bluuebunny/crossref_metadata_2025_split huggingface dataset:
Very late relapses in glioblastoma long-term survivors
Authors: Baehr O. , Herrlinger U. , Weller M. , Steinbach J. P. 
Published: August 2020

e13017 Background: Long-term survival of patients with histologically confirmed glioblastoma is a rare event with figures in the range of 2–3% for 5-year survival. Prognosis and further clinical course of these patients beyond 5 years after diagnosis are in essence unknown with only anecdotal reports of patients surviving for 10 years or more. Methods: We here report on the extended follow-up (mean, 139.4 months) of a cohort of 10 glioblastoma long-term survivors. Retrospective central histology, clinical monitoring, and regular magnetic resonance imaging were done. Results: A total of 5 patients of the 9 patients alive at a previous analysis have died during the extended follow-up. Four of these patients died from recurrent tumor. One patient died from leukoencephalopathy-associated complications without evidence of tumor progression. Details concerning the occurrence of relapses and their treatment are displayed in table 1. Notably, very late relapses occurred in three patients after 118, 124, and 126 months of progression-free survival. Thus, from the original cohort of 10 patients only 3 remain free from recurrence after the extended follow up of more than 10 years. Conclusions: Very late relapses pose a serious threat for glioblastoma long-term survivors and call for continuous vigilance. The maintenance of a tight control schedule even in patients surviving for more than 10 years should be considered. [Table: see text] No significant financial relationships to disclose.
Efficacy of protracted dose-dense temozolomide (TMZ) in patients with progressive high-grade glioma
Authors: Abacioglu M. U. , Caglar H. B. , Yumuk P. F. , Akgun Z. , Atasoy B. M. , Sengoz M. 
Published: August 2020

e13018 Background: The study was aimed to evaluate the efficacy of TMZ on a protracted dose-dense schedule after standard 5-day TMZ regimen in patients with progressive high-grade glioma. Methods: In this phase II prospective study, patients who had progression on standard 5-day TMZ for recurrence (group 1) or recurrence after concurrent radiotherapy+TMZ and ≥ 2 cycles of adjuvant TMZ (group 2) for high-grade glioma received TMZ 100 mg/m2× 21 q28 days until progression according to MacDonald's criteria. Patients were included in the study after ethical committee approval and written informed consent. The primary end-point was 6 months PFS. Secondary end-points were OS and toxicity. Results: Between October 2006 and October 2008, 25 patients were included in the study. Nine of the patients were group 1 and 16 of them were group 2. Male/female ratio was 18/7. The median age was 50 (range, 18–70) and median KPS score was 80 (range, 50–100). The histopathology was glioblastoma in 18 and grade 3 glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma or anaplastic oligodendroglioma) in 7. The median cycles of 5-day TMZ received before study entry was 6 (range, 2–18) in group 1 and 6 (2–7) in group 2. With a median follow up of 6 months (1–14 months) the median number of 21-day TMZ cycles received was 2 (range, 1–8). Radiological evaluation could not be performed in 5 patients because of early clinical progression. The best response during treatment was partial response in 2 (8%), stable disease in 9 (36%), and progression in 9 (36%) out of 20 patients assessed. The median time to progression was 2 months (1–8 months) and 6 months PFS rate was 11%. The median OS time was 8 months and 1 year OS rate was 38%. Out of 80 cycles received there was no anemia; 5 (6%) grade 1, 8 (10%) grade 2, 2 (3%) grade 3 leucopenia; 1 (1%) grade 1, 2 (3%) grade 2, 1 (1%) grade 3, 1 (1%) grade 4 thrombocytopenia; 9 (11%) grade 1, 7 (9%) grade 2, 32 (40%) grade 3, and 11 (14%) grade 4 lymphopenia. Study was terminated in 2 patients (one with grade 4 thrombocytopenia and the other with grade 4 hepatic toxicity). There was no dose reduction in the study drug due to toxicity. Conclusions: Protracted dose-dense TMZ after 5-day schedule for recurrent or progressive disease has modest efficacy with tolerable toxicity. No significant financial relationships to disclose.
Expression and prognostic significance of differentiation markers in primary CNS lymphoma (PCNSL)
Authors: Momota H. , Narita Y. , Miyakita Y. , Shinomiya A. , Maeshima A. , Maruyama T. , Muragaki Y. , Shibui S. 
Published: August 2020

e13028 Background: BCL-6 expression has been reported to be associated with a better prognosis in PCNSL. However, significant differences of B-cell lymphoma subtypes exist in different geographic regions. The objectives of this study were to characterize the immunophenotypes of PCNSL in Japan and to determine their utility in predicting clinical outcomes. Methods: Immunostaining for CD5, CD10, BCL-6, and MUM-1 was done to determine the profile of diffuse large B-cell lymphoma of PCNSL from 27 immunocompetent patients in Japan. Then, the authors evaluated whether clinical and immunophenotypic markers were associated with progression-free or overall survival. Results: Germinal center B-cell (GCB) marker CD10 was positive in 22% of PCNSL samples, while another GCB marker BCL-6 was positive in 48% of samples. Post-GCB marker MUM-1 was positive in 81% of samples. Poor prognostic marker of systemic B-cell lymphoma CD5 was expressed in 15% of samples. In univariate analyses, only BCL-6 expression had a significant effect on progression-free survival (median, 6.1 months in BCL-6-positive patients versus 15.6 months in BCL-6-negative patients; p = 0.037). Patients with BCL-6 expression had a trend towards longer overall survival but nonsignificant. GCB subgroup (CD10-positive or CD10-negative/BCL-6-positive/MUM-1-negative) was not significantly associated with favorable survival. Conclusions: BCL-6 expression is associated with a poor prognosis in patients with PCNSL. The discrepancy between the reports from other groups and our results is potentially due to the racial, geographic or immunophenotypic differences of PCNSL. No significant financial relationships to disclose.
Primary central nervous system lymphoma: An Irish clinical experience
Authors: Forde P. , Grant C. , Smith E. , Farrell M. , Brett F. , Bolger C. , Grogan L. , Breathnach O. 
Published: August 2020

e13032 Background: North American studies have demonstrated an increase in incidence of primary CNS lymphoma in recent decades. To our knowledge there have been no studies analyzing primary CNS lymphoma in the Irish setting. This prompted a review of cases diagnosed at our institution, the larger of two national neurosurgical/neuro-oncology referral centers. Methods: The records of 78 patients diagnosed with primary CNS lymphoma at our institution between January 1999 and October 2008 were reviewed. Patient's age, sex, and time to diagnosis were noted. Histology and radiology was reviewed for cell of origin, CD20 status, and sites of involvement. HIV serology results were available for 23 patients. Results: The median age was 60 (4–78). There was a slight female preponderance (1.1:1]). Median time from hospital presentation to histological diagnosis was 17 days (4–790). 92% (74) of primary CNS lymphomas were B cell and CD20 positive with 8% (4) being T cell. One-third of patients had multifocal brain involvement by lymphoma. 2 of 23 patients tested were HIV positive. Conclusions: In comparison with international published series primary CNS lymphoma in Ireland is diagnosed at an older median age, has a more even sex distribution and a relatively higher incidence of T cell origin. Multifocal tumor involvement was also more frequent than in other series possibly indicating later clinical presentations. There was a much lower incidence of HIV infection in patients who were tested than in similar North American studies. The wide range in time to diagnosis indicates the difficulties associated with diagnosing this uncommon condition. No significant financial relationships to disclose.
A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC)
Authors: Leal T. B. , Schelman W. , Traynor A. , Kolesar J. , Marnosha R. , Eickhoff J. , Alberti D. , Wilding G. 
Published: August 2020

e13502 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally-administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mc1–1, Bcl-W, and through upregulation of the proapoptotic proteins Noxa and Puma. Bcl- 2 is over-expressed in >80% of SCLC. In vitro study using SCLC cells showed that treatment with EP had synergistic cytotoxic effects in suppression of Bcl-2. This is a phase I dose-escalation study of AT in combination with EP with an expanded cohort of patients with ES-SCLC. This study is being conducted to determine the maximum tolerated dose (MTD), pharmacokinetics and activity of AT with EP ± pegfilgrastim (F) in patients with advanced, refractory solid tumors and/or ES-SCLC. Methods: This study used standard eligibility criteria except patients must not have received prior therapy that inhibits the Bcl-2 family. At dose level 1, patients received P 60 mg/m2 on day 1 and E 100 mg/m2 on days 1, 2, and 3 every 21 days. AT was administered 30 mg orally BID on days 1, 2 and 3 of each cycle. Results: 10 patients have been enrolled; 7 men, 3 women. Tumor types: 6 lung; 2 prostate; 1 head & neck; 1 unknown primary. 2 of 5 patients enrolled at dose level 1 experienced a DLT of neutropenic fever in cycle 1. Three subsequent patients were enrolled to dose level -1 (20 mg BID x 3 days, d1–3) which was well tolerated. Additional patients are being enrolled at dose level 1a (EP+AT with F). Grade 3/4 toxicities related to AT without F at dose level 1 and -1 were as follows: ANC (8), leucopenia (7), febrile neutropenia (2), low hemoglobin (1), thrombocytopenia (1), elevated AST (1), cardiac ischemia/MI (1), diarrhea (1). There were no reported grade 3/4 toxicities in two patients at level 1a. Four patients had stable disease; two progressive disease and four patients were unevaluable. Conclusions: The MTD without F was established at AT 20mg orally BID, P 60 mg/m2 on day 1, and E 100 mg/m2 on days 1, 2, and 3 every 21 days. The MTD with F has not yet been established. Accrual continues at dose level 1a. Subjective and objective evidence of clinical activity has been observed in patients with refractory solid tumors. This study was supported by NCI, UO1 CA062491, SAIC 25XS097 and 1ULRR025011. No significant financial relationships to disclose.
Dose-finding study of NKTR-102 in combination with cetuximab
Authors: Hamm J. T. , Richards D. , Ramanathan R. K. , Becerra C. , Jameson G. , Walling J. , Gribben D. , Dhar S. , Eldon M. , Von Hoff D. 
Published: August 2020

e13503 Background: NKTR-102 is an advanced polymer conjugate of irinotecan with broad single agent activity and a unique pharmacokinetic (pk) profile. The apparent half-life of the active metabolite SN-38 in patients (pts) administered NKTR-102 is approximately 50 days. NKTR-102 in combination with cetuximab was evaluated in pts with refractory solid tumors to define the maximum tolerated dose (MTD). Methods: NKTR-102 was infused over 90 minutes every 3 weeks per cycle. Cetuximab was infused over 2 hours at 400mg/m2 on day 1 followed by a weekly 1 hour infusion at 250mg/m2. Cohorts of 3 -12 pts were treated with escalating doses of NKTR- 102. MTD was established based on the dose limiting toxicities observed in cycle 1 and safety data from subsequent cycles. Serial plasma samples were collected throughout the study for PK analysis. Results: Eighteen pts were enrolled: main tumor types include colon (5), pancreas (4), rectal (2), breast (2), gastric (1), other (4). Pts received 100 mg/m2 (12) or 125 mg/m2 (6) of NKTR-102 for a median of 2.5 cycles (range 1 to 11+). At 125 mg/m2, 3 pts had G3 diarrhea, 1 in cycle 1; 2 in cycle 2. At 100mg/m2, 1 pt had G3 diarrhea in cycle 1 and a further pt had G4 fatigue in cycle 2. Other G3 toxicities for all patients in both dose groups include nausea (3), vomiting (3) and neutropenia (2). No G3 rash was reported. Partial responses (PR) were observed in 3 pts at 100 mg/m2: confirmed (rectal, colorectal) and unconfirmed (gastric). Another pt with pancreatic cancer had a decrease in CA19–9 from 2000 at baseline to 157 U/ml with associated symptomatic benefit. NKTR-102 resulted in sustained exposure to SN-38 with no evidence of PK drug interactions between NKTR-102 and cetuximab. Conclusions: NKTR-102 shows evidence of clinical antitumor activity in combination with cetuximab. Toxicity is manageable; diarrhea and neutropenia are dose limiting. The recommended dose of NKTR-102 with cetuximab is 100mg/m2 every three weeks. Data support further evaluation of this combination in appropriate tumor types. [Table: see text]
A phase I study dose escalation clinical study of hepatic intraarterial cisplatin, combination systemic intravenous liposomal doxorubicin in patients advanced cancer dominant liver involvement
Authors: Vaklavas C. , Tsimberidou A. M. , Moulder S. , Ng C. , Naing A. , Daring S. , Bedikian A. , Uehara C. , Kurzrock R. 
Published: August 2020

e13512 Background: Patients with liver metastases treated on phase I clinical trials have a median survival of 7.5 months (range, 6.0–9.5). We conducted a phase I study of hepatic arterial infusion (HAI) and intravenous (IV) chemotherapy in patients with advanced cancer and dominant liver involvement. Patients: Patients were treated with HAI cisplatin 100–200 mg/m2 intraarterially D1+ 3000 IU heparin intraarterially on D1; followed by liposomal doxorubicin 20–35 mg/m2 IV D1 every 4 wks using a conventional “3 + 3” design. Results: Thirty patients were treated (median age, 56 y; range, 15–76; 5 men, 25 women). Diagnoses were breast cancer (n=11), colorectal cancer (n= 8), ocular melanoma (n=4), and other (n=7). The median number of prior therapies was 5 (range, 1–13). Enrollment was: HAI cisplatin (mg/m2)/IV doxil (mg/m2): 100/20 (n=3); 100/25 (n=4); 100/30 (n=3); 100/35 (n=16) and 125/35 (n=4) and the maximum tolerated dose (MTD) was 100/35. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (1 of 4 patients). Among 30 patients who completed cycle 1, 7 (23%) patients had no toxicity >Grade 1. Overall, 77 cycles were administered (median per patient, 4; range, 1–6). The most common toxicities were nausea/vomiting (n=23), fatigue (n=15), and constipation (n=13). Twenty-one patients were evaluable for response. Treatment resulted in a partial response (PR)(n=4) or stable disease (SD)(n=6) by RECIST in 10 (48%) patients and lasted for ≥4 months (tumor reduction by 5% to 44%). Four (19%) patients achieved a PR (tumor reduction by 38%, 42%, 44% and 51%, for 4, 4, 6, and 4 months, respectively). Of the 11 patients with breast cancer, 3 had a PR and 4 had SD. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD. One patient with hepatocellular carcinoma had SD. Of 11 evaluable patients treated at the MTD, 3 (27%) had a PR and 4 (36%) had SD. Conclusions: The MTD of HAI cisplatin 100 mg/m2 and systemic liposomal doxorubicin 35 mg/m2 demonstrated antitumor activity in this patient subset. No significant financial relationships to disclose.
Safety and early efficacy results from a phase I study of volociximab (V) in combination with carboplatin (C) and paclitaxel (P) in patients (pts) with advanced non small cell lung cancer (NSCLC)
Authors: Besse B. , Almokadem S. , Planchard D. , Chico I. , Tsao C. L. , Ringeisen F. , Soria J. , Belani C. P. 
Published: August 2020

e13513 Background: Volociximab is a chimeric monoclonal antibody that blocks fibronectin binding to α5β1 and induces apoptosis in proliferating endothelial cells. Its anti-angiogenic actions are independent of the VEGF pathway. This is the first clinical study of voloxicimab in patients with advanced NSCLC. Methods: This phase 1b multi-center open-label, dose-escalation study was designed to determine the maximum tolerated dose of V in combination with full doses of C (AUC=6mg/ml.min) P (200mg/m2) with cycles repeated every 3 wks for a maximum of 6 cycles followed by a maintenance treatment with V alone. Eligible pts had histologically confirmed untreated stage IIIb or IV NSCLC. In cohorts 1 and 2, pts received V at 10 mg/kg and 20mg/kg IV, respectively, on days 1 and 8, of the first 21 day cycle then every 21 days. In cohort 3, pts received V 30 mg/kg IV every 21 days from day 1. We present here the interim safety analysis and RECIST response data of the combination therapy. Results: A total of 22 patients (9, 6 and 7 in cohorts 1, 2 and 3 respectively) who received at least one dose of treatment constitute the safety population. Reported salient adverse events (any grade) were constipation (68%), asthenia (64%), nausea (59%), arthralgia (55%) and paresthesia (46%). Grade 3 bowel obstruction in one patient was considered a DLT in cohort 2. No DLT's were observed in cohort 3. Seven pts reported at least one serious adverse event (all Grade 3) including deep vein thrombosis (1), peripheral arterial occlusion (1), proteinuria (1), pneumonitis (1), small intestinal obstruction (1), pleural effusion (1), hypoxia (1), dehydration (1) and orthostatic hypotension (1). Partial response was seen in 6 pts and stable disease in 12 out of 18 pts who were evaluable for response by RECIST. Conclusions: The highest dose of V tested (30 mg/kg q3w) in combination with CP appears well tolerated and the regimen has promising clinical activity in advanced NSCLC. [Table: see text]
A dose finding and PK/PD study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial
Authors: Kitagawa C. , Saka H. , Adachi T. , Kajikawa S. , Mori K. , Kogure Y. , Oki M. , Shimokata K. 
Published: August 2020

e13517 Background: Amrubicin (AMR) is a potent topoisomerase II inhibitor, and a promising agent for both small cell and non-small cell lung cancer. AMR is usually administered on days 1–3 intravenously. However, it causes severe, occasionally fatal, toxicity of leucopenia and neutropenia. The purpose of this study was to evaluate the safety and tolerability of AMR, to determine the recommended weekly dose, and to conduct a PK/PD study in patients with chemotherapy-refractory or recurrent lung cancer. Methods: Refractory or relapsed non-small cell and small cell lung cancer patients after 1 or 2 regimens, younger than 80 and with adequate main organ functions were eligible. AMR was initiated 45 mg/m2 given weekly (on day 1 and 8 q3wks). The dose level was increased by 5 mg/m2 by modified Fibonacci dose escalation scheme. Dose limiting toxicity (DLT) was assessed on the 1st cycle. Results: 16 patients were enrolled. Patients were 7 small cell lung cancer and 9 non-small cell lung cancer. 54 cycles (median: 3, range: 1–6) were administered in 5 dose levels. In 65 mg/m2 level, 3 patients had DLTs. The maximum tolerated dose was 65 mg/m2. The recommended weekly AMR dose was determined to be 60 mg/m2. Leucocytopenia, neutropenia, thrombocytopenia, and the dose level were correlated (p<0.001, p=0.0012, p=0.043) respectively. Leucocytopenia, neutropenia, and amrubicinol (AMR-OH) Cmax were correlated (p=0.042, p=0.047) respectively. AUC (AUC extrapolated to concentration-zero) of AMR and AMR-OH did not depend on the dose levels. The pharmacokinetic results are shown in the Table. [Table: see text] [Table: see text]
Oral metronomic chemotherapy using cyclophosphamide in metastatic patients (pts) after standard treatment: Results of a randomized phase II trial
Authors: Clisant S. , Adenis A. , Dansin E. , Desauw C. , Degardin M. , Mortier L. , Fournier C. , Penel N. 
Published: August 2020

e13519 Background: Oral metronomic chemotherapy (OMC) has antiangiogenic properties and megestrol acetate (MA) is an orexigen used to maintain the general condition in critically ill pts. Anecdotal responses have been reported with each treatment. We hypothesized that each treatment offer disease control without significant severe toxicity. Methods: This multi-center-randomized study was aimed to assess the efficacy and tolerance of both treatments. Primary endpoint was stable disease rate at 2 months: 2mSD (RECIST). Main eligibility criteria were as follows: non-breast cancer, pts with progressive disease refractory to standard therapies or without established standard care, ECOG=0–1, neither hypercalcemia nor hypoalbuminemia. Pts were randomized to receive MA 160 mg b.i.d or OMC 50 mg b.i.d until severe toxicity or progression. The sample size calculation was based on Simon Minimax design (α=10%, β =90%, P0=5%, P1=20%). The second stage was allowed because at least 2mSD were seen among 12 first pts. Results: 88 pts were included from 9/2006 to 12/2008 (44 in each arm). Median age was 61 (22–84). Most common primaries were: colorectal cancer (30 pts), soft tissue sarcoma (17), lung cancer (13), head & neck (8) and unknown primaries (4). The median number of previous lines of treatment was 4 (0–10). As of 28 December 2008, 80 pts are assessable for primary endpoint: 6/40 pts (15%) experienced 2mSD in OMC arm whereas 2/40 pts (5%) in MA arm. Three long-lasting SD (6 months +) are currently being observed in 3 pts receiving OMC (2 sarcomas and 1 RCC). No Grade 3 or 4 toxicity was notified. Treatment was discontinued in 1 case because of MA- induced deep venous thrombosis. Conclusions: OMC and MA offer SD in patients with advanced, refractory and progressive tumors, without any significant toxicity. The non-progression rate with OMC (15%) is in a same range of efficacy that was recently reported with new targeted therapy or anti-angiogenic agents administered in such pts. The accrual is now completed, and a longer follow-up is necessary to better analyze the clinical benefit and the prognostic factors. [Table: see text]