intravenous infusion on each of the first 3 days of a 21-day cycle. Five dose levels were tested until an MTD was reached. Pharmacokinetic samples were taken at multiple time points on days 1–5 of cycle 1. Tumor activity was assessed according to the MacDonald criteria. Results: As of December 2006, RTA 744 has been administered to 20 patients at doses ranging from 1.2 to 9.6 mg/m2/day. The MTD was determined as 7.5 mg/m2/day, and the DLTs were neutropenia and thrombocytopenia. No neurotoxicity, cardiotoxicity, alopecia, or drug-related nausea and vomiting were reported. The pharmacokinetic profile indicates dose proportionality, with a mean plasma half-life of 35 hours. Clear evidence of anti-tumor activity has been reported in 7 of 20 patients. A Complete Response was observed in a patient with GBM after seven cycles at 2.4 mg/m2/day, the patient continues greater than 5 months post-RTA744 treatment. Additionally, a Partial Response (81% tumor reduction) has been observed in a patient with AO after two cycles at 7.5 mg/m2/day who continues on treatment at this time. A Minor Response was observed at 2.4 mg/m2/day, and several patients have experienced Stable Disease of several months duration. Two patients with stable disease have shown radiographic evidence of necrosis. Median time to tumor progression was 6 weeks (range 2 to >50). Median number of cycles was 2 (range 1 to 7). The study is now enrolling additional patients at the MTD to further profile the drug’s safety and activity. Additionally, a once-weekly dosing schedule is being tested in a satellite cohort. Conclusions: RTA 744 is well tolerated when administered at doses up to and including 7.5 mg/m2/day for the first three days of a 21-day cycle. Based on clear evidence of drug activity, pivotal trials of RTA 744 in high-grade gliomas are planned as well as trials in patients with brain metastases.

[Table: see text]
Phase II open-label, safety, pharmacokinetic and efficacy study of 2-methoxyestradiol nanocrystal colloidal dispersion administered orally to patients with recurrent glioblastoma multiforme
Authors: Kirkpatrick J. , Desjardins A. , Quinn J. , Rich J. , Vredenburgh J. , Sathornsumetee S. , Gururangan S. , Sidor C. , Friedman H. , Reardon D.
Published: March 2020

2065

Background: 2-methoxyestradiol (2ME2) inhibits tumor cell proliferation and induces apoptosis by inhibiting microtubule polymerization and increasing reactive oxygen species-induced cell damage. In addition, 2ME2 downregulates HIF-1a at the posttranscriptional level and inhibits HIF-1a-mediated VEGF expression. Preclinical studies confirm significant in vitro and in vivo anti-glioma activity including tumor regression in combination with temozolomide. We therefore performed a single-center, phase 2 study to evaluate 2ME2 in recurrent glioblastoma multiforme (GBM) patients. Methods: Key eligibility include: adults with GBM at first or second recurrence; measurable disease; Karnofsky performance status = 70% and adequate organ function. 2ME2 was given orally 4 times/day at a dose of 1000mg for the first 11 patients and then escalated to 1500 mg for remaining patients. Patients are evaluated after every 28-day cycle. The primary efficacy endpoint is 6-month progression-free survival. Results: Sixteen patients (14 male) have been enrolled, including 7 at first recurrence and 9 at second recurrence. The median age is 52 years (range, 32–64 years). Thirty-five cycles have been administered to date. Grade II-IV, attributable toxicities include transaminase elevation (grade 3, n=3; grade 2, n=1); hypophosphatemia (grade 3, n=1); anorexia (grade 2, n=1) and rash (grade 2, n=1). Six patients (38%) have achieved stable disease including one minor response. PK studies revealed similar 2ME2 exposures to those achieved among solid tumor patients treated at the same dose level and no differences between GBM patients on or not on CYP3A-inducing anti-epileptic agents. Further accrual and follow-up is ongoing. Conclusions: Continuous daily 2ME2 dosing, administered as a monotherapeutic, is well tolerated and is associated with modest anti-tumor activity among recurrent GBM patients. Combination studies with temozolomide are underway.

No significant financial relationships to disclose.
Rechallenge of malignant gliomas with temozolomide —Can it be effective?
Authors: Strik H. M. , Buhk J. H. , Bock H. C. , Nitsche M. , Giese A. , Baehr M.
Published: March 2020

2072

Background: No standard treatment of recurrent malignant glioma is established. Moreover, it is unclear if a rechallenge with temozolomide is effective. We present here feasibility and first treatment results of a dose-dense, individually dose adapted 21-day regimen with temozolomide. Methods: 13 consecutive patients with recurrent malignant gliomas (11 glioblastomas [GBM], 1 anaplastic astrocytoma, 1 anaplastic oligodendroglioma) were treated. The basic data are: median time to first relapse 8.3 months; median Karnofsky performance status 60% (7 x 50+60%; 6 x 70–100%); median age 52.2 (32–73) years; gender: 9 males (69%), 4 females (31%). All patients were pretreated with radiochemotherapy and temozolomide 200mg/m2 days 1–5/28 in first line. In eight of the 13 patients, therapy was switched without delay to the dose-dense schedule: temozolomide 100mg/m2 day 1–21/28. During treatment, the dosage was adapted individually, aiming towards total leukocyte counts of approximately 4,000/μL. Results: The 21/28-days regimen was better tolerated than the 5/28-days schedule regarding nausea and fatigue. Blood counts decreased continuously, enabling a gradual dose adaptation. The dosage was kept at 100mg/m2 in 9 patients, reduced to 75 mg/m2 in 3 and gradually increased to 130 mg/m2 in 1 patient. Hematotoxicity was WHO grade 3 in 2, and grade 4 in 1 patient without clinical signs. One patient had a pneumonia WHO grade 4 in the terminal stage of the disease several weeks after discontinuation of the chemotherapy. Response after 2 months was: 3 partial and 1 complete remission (31%; GBM only: 18%), 4 stable diseases (31%), 5 progressive diseases (38%). The progression free survival at 6 months (PFS) was 54.5% (GBM: 44%). In the 9 glioblastoma patients with an observation period of more than 6 months, the median survival time after relapse was 35.8 weeks, median overall survival 18.2 months. Conclusions: Second line treatment with dose dense temozolomide at 100 mg/m2 day 1–21/28 and individual dose adaptation is feasible for recurrent malignant gliomas. Even in this series with relatively unfavorable prognostic criteria, the rate of objective responses and 6-months PFS after rechallenge with temozolomide compares well with other series. The results will be controlled in a prospective study.

No significant financial relationships to disclose.
Longitudinal assessment of childhood optic gliomas: Relationship between brain imaging and optic pathway function
Authors: Falsini B. , Lazzareschi I. , Ruggiero A. , Ziccardi L. , Placentino L. , Colosimo C. , Di Rocco C. , Riccardi R.
Published: March 2020

2087

Background: To evaluate longitudinally the relationship between brain imaging and functional findings in childhood optic gliomas (OG) by comparing over time magnetic resonance imaging (MRI) with flicker visual evoked potential (FVEP) changes. Methods: Fourteen children (median age 3 yrs, range: 2–7) suffering from OGs involving chiasm and retro-chiasmatic visual pathways underwent serial MRI and FVEP examinations over a median follow-up time of 38 months (range 12–76). FVEPs were monocularly recorded in response to 8 Hz sine-wave flicker stimuli presented in a mini-Ganzfeld according to a published technique (Trisciuzzi et al., Clin. Neurophysiol., 2004). MRI examinations were performed according to standard procedures. Longitudinal results of both tests were examined in a blind fashion by independent evaluators. FVEPs were judged to be improved, stable or worsened if changes in the amplitude and/or phase of the fundamental response component exceeded the limits of test-retest variability (±90th percentile) established in the same patients. MRI results were judged to show regression, stabilization or progression of OG based on its changes in size (±20%) or extension. Two to seven pairs (< one month apart) of FVEP/MRI examinations per patient (median: 4, range 2–7) were collected. Agreement between test changes over time were evaluated by K-statistics. Results: Based on a total of 38 pairs of longitudinal FVEP/MRI examinations, both tests agreeed in showing worsening (progression), stabilization and improvement (regression) in 5, 10 and 15 cases, respectively. In 3 cases, FVEPs showed a worsening and MRI a stabilization, while in 5 cases FVEPs showed an improvement and MRI a stabilization. Agreement between FVEP and MRI changes was 78.9% (95% CI: ± 37%, K = 0.67, p < 0.001). Conclusions: The results indicate that changes over time in FVEPs, an objective and non-invasive test of visual function, can accurately predict associated changes in OG size and extension as assessed by MRI, and suggest that the latter changes may have a significant impact on visual function during developmental age.

No significant financial relationships to disclose.
A substantial change in breast cancer (BC) biology arises after 50 years old regardless of patient (pt) menopausal status
Authors: Veys I. , Durbecq V. , Ameye L. , Desmedt C. , Paesmans M. , Sirtaine N. , Sotiriou C. , Nogaret J. , Piccart M. , Larsimont D.
Published: March 2020

21002

Background: To explore the hypothesis that ageing alters BC biology, we correlated pt age at diagnosis with biopathological data collected retrospectively from 2723 BC pts treated at the Bordet Institute between 2000 and 2003. Pt's characteristics: Median pts’ age was 56 years old [25–96] and 36% of pt had nodal invasion. Seventy-eight and 63% of the BC were ER+ and PR+ respectively, 33% were grade 3, 24% overexpressed Ki67 (>25%) and 8% were Her2 FISH+. Results: Pts <40 years old had the highest Her2 FISH+ (12%) and hormone-independent (39%) BC rates. More than 50% of the BC were undifferentiated (grade 3) and highly proliferative (Ki67>25%). Moreover, lobular BC were almost absent in young pts (p<.0001); in agreement with the fact that lobular BC were less aggressive than ductal ones (less grade 3, Her2 FISH+ and ER- BC; p<.0001). Hence pts <40 years had a statistically higher rate of “Her2” and “basal-like” BC subtypes. On the contrary, pts >50 years had ‘better prognostic luminal-A” BC with 60% of hormone-dependent BC and a significant drastic decrease of Ki67 expression, tumor grading and Her2 FISH+ (all p=.002). No biological difference was observed between BC of pts >50 years. However, in this group we observed that high ER scores (7–8 vs 3–6) were statistically associated with Her2 FISH- and PR+ characteristics (all p<.0004). Interestingly, the 40–50 years old group which contains 16% of postmenopausal pts, appeared as a transition group according to its biology. Nevertheless, no statistically biological difference could be observed between the BC of pre- and postmenopausal pts. Additionally, when considering the postmenopausal pts from all ages, a clear difference was observed for the different parameters between tumors from pts <50 years compared to older ones (ER, p=.046; grade, p=.0007; Ki67, p=.0001), suggesting that age, and not the menopausal status, is responsible for changes in BC biology Conclusions: BC biology is greatly different in pts before and after the age of 50 but after 50 years old, all pts have BC with similar characteristics. Nevertheless, menopausal status can not account by itself to all these differences and pt ageing appears to have a great impact on BC biology (i.e. Her2 FISH+).

No significant financial relationships to disclose.
Relapse free survival in a prospective cohort of hormone receptor/Her2neu defined breast cancer patients
Authors: Kaplan H. G. , Malmgren J. A. , Atwood M. K.
Published: March 2020

21003

Background: Adjuvant trastuzumab for Her2/neu (Her2) positive breast cancer (BC) is now standard treatment. We describe hormone receptor (HR)/Her2/neu defined phenotypic BC subgroups and evaluate recurrence risk prior to widespread use of adjuvant trastuzumab. Methods: A prospective cohort of patients at our institution diagnosed with primary BC between 1998 and 2003 were categorized by HR and Her2 status into ER+/PR+/Her2- (HR+/Her2-) (N=1114), ER+/PR+/Her2+ (TP) (N=134), ER-/PR-/Her2- (TN) (N=176), and ER-/PR-/Her2+ (HR-/Her2+) (N=91) (n= 1550). Patients with discordant ER/PR status (n=262) or equivocal IHC Her2 results were excluded (n=179). Clinical variables including age, race, TNM stage, histologic type and detection method were chart abstracted and vital and disease status were updated annually. The endpoint was disease recurrence; local, regional, distant, or combination. Average length of follow up was 7 years and relapse free survival (RFS) was calculated using Kaplan-Meier procedures with Cox proportional hazards modeling for risk and 95% confidence intervals (CI). Results: Mean patient age at diagnosis was 57, ranging from 21–94 years. Compared to HR+/Her2- and TP patients, TN and HR-/Her2+ patients were significantly more likely to be younger, higher TNM stage, higher histologic grade and patient vs. mammography detected. Disease recurrence was 24% in HR-/Her2+ patients, 16% in TN patients, 8.4% in TP patients, and 3.3% in HR+/Her2- patients (Pearson chi square = 101.56, p<.001). Excluding TNM stage IV patients (n=35), RFS at five years was in rank order HR+/Her2- (95%), TP (89%), TN (84%), HR-/Her2+ (76%) (log rank test = 53.14, p<.001). When adjuvant trastuzumab treated patients (n=34) were removed from the analysis the 5 year RFS only changed in the HR-/Her2+ group to 73%. In a model adjusted for age, race, menopause, TNM stage and treatment using HR+/Her2- patients as the reference group, recurrence risk was 1.98 for TP (95% CI = 1.02 to 3.84), 2.32 for TN (95% CI = 1.32 to 4.08), and 4.25 for HR-/Her2+ patients (95% CI = 2.33, 7.75). Conclusions: All three subgroups had significantly worse RFS compared to HR+/Her2- patients. Even though TN and HR-/Her2+ share many poor prognostic characteristics, HR- /Her2+ BC had the highest risk of recurrence.

No significant financial relationships to disclose.
Livin, a regulator of apoptosis protein, is deregulated in melanoma and serves as an independent prognostic factor—a study of 114 melanoma patients
Authors: Lazar I.
Published: March 2020

21006

Background: Inhibitor of Apoptosis Proteins (IAP) family members inhibit apoptosis mainly by direct binding and inhibition of caspases. We previously identified the IAP Livin and demonstrated that following strong apoptotic stimuli the protein was cleaved by effector caspases to produce a truncated form with paradoxical pro-apoptotic activity. We also demonstrated that Livin is overexpressed in melanoma (M) and plays a role in chemoresistance and survival. More recently we identified synonymous single nucleotide polymorphism (SNP) in Livin at position 528(C/T) that determines expression levels of Livin protein. We found that Livin is expressed in a monoalleic manner. Normal heterozygous samples express the 528T mRNA allele and the Livin protein is not expressed. The monoallelic regulation is lost in metastatic M and the Livin protein is expressed. Methods: This study included 114 M patients that were grouped into clinical categories according to prognosis. Correlation between Livin expression and clinical parameters was examined using ANOVA, chi-square test and Kaplan-Mayer curves. Results: We found that in primary cultures from 114 M patients high, low and absence of Livin protein expression were associated with the T/C, CC and TT genotypes, respectively, at the 528(C/T) polymorphic site. Correlation of Livin expression with overall survival was significant: high expression of the Livin protein was associated with bad prognosis; survival in patients with medium expression of Livin was significantly longer compared with those without livin expression For 23 patients samples were obtained both at diagnosis and upon disease progression. All 23 first tumor sample did not express the Livin protein. Remarkably, Livin was expressed in second tumor samples from 9 of the 23 patients.and was associated with poor prognosis. Conclusions: We found that Livin expression is an independent prognosis factor in malignant M. furthermore, we describe a direct correlation between the level of Livin protein expression and survival of M patients. We also provide evidence for a novel mechanism associating synonymous SNP with control over protein expression and its deregulation during tumor progression.

No significant financial relationships to disclose.
registHER: Patient characteristics, treatment patterns, and preliminary outcomes in patients with HER2-positive (HER2+), hormone receptor-positive (HR+) metastatic breast cancer (MBC)
Authors: Yardley D. A. , Kaufman P. A. , Mayer M. , Ulcickas Yood M. , Tan-Chiu E. , Brufsky A. M. , Rugo H. S. , Tripathy D. , Paik S. , Brammer M. G.
Published: March 2020

21007

Background: Approximately 50% of HER2+ breast cancers are HR+, however, the interaction between HER2 and HR is not completely understood. Patients with HR+/HER2+ or HR-/HER2+ tumors treated with trastuzumab + chemotherapy (CT) achieve similar clinical benefit. Retrospective analyses suggest that HER2+ tumors are resistant to hormone therapy (HT), particularly anti-estrogens, possibly due to estrogen receptor /HER2 interactions and quantitatively lower HR expression in HER2+/HR+ tumors. Conducting randomized clinical trials in HER2+/HR+ MBC is challenging given the small patient population. Methods: registHER is a prospective observational study of approximately 1000 patients with newly diagnosed (<6 months) HER2+ MBC treated in community or academic settings. Baseline characteristics and treatment patterns in patients with HR+ vs HR-, HER2+ MBC receiving first-line therapy were studied in this analysis. The influence of adjuvant HT on disease-free intervals (DFI) from time of diagnosis and MBC treatment selection in patients with HR+/HER2+ tumors was examined. Results: Of 976 patients with HER2+ MBC and recorded tumor HR status, those with HR+ MBC (54.9%) tended to be white (81.7% vs 77.0%), were more likely to have bone only metastases (18.1% vs 6.4%), less likely to have CNS metastases (2.8% vs 8.2%), and have fewer metastatic sites at diagnosis (49.1% vs 43.2%) than those with HR- MBC. Of patients with HR+ MBC, who were stage I- III at initial diagnosis, 51.3% received adjuvant HT, of which 73.2% received tamoxifen. Median DFI was 48.8 vs 29.4 mo for patients receiving tamoxifen vs an aromatase inhibitor. First-line MBC treatment regimens included: HT only (13.8%); HT + trastuzumab (8.4%); HT + trastuzumab + CT (6.2%); trastuzumab only (6.0%); CT only (11.0%); trastuzumab + CT (53.5%). Analyses of progression-free survival by HR status and first-line treatments (HT only, trastuzumab ± HT or ± CT), are ongoing and will be described. Conclusions: registHER represents the largest dataset of patients with HER2+/HR+ MBC and provides a unique opportunity to characterize treatment patterns, efficacy and safety, and the natural history of this subset of breast cancer patients.

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