bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between epidermal growth factor receptor gene status and clinical outcome of gefitinib in Japanese patients with non-small cell lung cancer
Authors: Kasahara K. , Sone T. , Kimura H. , Nishio K. , Tamura T. , Shibata K. , Mizuguchi M. , Yoshimoto A. , Fujimura M. , Nakao S.
Published: March 2020

7192

Background: Epidermal growth factor receptor (EGFR) gene amplification and mutation have been reported to be predictors of response to EGFR inhibitors. We evaluated EGFR gene copy number and mutations in biopsy samples of non-small cell lung cancer (NSCLC) treated with gefitinib (G) and analyzed the correlation between gene status and clinical outcome. Methods: EGFR gene copy numbers in biopsy samples were evaluated using FISH and categorized as described by Cappuzzo et al. We also performed mutational analysesof exons 18, 19 and 21 of EGFR by PCR and direct sequencing. Response was judged using the RECIST guidelines. Time to progression (TTP) and overall survival (OS) were calculated and evaluated by the Kaplan-Meier method. Groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. Results: Of 59 patients (pts) enrolled in this investigation, 24 pts (41%) were female and 21 pts (35%) had never smoked. The most common histological subtype was adenocarcinoma (73%) and 36 pts (61%) had good PS 0–1. Gene copy numbers could be analyzed in 54 pts. Gene amplification was observed in 21 pts, high polysomy in 5 pts, low polysomy in 18 pts, low trisomy in 5 pts and disomy in 5 pts. FISH positivity was observed in 26 pts (48%). EGFR mutations were detected in 18 pts (31%); point mutations in exon 21 were observed in 5 pts, in-frame deletions in exon 19 in 12 pts, a point mutation in exon 18 in 1 pt. Response rate in pts with EGFR mutations was significantly higher than in pts without mutations (56% vs. 15%, p = .0011). Response rate in FISH-positive pts was 31% and that in FISH-negative pts was 21%, the association with response was not significant. EGFR mutations were also correlated with improved TTP (median 8.3 m vs. 1.8 m, p = .0014) and OS (median 18.8 m vs. 6.4 m, p = .0059). There were no significant differences in TTP and OS based on FISH positivity. On multivariable analysis, EGFR mutations remained significantly associated with improved TTP and OS. Conclusions: Our results suggest that EGFR mutations are a better predictor of clinical benfit of G when compared with gene copy number in Japanese NSCLC pts.

[Table: see text]
The influence of tumor size, histological differentiation and smoking history in patients with completely resected stage I adenocarcinoma of the lung
Authors: Tsuboi M. , Kato H. , Ichinose Y. , Ohta M. , Hata E. , Tsubota N. , Tada H. , Wada H. , Hamajima N. , Ohta M.
Published: March 2020

7197

Background: To test the hypothesis that patients with completely resected p-stage I adenocarcinoma [Ad.] of the lung contain a favorable subgroup of patients with well differentiated histology and tumor 2.0 cm or less in greatest dimension, we analyzed the results of the JLCRG trial (a randomized prospective trial of adjuvant chemotherapy with Uracil-Tegaful for stage I adenocarcinoma of the lung) by tumor size, smoking history, degree of histological differentiation and more. Methods: Patients were randomized to receive either oral uracil-tegaful (250 mg of tegaful /m2/day) for 2 years postoperatively or no adjuvant treatment. Multivariate analyses and interactions with the Cox proportional-hazards model were used to estimate the simultaneous effects of prognostic factors on survival. Results: The 5-year survival rate of the 412 patients with tumor 2cm or less in size was 89.8% (95% confidence interval [CI]: 86.8 to 92.8) versus 84.4% (95% CI: 81.3–87.4) for the 569 patients with tumor more than 2cm in size (median follow-up 72 months, p = 0.002). Although univariate analysis demonstrated improved survival for the patients with no smoking history and female gender, the selected covariates by multivariate analysis were as follows: age (hazard ratio [HR] for patients aged 70 years or more, 2.25; 95% CI: 1.58 to 3.14, p < 0.0001), tumor size (HR for more than 2cm in size, 1.55; 95% CI: 1.10 to 2.21, p = 0.012), histological differentiation (HR for moderate and poor differentiation, 1.75, 95% CI: 1.25 to 2.47, p = 0.001), and treatment group (HR for the uracil-tegaful group, 0.68; 95% CI: 0.49 to 0.94, p = 0.02). For these prognostic factors, there was only one significant interaction between tumor size and the adjuvant treatment. Conclusions: 1) Patients with completely resected stage I Ad. of the lung contain a favorable subgroup of patients with aged less than 70 years, well differentiated histology, and a maximum tumor dimension of 2.0 cm or less. 2) Adjuvant chemotherapy with oral uracil-tegaful should also be considered for stage I Ad. patients more than 2 cm in tumor size. 3) 2cm in tumor size might be a good benchmark candidate of the description of T factor to facilitate treatment strategies and revisions of the TNM staging system.

No significant financial relationships to disclose.
Can PET/CT substitute for bone scintigraphy in assessment of bone metastases in lung cancer patients?
Authors: Watanabe H. , Monzawa S. , Adachi S. , Hamanaka A. , Kitamura Y. , Izaki K. , Okada M. , Satouchi M. , Negoro S. , Takada Y.
Published: March 2020

7203

Background: Bone is a frequent site of lung cancer metastasis. However, false positive lesions detected by conventional bone scintigraphy often become problematic. We compared the efficacy of whole-body [18F]-2-Fluoro-2-deoxy- D- glucose PET/CT imaging and conventional bone scintigraphy for assessment of bone lesions in lung cancer patients on an individual patient basis. Methods: The study population comprised 106 consecutive patients with suspected or proven lung cancer (73 men and 33 women; age range: 40 to 85 years) who underwent both whole-body PET/CT imaging and conventional bone scintigraphy using 740 MBq of Tc-99m hydroxymethylene diphosphonate for cancer staging. Diagnostic radiologists interpreted and assessed all images on a patient-by-patient basis. Clinical information and the findings of follow-up imaging studies were used as the gold standard for the identification of bone metastases. Results: On the basis of the gold standard, 11 of the 106 patients were identified as having bone metastases. Bone scintigraphy showed a sensitivity of 67% (7/11) while that of PET/CT was 100% (11/11) for detection of bone metastases. Seven of these 11 patients were deemed positive based on both bone scintigraphy and PET/CT. Bone metastases not identified on bone scintigraphy were detected on PET/CT in another four patients. For 39 of 95 patients without bone metastases, the assessment was false-positive for bone scintigraphy but negative for PET/CT. In two of the 39 patients, CT images of PET/CT could identify a benign fracture causing a false positive finding for bone scintigraphy. Conclusions: PET/CT might actually substitute for bone scintigraphy in lung cancer patients because of its superior ability to detect unsuspected bone metastases and to differentiate bone metastases from false positive lesions detected by bone scintigraphy.

No significant financial relationships to disclose.
A multicenter prospective randomized study testing non-inferiority of thalidomide 100 mg/day as compared with 400 mg/day in patients with refractory/relapsed multiple myeloma: Results of the final analysis of the IFM 01–02 study
Authors: Yakoub-Agha I. , Doyen C. , Hulin C. , Marit G. , Voillat L. , Grosbois B. , Harousseau J. , Duguet C. , Zerbib R. , Facon T. , Mary J.
Published: March 2020

7520

Background: Thalidomide (THAL) is effective in pts with relapsed or refractory multiple myeloma (RRMM). A study by Yakoub-Agha et al of 83 patients (Hematol J, 2002) supported this effectiveness but showed a high incidence of THAL toxicity ≥ grade II, related to either THAL cumulative dose or dose-intensity. Themean daily dose of THAL in the first 90-day treatment period, however, did not influence response, overall survival (OS), or event-free survival. Given the dose-related toxicities and an unknown minimally effective THAL dose, the IFM conducted a prospective randomized study to compare the efficacy of THAL 100 mg/d with 400 mg/d in pts with RRMM after ≥2 lines of prior therapy. Methods: The study design was approved by the ethics committee at Lille University Hospital, and all pts gave written informed consent. Given the improved response seen with THAL plus dexamethasone (DEX), this combination was specified per protocol in both study arms for treatment failure (TF) defined as progression at any time or stable disease after 3 months of THAL treatment. THAL dose reduction for toxicity was permitted, but no increase over the initial dose was allowed. All pts received pamidronate routinely. The primary end point was 1-year OS. Secondary endpoints were response rate, EFS, and safety. Results: All results are based on intent-to-treat analyses. In all, 400 pts were enrolled (400 mg, n = 195; 100 mg, n = 205). The 2 groups were comparable in terms of patient characteristics, disease features including Ch13 deletion and prior therapy. Pts in the THAL 100 mg arm received DEX more frequently for TF than those in the 400 mg group, but this difference did not influence 1-year OS: 73 ± 3% vs 69 ± 3% in the 400 mg and 100 mg groups, respectively. The hypothesis of inferiority of 100 mg was rejected. Also, THAL 100 mg was better tolerated than 400 mg with less high-grade somnolence, constipation, and peripheral neuropathy (p < .001, p = .01 et p = .05, respectively). There was no difference regarding deep vein thrombosis. Conclusion: THAL 100 mg/d is comparable in terms of survival with 400 mg/d (with DEX as salvage therapy in case of TF in both arms) in pts with RRMM and better tolerated.

[Table: see text]
Dose finding trial of Yttrium 90 ibritumomab tiuxetan (90YIT) with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL)
Authors: Flinn I. W. , Kahl B. S. , Frey E. C. , Bianco J. A. , Hammes R. J. , Webb J. , Swinnen L. J. , Sgouros G. , Wahl R. L.
Published: March 2020

7535

Background: 90YIT is an effective agent for patients with lymphoma. Unfortunately, dose escalation is limited by hematopoetic toxicity. In order to determine the non-hematopoetic maximum tolerated dose, we are conducting a dose finding study of 90YITwith ASCT. Methods: Eligible patients had relapsed or refractory NHL, rituximab sensitive disease, age ≥18 years, platelet count ≥75,000/mm3, WBC >3,000/mm3, bone marrow involvement ≤35%, and acceptable renal and hepatic function. Patients receive weekly rituximab (375 mg/m2) for 4 consecutive weeks followed by a single dose of cyclophosphamide (2.5 g/m2). Filgrastim 10 mcg/kg is administered post cyclophosphamide until stem cell collection. Following successful collection of at least 2 X 106 CD34/kg, patients receive a dosimetric dose of indium 111 (111In) ibritumomab tiuxetan (5 mCi) on day 1, quantitative planar and SPECT/CT scans followed by cohort specific dose of 90Y IT on day 15. Stem cell infusion occurs when estimated marrow dose rate is < 1 cGy/hour. Results: 22 patients (12M:10F) (median age 55, 44–70) with a median of 2 prior regimens (range, 1–8) have been entered onto study. 5 patients failed to mobilize stem cells and did not receive 90YIT. 16 patients have been treated with 90Y IT to the following dose cohorts based on dosimetry-predicted maximal organ radiation absorbed dose: 0.4 mCi/kg = 3; 14–18 Gy = 5; 24 Gy = 6, 28 Gy = 2. The range of administered 90Y IT activities was 20.2–143.1 mCi. All patients engrafted rapidly. One patient died from treatment-related causes: pneumonia day 27 post-transplant. At 60 days post-transplant, 10 patients achieved a CR, 3 patients had a PR, and 2 had progressive disease. The most common treatment-related toxicities were hematologic, as expected. This therapy was delivered completely in the outpatient setting. 4 patients required admission post 90YIT for febrile neutropenia. No significant hepatotoxicity has been seen to date despite the fact that the liver is the organ that receives the highest absorbed dose of radiation. Conclusions: Significant dose escalation with 90YIT can be achieved with ASCT. Dose escalation continues and the MTD has yet to be determined.

[Table: see text]
A prospective study of the effects of once weekly bortezomib on markers of bone metabolism in patients with multiple myeloma (MM)
Authors: Peles S. , Fisher N. M. , Gao F. , Tomasson M. H. , Dipersio J. F. , Vij R.
Published: March 2020

7548

Background: Increased osteoclast activity in MM leads to bone resorption, osteoporosis and osteolytic bone lesions. Urinary excretion of N-telopeptide (NTX), a marker of bone resorption, decreases by 20–70% following treatment with bisphosphonates. Preclinical studies have shown bortezomib to decrease osteoclast function through inhibition of NF-kB. However, no clinical data exists on the effect of bortezomib on markers of bone resorption. Methods: Six cycles of consolidation bortezomib 1.3mg/m2 were given once weekly for 4 of every 5 weeks, 90–120 days post transplant. Urinary NTX excretion and serum osteocalcin were measured on day 1 of cycles 1, 2 and 3 of therapy. Bisphosphonates were prohibited from 42 days prior to stem cell collection and until cycle 3 of consolidation therapy. Results: 33 of 40 enrolled patients received bortezomib consolidation. Patient population and disease characteristics (no. of patients): male (22), female (11), median age 56 years (range 39–70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). The median duration between discontinuation of bisphosphonates and initiation of consolidation bortezomib was 158 days (Range 110–196). Only one patient had a >50% reduction in myeloma paraprotein. Nevertheless, excretion of NTX declined by a mean of 32% over baseline values after 2 cycles of consolidation therapy. The only patient with an increase in NTX of >30% was also the only patient with evidence of disease progression during this period of therapy. Contrary to reports of proteasome inhibition resulting in increased osteoblastic bone formation, a decline was seen in osteocalcin. Conclusions: Bortezomib has an inhibitory effect on osteoclastic bone resorption in MM similar to that with bisphosphonates even in the absence of effects on malignant plasma cells. Bisphosphonates may result in nephrotoxicity and osteonecrosis of the jaw and bortezomib represents an alternative agent that may control both the myeloma and bone disease.

[Table: see text]

No significant financial relationships to disclose.
Incidence of AIDS- and non-AIDS-defining malignomas in HIV-positive patients—A nation-wide German overview 2000–2002
Authors: Mosthaf F. A. , Goetzenich A. , Ostrop-Hanhoff N. J. , Wolf E. , Knechten H. , Von Wussow P.
Published: March 2020

7554

Background: The primary purpose of this study was to gather data on the epidemiology of AIDS- and non-AIDS-defining malignomas in HIV-positive patients nation-wide in Germany. The secondary objective was to obtain information on their therapy and outcomes. Methods: Surveys were conducted targeting all HIV-specialty clinics and ambulatory care centres as well as all members of the national society of oncologists (BNHO). The surveys requested information on all AIDS- and non-AIDS-defining hematological neoplasms and solid tumors over 3 years (2000–2002) in HIV-positive patients, their tumor stage, their treatments and their clinical course. Further parameters were the CDC (Center for Disease Control)-stage of the HIV-infection and for 2002 the sex of the patient. Results: 60 centres participated in the evaluation and provided 382 data sets. Two data sets were dismissed, where the diagnosis was not made within the defined time frame. Thus 380 data sets from 376 patients could be evaluated (4 patients had 2 malignomas). 180 (47.4%) were AIDS-defining as follows: 89 Kaposi Sarcomas, 82 aggressive B-cell lymphomas, 9 invasive cervix carcimomas. The B-cell lymphomas further included 19 Burkitt’s lymphomas, 8 Castleman diseases, 12 primary cerebral lymphomas. Among the 200 cases (52.6%) of non-AIDS defining malignomas were 133 solid tumors including 40 anal carcinomas (= 20.0% of all non-AIDS defining malignancies) and 67 hemoblastoses including 22 Hodgkin lymphomas (= 11% of all non-AIDS defining malignancies). Conclusions: Our observation showed an unexpected high incidence of non AIDS-defining malignomas over the 3-year time interval followed. Anal carcinomas and M. Hodgkin lymphomas in particular were markedly more prevalent in our HIV-positive cohort compared to published reports of the general population. A conservative estimate showed the incidence of Hodgkin lymphomas to be 6- to 17-times higher, and that of anal carcinomas to be 30- to 60-times elevated.

No significant financial relationships to disclose.
Randomized, double-blind, phase 2, study evaluating same-day vs next-day administration of pegfilgrastim with R-CHOP in non-Hodgkin’s lymphoma patients
Authors: Saven A. , Schwartzberg L. , Kaywin P. , Bartlett N. , Dean L. , Shahin S. , Dreiling L.
Published: March 2020

7570

Background: R-CHOP is associated with a high risk of febrile neutropenia (FN). Pegfilgrastim is indicated to lower infection incidence, manifested by FN, when administered once-per-cycle 24 hrs after chemotherapy (CT). However, eliminating an office visit the day after CT is desirable. Methods: Pts ≥ 18 years with previously untreated non-Hodgkin’s lymphoma (NHL) who received R-CHOP (rituximab 375 mg/m2, C 750 mg/m2, H 50 mg/m2, O 1.4 mg/m2, prednisone 100 mg; for 6 cycles Q21D) were randomized 1:1 to pegfilgrastim 6mg within 4 hours or ∼24hrs after CT. The primary endpoint was the duration of severe (grade 4) neutropenia (DSN) in cycle 1. Same-day administration was considered noninferior to next-day if the upper limit of the 2-sided 95% CI for the difference in mean cycle 1 DSN (same day - next day) was <2 days. Results: 77 pts (8 mantle-cell, 69 diffuse large B-cell) were enrolled of 90 planned (due to slow accrual). 75 pts (36 same-day, 39 next-day) received CT and pegfilgrastim. Most pts had stage 3/4 disease (69% same-day, 74% next-day), no bone marrow involvement (75% same-day, 69% next-day) and ECOG status 0 or 1 (94% same-day, 97% next-day). Difference in mean cycle 1 DSN was 0.9 days (95% CI: 0.3–1.4) longer in the same-day than the next-day group (mean [SD]: 2.1 [1.22] vs 1.2 [1.20] days; grade 4 neutropenia incidence: 86% vs 64%). In cycle 1, more pts had a DSN ≥ 3 days in the same-day (36%) than the next-day group (15%). In cycle 4, mean DSN was longer in the same-day than the next-day group (mean [SD] 1.4 [1.40] vs 0.7 [0.94] days; grade 4 neutropenia incidence: 57% vs 42%). Pts in the 2 groups had similar occurrence of FN (17% vs 15%) and serious adverse events (33% vs 36%) across the study. Full dose on schedule, and the incidence of IV anti-infective use or hospitalization due to FN were also similar between groups. Conclusions: In cycles 1 and 4, the mean DSN was nearly 1 day longer for pts in the same-day group compared with the next-day group. Although the protocol-specified 2-day non-inferiority margin for DSN was met, for pts with NHL receiving R-CHOP, we recommend administering pegfilgrastim 24 hours after CT per labeling guidelines.

[Table: see text]
Brief duration rituximab(R)/chemotherapy (CNOP or CVP) followed by maintenance rituximab in elderly/poor performance status patients (pts) with diffuse large B-cell lymphoma (DLBCL): A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Raefsky E. L. , Greco F. A. , Spigel D. R. , Doss H. H. , Farley C. , Saez R. , Kommor M. , Hainsworth J. D.
Published: March 2020

7577

Background: R-CHOP is the standard first-line treatment for pts with DLBCL; however, some pts are poor candidates due to general debility, cardiac disease, or other medical problems. Maintenance R is not effective after full course R-CHOP chemotherapy for DLBCL (ECOG 4494), but improves outcome following CHOP alone. In this phase II trial, we evaluated short course R/chemotherapy, followed by maintenance R, in pts who were not candidates for full-course R-CHOP. Methods: Eligibility: previously untreated DLBCL; stage II-IV; ECOG PS 0–2; age ≥ 70 years or poor CHOP candidate; adequate kidney, liver, bone marrow function; no HIV infection; informed consent. Pts received 3 courses of R-CNOP (cyclophosphamide 500mg/m2, mitoxantrone 10mg/m2, vincristine 1.0mg/m2, prednisone 80mg PO days 1–5, rituximab 375mg/m2) followed by pegfilgrastim 6mg sq day 2, at 21-day intervals. Mitoxantrone was omitted for pts with EF < 40%. Pts with response/stable disease after chemotherapy began maintenance R (375mg/m2 weekly × 4 doses, administered at 6-month intervals × 4 courses). Results: 31 pts entered this trial between 5/03 and 11/05. Clinical characteristics: median age, 78 years; ECOG PS 2, 45%; IPI 3–5, 79%. 27 pts (87%) have completed short course R-chemotherapy; 20 pts (65%) are currently receiving maintenance R. After completion of R-chemotherapy, 17 pts (63%) had responses (9 CR/CRu, 8 PR); 10 pts had stable disease/minor response. After median 16 month follow-up, 29 of 31 pts (94%) are progression-free; actuarial 2-year PFS is 90%. The 2-year overall survival is 74%. 4 pts have died (progressive lymphoma 2, intercurrent illnesses 2). Grade 3/4 toxicities: neutropenia 38%, other toxicities < 10%, no treatment-related deaths. Conclusions: Short-course R-chemotherapy followed by maintenance R was active and well tolerated in a group of elderly, poor prognosis pts with DLBCL. In spite of modest CR/CRu rate; the 90% 2-year PFS suggests a role for maintenance R. If these findings persist with further followup, this approach is worthy of further study in this patient group.

[Table: see text]
Changing prevalence of indolent lymphoid malignancies among the elderly
Authors: Swenson W. T.
Published: March 2020

7579

Background: Reported changes in incidence rates and improved survival rates among patients with common indolent B-cell lymphoid malignancies have potential implications for increased disease burden among the elderly. This study examines incidence, survival, and prevalence rates of elderly patients with follicular lymphoma (FL) and CLL/SLL using a large population based database. The indolent and incurable nature of these diseases makes the prevalence rate a good indicator of total disease burden. Methods: The SEER 9 public use database was analyzed using SEER*Stat software version 6.1.4. Subjects were identified by ICD-O-3 diagnostic codes. Incidence rates and trends (from 1973 to 2002) were calculated (per 100,000 population) and were age-adjusted to the 2000 US standard population. Survival rates were calculated for patients diagnosed during the periods 1980–1985 and 1990–1995. Prevalence rates include patients diagnosed within 15 years prior to the prevalence date (15-year limited prevalence). Results: Annual percent change of incidence rate (per 100,000) among patients ≥65 years (from 1973 to 2002) was 2.76 (95% CI: 1.92, 3.60) for FL and -0.18 (95% CI: -0.47, 0.11) for CLL/SLL. Survival rates for patients ≥65 years was improved for both FL and CLL/SLL. Among patients with FL diagnosed between 1975–1980 and 1990–1995, 5-year survival rates were 42.2% (95% CI: 38.8, 45.6) and 50.3% (95% CI: 47.9, 52.7). Among patients with CLL diagnosed between 1975–1980 and 1990–1995, 5-year survival rates were 40.6% (95% CI: 38.8, 42.4) and 50.4% (95% CI: 48.9, 51.9). Prevalence percent increased for FL patients among ages 65–74 years, 75–84 years, and ≥85 years. Prevalence percents were unchanged among CLL/SLL patients. Conclusions: Increased FL incidence and increased survival rates have resulted in a growing disease burden among the elderly over the last decade; the prevalence of CLL/SLL has remained static.

[Table: see text]

No significant financial relationships to disclose.
High-dose chemotherapy and autologous peripheral blood stem cell rescue (Auto-SCT) in multiple myeloma (MM) patients: Busulfan + melphalan-140 (BuMel) versus (vs) melphalan-200 (Mel-200) as conditioning regimens
Authors: Carrion Galindo R. , Serrano D. , Perez-Corral A. , Balsalobre P. , Buno I. , Anguita J. , Gomez-Pineda A. , Mayayo M. , Diez-Martin J.
Published: March 2020

7612

Background: Auto-SCT is the preferred treatment modality for MM. From the results of IFM 9502 (Moreau et al. Blood, 2002) melphalan 200 mg/m2 was considered the new standard as conditioning regimen due to its lower toxicity. However, many chemotherapy regimens have been tested. We present our results with two cohorts of consecutive patients (pts) diagnosed of MM and treated with Auto-SCT between 1996 and 2005 in our BMT Unit. Methods: Following induction chemotherapy (median of 6 courses) 20 pts were conditioning with busulfan 16 mg/kg + melphalan 140 mg/m2 (BuMel) and 23 (since September-2002) with melphalan 200 mg/m2 (Mel-200). Clinical features: median age (BuMel vs Mel-200) 55 vs 58 (p=0.5); female sex 10 vs 10; Bence-Jones MM 5 vs 5; renal failure (B) 2/20 (10%) vs 7/23 (30%)(p=0.48); previous treatment with local irradiation 6/20 vs 3/23; status previous Auto-SCT (complete remission, CR) 7/20 (35%) vs 6/23 (26%), p=0.5. A median of 4.8 vs 4.4 x 10e6/kg CD34+ cells were infused, respectively (p=0.15). Results: Four toxic deaths: 2 pts by hemorrhagic cystitis-enterocolitis (at day +84 and +96), 1 pt with disseminated candidiasis (day +7), and 1 pt by pulmonary fibrosis (day +452). At 3 months following Auto-SCT, 13/19 (68%) treated with BuMel and 12/23 (52%) of those treated with Mel-200 achieved CR (p=0.28). At 24 months, probability of remaining disease free was 87% for BuMel group and 55% for Mel-200 (p=0.08). Conclusions: 1) Conditioning regimen BuMel was associated with a higher toxicity than Mel-200, as well as a higher mortality treatment related. 2) However, a trend for higher CR rates and probability of disease free progression were shown in BuMel group without statistical significance

[Table: see text]

No significant financial relationships to disclose.
Solid organ second malignant neoplasms among children diagnosed with malignant bone tumors treated on Children Cancer Study Group/Pediatric Oncology Group protocols after 1980
Authors: Goldsby R. , Burke C. , Nagarajan R. , Zhou T. , Chen Z. , Inskip P. , Marina N. , Friedman D. , Neglia J. , Bhatia S.
Published: March 2020

9007

Background: The growing number of individuals surviving childhood cancer has increased the awareness and recognition of long-term sequelae. One of the most worrisome complications following cancer therapy is the development of second malignant neoplasms (SMN), in particular, late-occurring solid second malignancies related radiation therapy. Methods: We describe the incidence of solid organ SMN in survivors of pediatric malignant bone tumors (MBT) treated on legacy CCG/POG protocols from 1980 to 2005. This retrospective cohort study included 2,842 patients, 1,686 treated for osteosarcoma (OS) and 1,156 treated for Ewings Sarcoma (ES). The cohort included 56% males and 44% females, with a median age at primary diagnosis of 13 years. The median length of follow-up was 4.3 years (range: 0 to 20.9 years). Results: At the time of the analysis, 64% of patients in this study are alive. Seventeen patients with solid organ SMN were identified, and included three patients with breast cancer, three with malignant fibrous histiocytoma, two with osteosarcoma, and 9 patients with other solid organ malignancies. The standardized incidence ratio (SIR=observed/expected cases) was 2.9 (95% confidence interval [CI], 1.4–5.4) for patients treated for OS and 5.0 (95%CI 2.6–9.4) for patients treated for ES. The median time from diagnosis to develop solid organ SMN was 7 years (range: 1 to 13 years). The 10-year cumulative incidence of solid organ SMN for the entire cohort was 1% (95%CI 0.6–2%). In univariate analysis, treatment with etoposide, cyclophosphamide or radiotherapy were each associated with a higher than expected incidence of cancer with SIR of 4.8 (95% CI, 2.5–9.5), 5.8 (95% CI, 3.5–9.5) and 4.1 (95% CI, 2.4–7.1), respectively. Conclusions: Solid organ SMNs are rare after treatment for OS and ES, although higher in patients treated for ES. Recurrence remains the most significant problem for patients diagnosed with MBT and development of improved therapies with fewer long-term consequences remains paramount. However, solid organ cancers are likely to increase with longer follow-up. Therefore, surveillance should focus on monitoring for both recurrence of primary malignancies and development of SMN.

No significant financial relationships to disclose.
Pharmacokinetics and pharmacodynamics of asparaginases in antibody-negative pediatric patients with higher risk acute lymphoblastic leukemia (ALL): A report from CCG-1961
Authors: Arce F. J. , Seibel N. , Gaynon P. S. , Tiwari P. N. , Avramis I. A. , Ettinger L. J. , Sather H. N. , Franklin J. , Fu C. , Siegel S. E. , Avramis V. I.
Published: March 2020

9027

Background: Asparaginase (ASNase) induces apoptosis in ALL lymphoblasts by depleting cells of extracellular asparagine (ASN) and possibly glutamine (GLN). On CCG-1961 [Seibel NL et al. Blood 2003; 102(11): 224a (abstract #787)], all patients (pts) received 9 doses of native E.coli-ASNase in induction (IND). Pts with rapid early response (marrow blasts < 25% on Day 7, RER) were randomized to standard intensity therapy and received native ASNase thereafter or to stronger intensity therapy and received PEG-ASNase post induction. All pts with slow early response (marrow blasts ≥ 25% on Day 7, SER) received PEG-ASNase after induction. Pts with clinical allergy to E.coli-ASNase were switched to Erwinase. Methods: Anti-ASNase Antibody (Ab) titers were assayed at the end of IND, prior to Delayed Intensification #1 and prior to starting Maintenance. Amino acid levels were measured in 430 sera from 187 patients with measurable ASNase activity. Results: Population pharmacokinetics (PK) and pharmacodynamics (PD) of the ASNase formulations demonstrated half-lives of native ASNase (6000 IU/m2): 30 hours, PEG-ASNase (2500 IU/m2): 156 hours, and Erwinase (6000 IU/m2): 18 hours. Subsequent exposures to either formulation resulted in increased activity with moderate prolongation of the elimination half-lives. One-hundred forty-two sera from 70 patients with ASNase activity between 0.03 and 1.11 IU/ml, had a mean ± SDEV ASNase activity, ASN levels, and GLN levels of 0.21 ± 0.23 IU/ml, 14.6 ± 17.7 μM, and 300.4 ± 233.8 μM, respectively; with median values of 0.11 IU/ml (range: 0.03–1.114 IU/ml), 4.7 μM (range: 0.38 - 81.34 μΜ), and 270.2 μM (range: 5.3 - 1189.1 μM), respectively. TTEST analyses linked higher ASNase activity with lower ASN levels and greater % ASN deamination. Higher ASNase activity did not assure greater GLN depletion. Conclusions: A sigmoid relationship between ASNase levels and % ASN deamination showed that activity of 0.41 ± 0.24 IU/ml (mean ± SDEV) provided 93% ± 13% ASN deamination. Therefore, >90% ASN deamination required ASNase >0.4 IU/ml. Kaplan-Meier analyses are pending.

[Table: see text]
Treatment of EBV-associated T cell post-transplant lymphoproliferative disorder with CNS involvement in a pediatric solid-organ transplant patient
Authors: Harker-Murray P. D. , Dayton V. , Neglia J. , Tolar J.
Published: March 2020

9040

Background: Post-transplant lymphoproliferative disorder (PTLD) is a known complication of immunosuppression following solid organ and stem cell transplantation. It ranges from benign lymphoid hyperplasia to fulminant systemic disease with high mortality. Most cases are B lineage and associated with Epstein-Barr virus (EBV+). T cell PTLD is rare and usually EBV negative. To date only 5 cases of EBV+ T cell PTLD have been reported in pediatric patients and none have had documented involvement of the central nervous system (CNS). Methods: We provide clinical, histologic, immunophenotypic and molecular details of a case of fulminant EBV+ T cell PTLD with CNS involvement and compare our data to the clinical presentations, biology and outcomes of the other reported cases of pediatric T cell PTLD (these include 5 EBV+ CNS− cases, 3 EBV− CNS+ cases, and 4 EBV− CNS− cases with dissemination or marrow involvement). Results: A 4.5 year old male developed EBV+ T cell PTLD with CNS involvement 3 years following a cadaveric renal transplantation. His fulminant presentation included fever, hypotension, splenomegaly, pancytopenia, coagulopathy, and bilateral pleural effusions. He had lymphocytosis in his CSF and his MRI showed brain white matter changes consistent with leukoencephalopathy. T lineage was confirmed by the presence of T cell markers CD3, 5, 7, 45 and TCRγ. The presence of EBV was demonstrated by in situ hybridization for EBER. His treatment followed the Children’s Oncology Group protocol A5971 for disseminated lymphoblastic lymphoma that employs a standard NHL/BFM-95 regimen with cyclophosphamide and anthracycline intensification during the induction and delayed intensification phases with a treatment duration of 2 years. He has received no irradiation. After 16 months, he has no measurable disease. Conclusions: EBV+ T cell PTLD is extremely rare in pediatrics and has resulted in mortality in 12 of 17 reported cases. This is the first report of EBV+ T cell PTLD with CNS involvement in a pediatric patient. Although no standardized treatment exists, the fulminant presentation, T lineage disease, and CNS involvement warranted aggressive systemic and intrathecal chemotherapy.

No significant financial relationships to disclose.
Comparison of doxorubicin cardiotoxicity in pediatric patients when given with dexrazoxane versus a continuous infusion
Authors: Herzog C. E. , Huh W. , Jaffe N. , Durand J.
Published: March 2020

9044

Background: Despite the effectiveness of doxorubicin (D) in sarcomas, its use is limited by cardiotoxicity. Both delivery by continuous infusion (CI) and use of the cardioprotectant dexrazoxane (Z) have been used to reduce cardiotoxicity. Since 1998 patients with Ewing’s sarcoma seen at MDACC have been treated with a total of 540 mg/m2 D given with Z (ZD). During this period patients with osteosarcoma have been treated with 360–540 mg/m2 D given as a 48-hour infusion (CID). Methods: To compare the cardiotoxicity of ZD versus CID, we did a retrospective review of patients seen on the pediatric service at MDACC since 1998. Patients included needed to have had 1) planned therapy of at least 360 mg/m2 D, given either as ZD or CID; 2) measurement of ejection fraction (EF) prior to any D; and 3) routine monitoring of cardiotoxicity with EF. Patients were recorded as having cardiotoxicity for any EF<50% or clinical symptoms. Groups were compared by 2-sided t-test and Fisher’s Exact test. Results: A total of 64 patients were treated with ZD or DCI, 52 of which are evaluable. Comparison of ZD to CID showed no significant difference in age or male:female ratio. Total D dose was higher in ZD. Cardiotoxicity was higher in DCI as determined by number of patients with cardiotoxicity and EF on worst Echo. Conclusions: Despite the higher total dose of D, patients treated with ZD had less cardiotoxicity. Whether this is due to giving a cardioprotectant or other factors, such as, higher degree of electrolyte abnormalities or greater degree of anemia in patients treated with CID needs to be investigated.

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No significant financial relationships to disclose.
Outcomes of a two-drug chemotherapy regimen for retinoblastoma
Authors: Zage P. E. , Weinstein J. , Mets M. B. , Lasky J. B. , Goldman S.
Published: March 2020

9064

Background: Retinoblastoma is the most common intraocular tumor of childhood in the U.S. and has an overall survival rate of over 90%. The optimal treatment regimen for intraocular retinoblastoma has not yet been established. Current treatment regimens for retinoblastoma involve combinations of chemotherapy with focal therapy. We report here the results of an institutional retinoblastoma treatment trial to determine the vision- and globe-salvage rates and associated toxicity of a regimen combining carboplatin and etoposide with focal therapy. Methods: 29 patients diagnosed with either bilateral retinoblastoma or unilateral retinoblastoma in infants under 12 months of age were treated prospectively with carboplatin and etoposide plus focal therapy between 1992 and 2004 at Children’s Memorial Hospital in Chicago. External beam radiation therapy (EBRT) and enucleation were utilized as needed. Results: The regression rate after 6 cycles of chemotherapy was 85.4%. 7 eyes received EBRT and 22 eyes were enucleated. The overall vision salvage rate without EBRT was 50%, with a vision salvage rate of eyes with Reese-Ellsworth (R-E) groups I-IV tumors of 82.6%. The vision salvage rate of eyes with R-E group V tumors was 20%. The vision salvage rate for eyes with Murphree groups A and B was 77.3%, but only 26.9% for groups C and D. The 10-year estimated EBRT/enucleation-free survival rate was 47%. There were no treatment related mortalities and minimal long-term side effects, with one case of secondary malignancy. Conclusions: The combination of carboplatin and etoposide with focal therapy is a well-tolerated regimen that avoids EBRT and has acceptable vision salvage rates for R-E groups I-IV and Murphree groups A and B retinoblastoma. Patients with R-E group V and Murphree groups C and D retinoblastoma do less well with chemotherapy and require more intensive or novel approaches to therapy.

No significant financial relationships to disclose.
Do patients with initially resected metastatic GIST benefit from ‘adjuvant‘ imatinib (IM) treatment? Results of the prospective BFR14 French Sarcoma Group randomized phase III trial
Authors: Bui B. N. , Le Cesne A. , Ray-Coquard I. , Duffaud F. , Rios M. , Adenis A. , Bonpas E. , Perol D. , Berthaud P. , Blay J.
Published: March 2020

9501

Background: Metastatic GIST patients (pts) without residual disease after surgical resection are considered as at very high risk of relapse (VHR) but the impact of imatinib (IM) treatment while in CR (‘adjuvant‘ IM) is still debated. Preliminary data for such patients included in the modified BFR14 (continuation vs discontinuation of IM after 3 years of treatment) are presented. Methods: Characteristics and outcome of patients with VHR at inclusion and treated with IM were analyzed. Pts initially allocated to the discontinuation of BFR14 after 1 year of IM were excluded from this analysis. Results: Out of 265 pts with advanced disease, 96 metastatic, completely resected, GIST pts (52 males and 44 females) were included in the trial with a median age of 61 years (range 28 to 87). Primary resected sites were gastric and small bowel in 40% and 42% of cases respectively. Site of dissemination in synchronously resected (R0/R1 resections) metastases was liver only (45%), peritoneum only (15%) and liver plus peritoneum (22%). The median duration of ‘adjuvant‘ IM in the whole population of 96 pts was 13 months (range 0 to 34.3). At time of analysis (december 2005), 34 pts have progressed and 13 pts died of their disease. The median PFS was 25 months (CI 95%: 20.3 ; 34.4) and the 2 year-OS was 80.7% (CI 95%: 68.6 ; 92.8). Conclusions: These results confirm the poor prognosis of VHR GIST pts and justify IM treatment of initially resected metastatic GIST like other metastatic diseases. Optimal duration of IM has to be validated in a prospective way and these pts are considered in BFR 14 trial Updated results will be presented at the meeting. This work is supported by research funding from Novartis Pharma.

[Table: see text]
A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS)
Authors: Maki R. G. , Hensley M. L. , Wathen J. K. , Patel S. R. , Priebat D. A. , Okuno S. , Reinke D. , Thall P. F. , Benjamin R. S. , Baker L. H.
Published: March 2020

9514

Background: We sought to compare the response of metastatic STS to G vs. G+D in a phase III study using a novel Bayesian adaptive randomization strategy. Methods: Entry criteria included non-GIST STS diagnosis, age > 10, measurable disease, ≤ 3 prior regimens, normal organ function, and Grade (Gr) ≤ 1 neuropathy. Pts were stratified by histology (leiomyosarcoma [LMS] vs. other), and history of prior pelvic radiation (PPR) or not, yielding 4 diagnostic subgroups. Therapy was G 1200 mg/m2 (over 120 min, d1+d8) or G 900 mg/m2 (over 90 min, d1+d8) and docetaxel (100 mg/m2 d8) q21d; all pts received (peg)-filgrastim starting d9. 25% dose reductions were employed for PPR or toxicity. The primary endpoint was tumor response (CR, PR, or 24+ weeks stable), using a double-blind Bayesian adaptive randomization procedure to incrementally assign more pts to the superior treatment arm, while accounting for possible treatment-subgroup interactions. Although this study is not based on a 1:1 randomized phase III design, enrolling ∼120 pts would show a difference between a response rate (RR) of 10% for G and 30% with G+D with a power of 0.8 and two-sided alpha of 0.05. Results: 122 pts were randomized; 119 pts had evaluable outcomes. Median number of prior regimens was 1; median number of cycles was 4 (range 1–26). 49 pts were adaptively randomized to G and 73 to G+D, indicating superiority of G+D. Of 119 evaluable pts, 27% (G) and 32% (G+D) showed response as defined. The odds of pts with LMS receiving G+D instead of G increased from 1:1 at the start of the study to ∼6:1 at its completion. RR was 10% (G) vs. 16% (G+D) (p=0.15, Fisher exact test). Consistent with the RR outcomes, progression free survival (PFS) was 6.2 m (G+D, K-M 95%CI 3.6–8.8) vs. 2.6 m (G, 95%CI 2.0–3.2). Overall survival (OS) was 18.0 m (G+D, K-M 95%CI 11.7–24.1) vs. 11.2 m (G, 95%CI 6.8–15.5). Pts receiving G+D had a higher rate of discontinuation due to toxicity than those receiving G (p<0.01, log rank). Conclusions: We observed substantial clinical activity in this pre-treated STS population. G+D yields superior PFS and OS to G, but at the price of increased toxicity. Adaptive randomization is an effective method that substantively reduces the number of pts receiving inferior therapy.

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The Type2 EWS-Fli1 protein causes a greater up-regulation of elements of the human stromelysin 3 promoter compared with EWS-Fli1 Type 1 and Fli1
Authors: Ubhi B. S.
Published: March 2020

9538

Background: The role of EWS-Fli1 in the pathogenesis of Ewing’s sarcoma has been extensively investigated. This translocation is found in 85% of Ewing’s tumours. The translocation brings together two genes, EWS and Fli1. EWS is thought to have homology with RNA polymerase whilst Fli1 is a member of the ETS family of transcription factors. The EWS-Fli1 translocation was previously thought to result in an increase in Fli1 activity at target gene promoters including human stromelysin 1. Mutants of the human stromelysin promoter were therefore constructed and cloned into the pGL-3 luciferase reporter vector system and co-transfected with either EWS-Fli1 (type 1 or 2) and/or Fli1 expression vectors. We had previously detemined that EWS-Fli1 appeared to have greater activity at the 5’ end of the stromelysin promoter compared with Fli1.This system was therefore used to investigate the activity of EWS Fli1 type1, Ews-Fli1 type 2 and Fli1 on a 5’ element of the human stromelysin 1 promoter (containing the 5’ 335bp of the promoter). Methods: 1μg of the reporter vector strom-3’Δ5 (containing the 5’ 335bp of the human stromelysin 1 promoter) was co-transfected into NIH3T3 cells with 1μg of the expression vectors ES-TPF10 (EWS-Fli1 Type1),ES-RDP20 (EWS-Fli1 type 2) or Fli1-DH6 (Fli1). The cells were incubated at 37oC in 5% CO2 for 24 hours before being lysed and assayed for luciferase activity. Conclusions: Ews-Fli1 (type 1 and 2) caused a higher level of stimulation of this promoter element compared with Fli1. Interestingly, the type 2 translocation caused a significantly higher level of expression of this promoter element compared with type 1, a finding which may reflect the disease pattern observed clinically.

[Table: see text]

No significant financial relationships to disclose.
The contribution of epigenetic and genetic changes to predict gastrointestinal stromal tumors (GIST) behavior
Authors: Braggio E. , Guimaraes D. P. , Bacchi C. E. , Lopes L. F. , Small I. A. , Valadão M. , Portella M. J. , Romano S. , Zalcberg I. R. , Ferreira C. G.
Published: March 2020

9542

Background: To search for markers for better prognostic evaluation in patients (pts) with GIST was our goal. Loss of E-cadherin expression and/or function by hypermethylation has been correlated with increase in the invasive potential of human tumors. Recently, loss of p16INK4a expression was considered as an independent prognostic factor in pts with GIST. Methods: We investigated the methylation (MT) status for p16Ink4a and E-cadherin by the MT -specific PCR, c-KIT mutation by SSCP-sequencing, p16INK4a and cKIT expressions and KI-67 index by IHC, in 81 pts with completely ressected GIST between Jan 1990 and April 2003. Clinical data and follow-up information were obtained from medical records.A cutoff at 20% and 5% positivity was used for p16INK4a and KI-67, respectively. Univariate analysis of disease-free survival (DFS) and overall survival (OS) were performed by Kaplan Meier method with the log-rank test. Results: Median age was 55 (9–78); Male/female 42/58%; primary tumor sites were stomach (46.9%), small bowell (37.0%), colorectal (8.6%) and peritoneal (6.2%). Median tumor size was 8cm (1.2–35.0). The median follow-up was 24 months. Pts were stratified into low- (24.7%), intermediate- (37.0%) and high- (38.3%) risk pts based on tumor size and mitotic index. There was a significant correlation between risk classification and disease free survival (DFS) (p=0.023) and overall survival (OS) (p=0.010). The p16Ink4a and E-cadherin MT were observed in 19.4% and 63.3% pts, respectively. We observed loss of p16INK4a expression in 64.9% of GISTs. Overall, 78.4% had KIT mutation in exon 11 or 9. There was non-significant correlations between epigenetic alterations, cKIT mutation, p16INK4a expression, KI-67 index and survival. By analysing the three groups separately we found a significant correlation between E-cadherin MT with DFS (p<0.047) only in the intermediate risk group. Conclusion: Our results suggest that E-cadherin MT may be a helpful prognostic factor particularly in the intermediate risk group of GISTs. In contrast with previous results from the literature p16INK4a alterations had no prognostic impact in our samples.

No significant financial relationships to disclose.