bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective comparison of open and thoracoscopic lobectomy techniques: Thoracoscopic lobectomy is an equivalent cancer operation for early lung cancer
Authors: Roberts J. R.
Published: March 2020

7225

Background: Minimally invasive pulmonary lobectomy is less painful than classical techniques, and thus potentially safer. Much research has demonstrated that the surgery is at least as safe as standard techniques. However, though the techniques are decades old, they are still not widely practiced. Opponents to these techniques argue that minimally invasive pulmonary surgery has not been demonstrated to be equivalent cancer surgery. Methods: We compared our patients stage by stage undergoing open and minimally invasive resections (case-control). All patients who underwent elective anatomic lobectomy were compared with respect to demographic parameters, hospital stay, and survival, by stage. Means were compared using two-tailed student’s t test, proportions, with chi-square, and survival by nonparametric statistics. p values less than 0.05 were accepted as significant. Results: Four hundred fifty-three patients (453)underwent lobectomy over a seven year period (317 were open (OL), and 146 were thoracoscopic (TL)). No differences were seen between the ages, functional vital capacity (FVC%) and residual volume (RV%). However, TL patients had poorer FEV1% (open-69%, TL-60%, p = 0.0245) and poorer diffusing capacity (open-87%, TL-64%, p = 0.000906). Further, the open lobectomies had longer length of stays (open-9.5 dyas, TL–7.3 days, p = 0.001), longer intensive care unit stays (open-1.6 days, TL-0.129 days, p = 0.00013), and higher perioperative mortality (open open-3%, TL-0%). The survival values for stage I NSCLC patients are shown below. No differences in survival between the two techniques was seen. Conclusions: Thoracoscopic or minimally invasive lobectomy is an established technique that has been refined for more than a decade. Several studies suggest an earlier recovery from thoracoscopic lobectomy. This study demonstrates that the two approaches are equivalent cancer operations.

[Table: see text]

No significant financial relationships to disclose.
Effects of zoledronic acid on survival in patients with lung cancer and high baseline N-telopeptide (NTX) levels: Stratified by baseline bone alkaline phosphatase (BALP)
Authors: Matczak E. , Hirsh V. , Lipton A. , Cook R. J. , Langer C. , Hei Y. J. , Major P.
Published: March 2020

7228

Background: Recently, it was shown that patients (pts) with bone metastases from lung cancer who had high NTX or BALP levels on study had a higher risk for skeletal-related events (SREs) and death compared with pts with low NTX or BALP. Zoledronic acid has been shown to prevent SREs; however, it is unknown whether there is a secondary survival benefit in this pt population. To assess the potential effect of zoledronic acid on survival in pts with bone metastases from lung cancer and high baseline NTX, we conducted a retrospective analysis of pts in a large, randomized, controlled trial. Methods: Patients with lung cancer and bone metastases were randomized to receive either 4 mg zoledronic acid or placebo for a total of 21 months. Survival data were evaluated in pts who had a high baseline NTX level (≥ 64 nmol/mmol) and baseline BALP level (retrospectively stratified by baseline BALP level according to these criteria: normal BALP < 146 U/L and high BALP ≥ 146 U/L). The relative risk (RR) of death was calculated for each pt group and for pts with high NTX levels overall compared with placebo. Results: The pts with high NTX levels (n = 144; men, 65% women, 35%) had a median age of 64 years. Among these pts, the RR of death was significantly reduced by 35% in pts who received zoledronic acid compared with placebo (RR = 0.650; P = .0244). The RR of death on study for pts who had both high baseline NTX and BALP levels (n = 97) was also significantly reduced by 46% in pts who received zoledronic acid compared with placebo (RR = 0.537; P = .0059). Among pts who had high baseline NTX and normal BALP levels (n = 47), the RR of death was similar between treatment groups (RR = 1.012; P = .9736). Conclusions: High levels of bone resorption may correlate with an increased risk of SREs and death. Zoledronic acid reduces bone turnover and the risk of SREs and may delay the progression of bone lesions. This retrospective analysis suggests that treatment with zoledronic acid may improve survival compared with placebo in pts with lung cancer who have high levels of bone metabolism, warranting further study in either other database analyses or prospective trials.

[Table: see text]
Photodynamic therapy using Laserphyrin for centrally located early stage lung cancer
Authors: Usuda J. , Kato H. , Okunaka T. , Furukawa K. , Honda H. , Suga Y. , Hirata T. , Ohira T. , Tsuboi M. , Hirano T.
Published: March 2020

7229

Background: In central type early stage lung cancer, the tumor must be located only as far as the segmental bronchi and be carcinoma in situ or with only limited invasion into the bronchial wall. Laserphyrin (mono-L-aspartyl chlorine e6, NPe6) is a second generation photosensitize and approved by the Japanese government and has been on sale from June 2004. Methods: Four h after the administration of Laserphyrin 40 mg/m2, we irradiated using diode laser (100 mJ/cm2). Before PDT, we evaluated the tumor lesions and tumor depth using autofluorescence bronchoscopy and endobronchial ultrasonography (EBUS), and we confirmed the area of laser irradiation. Results: From February 1980 to December 2005, a total number of 204 patients with 264 lesions of centrally located early stage lung cancer underwent photodynamic therapy (PDT) in the Department of Thoracic Surgery, Tokyo Medical University Hospital. There were 185 clinical stage 0 lesions and 79 stage I lesions. CRs and PRs were obtained in 224 lesions (84.8%) and 40 lesions (15.2%) out of 264 lesions. From July 2004 to December 2005, we performed Laserphyrin-PDT for 28 lesions of centrally located early stage lung cancer in Tokyo Medical University Hospital. The rate of CR was 92.9% (26 lesions) in 28 lesions. For Laserphyrin-PDT, Skin photosensitivity was very low and the clean-up bronchoscopies were not frequently needed, and the period of hospitalization was shorter compared to that for Photofrin-PDT. Conclusions: We conclude that PDT using Laserphyrin will be a standard option for stage 0 (TisN0M0) and stage I (T1N0M0) centrally located early stage lung cancer.

No significant financial relationships to disclose.
LBH589, a novel histone deacetylase inhibitor (HDACi), treatment of patients with cutaneous T-cell lymphoma (CTCL). Changes in skin gene expression profiles related to clinical response following therapy
Authors: Prince H. M. , George D. J. , Johnstone R. , Williams-Truax R. , Atadja P. , Zhao C. , Dugan M. , Culver K.
Published: March 2020

7501

Background: LBH589 is a novel histone deacetylase inhibitor in Phase I trials. Since other HDACi have induced disease regression in CTCL, we evaluated the activity of LBH589 and resulting changes in gene expression of LBH589 in CTCL patients (pts). Methods: Pts with advanced-stage CTCL, who had progressed following prior systemic therapy were entered into the DLT dose level 30mg M,W,F cohort (n = 1) or the subsequent MTD dose level 20mg M,W, F weekly (n = 10). LBH589 was continued until disease progression or unacceptable toxicity. The first three pts had 3mm punch biopsies from CTCL-involved skin lesions at 0, 4, 8 and 24h after administration, which were subjected to gene expression profiling using Affymetrix U133 plus 2.0 GeneChips with 47,000 probesets. Results: Eleven pts with CTCL have been entered to date. Two of the pts attained a complete response (CR), 3 attained a partial response (PR), 2 achieved stable disease (SD) with ongoing improvement, and 4 progressed on treatment (PD). Of particular interest, 2 pts who were initially SD required discontinuation because of toxicities (Grade III diarrhea at week 4, Grade II fatigue at week 12). Both had ongoing improvement in their disease achieving a CR and PR, respectively 3 months later. Of the 5 responding pts, one with a CR (discontinued after 10 doses due to Grade III diarrhea) progressed at 8m. Microarray data on the first 3 pts (2CR and 1PD) demonstrated distinct gene expression response profiles between the 3 pts. Surprisingly, the pt with PD showed the greatest transcriptional response with more than 16,000 genes activated or repressed over the 24 hr time course. Of these responsive genes, close to 60% were activated while 40% were repressed. In contrast, less than 1000 genes showed a 2-fold change in expression in the 2 pts with a CR with greater than 85% of the genes being repressed. Conclusions: LBH589 induce CR’s in CTCL pts. Regression of disease can occur some weeks after discontinuation of therapy. Preliminary microarray analysis of tumor samples indicated that LBH589 mediates changes in gene expression in vivo with an unexpected observed inverse relationship between the number of genes altered and clinical outcome.

[Table: see text]
Rituximab-supplemented high-dose sequential chemotherapy (R-HDS) has better EFS and PFS than R-CHOP in poor risk follicular lymphoma (FL) at diagnosis: A multicenter randomized GITMO/IIL trial
Authors: Ladetto M. , Benedetti F. , Vitolo U. , Patti C. , Rambaldi A. , Liberati A. , Musso M. , Pulsoni A. , Gianni A. M. , Tarella C.
Published: March 2020

7525

Background: HDS with ASCT is effective and feasible in FL at the multicenter level and suitable for Rituximab supplementation (R-HDS). This randomized trial compared R-HDS with Rituximab-supplemented CHOP (R-CHOP) in poor risk FL patients (pts) <60 yrs. Methods: Between 2000 and 2005, 136 pts have been randomized (68/arm). Eligibility required age-adjusted IPI ≥2 (125 pts) or, in the absence of this criterion, ≥3 IIL adverse factors (11 pts). Primary endpoint was EFS. Clinical features were: median age 50 yrs (22–60), stage III-IV 98%, elevated LDH 78%, bulky disease 66%, B symptoms 47%, extranodal disease (other than BM) 45%, ECOG PS >1 47%. R-HDS consisted of: i. 2 APO and 2 DHAP; ii. sequential administration of Etoposide 2g/sqm, 2 Rituximab, Cyclophosphamide 7 g/sqm with PBPC collection (in vivo-purged with 2 additional Rituximab); iii. Mitoxantrone (60 mg/sqm) + L-Pam (180 mg/sqm) followed by 5–8 × 106 CD34+ cells/kg. R-CHOP consisted of 6 CHOP courses followed by 4–6 doses of Rituximab. Cross-over was allowed. bcl-2/I gH-based minimal residual disease analysis was planned. Assessement was “intention to treat”-based. Results: Current data are updated at 31/5/05. Next closing date will be April 2006. The two arms were balanced. 68% patients concluded R-CHOP (failures were due to progression 29% and toxicity 3%) and 78% R-HDS (failures due to progression 9%, toxicity 5%, poor mobilization/refusal 8%). Toxic deaths were 4 (2 in each arm); in addition 1 gastric cancer and 1 AML occurred in the R-HDS arm. Progressions and non-responses were 31% with R-CHOP and 11% with R-HDS (p < 0.05) CRs were 58% and 87% respectively. Current median follow-up is 24 months. EFS and PFS at 24 months are 41% and 48% for R-CHOP and 66% and 75% for R-HDS (p < .001). At present OS is similar. Salvage treatment following R-CHOP is currently known in 22 pts: 16 received R-HDS, with 10 achieving CR. Molecular remission, (two PCR-neg BM samples at 6 months intervals), was observed in 54% of R-CHOP and 77% of R-HDS pts Conclusions: R-HDS induces more CRs and has better EFS and PFS than R-CHOP in this rare and aggressive population of high-risk FL patients. These results cannot be extrapolated to standard-risk pts.

[Table: see text]
Initial therapeutic strategy in follicular lymphoma (FL): An analysis from the National LymphoCare Study (NLCS)
Authors: Friedberg J. W. , Huang J. , Dillon H. , Farber C. , Feliciano S. , Hainsworth J. , Link B. , Steis R. , Vose J. , Zelenetz A.
Published: March 2020

7527

Background: Initial treatment strategies in FL include observation (obs), rituximab (R), chemotherapy ± R, and XRT. A recent study suggests initial therapy may impact FL survival (JCO 23:8447). NLCS is the first prospective observational study in the US designed to assess FL presentation, prognosis, treatment, and clinical outcomes. We describe initial therapeutic strategy in NLCS FL pts. Methods: FL pts diagnosed within 6 months with no prior lymphomas were recruited in this ongoing study. Data collected includes histology, stage, therapy, response, relapse and death. There is no specified treatment regimen. Results: From 3/04 to 11/05 1493 pts enrolled at 237 sites in the United States. Demographics have been initially reported at ASH 2005 (Blood 106:293a) and are comparable to SEER. Initial therapeutic strategy was: obs, 19%; R-monotherapy, 13%; chemo+R, 51%; XRT, 5%; chemo only, 4%. Chemo+R regimens were: R-CHOP, 59%; R-CVP, 19%; R-fludarabine based,11%; other, 11%. Choice to initiate therapy was associated with FLIPI, stage, and grade (p < 0.0001). Significant regional differences (p < 0.0001) were noted: obs was used in 13% of pts in Southeast and 31% in Northeast (NE); fludarabine-based R-chemo was used in 18% of pts in Southwest and only 3% in NE. Academic sites were more likely than community sites to treat pts on clinical trials (12% vs 4%). In pts treated with R or chemo+R, a higher FLIPI was not associated with decision to utilize chemotherapy. 26% of initially observed pts have switched to active therapy after a median of 2.8 months on obs since diagnosis; this was associated with baseline grade (III>II>I), but not stage or FLIPI. Conclusions: Diverse regimens are used for initial management of FL in the United States. Few pts are treated on clinical trials. Significant differences among regions and between center types suggest physician preference may drive initial therapy. Studies such as NLCS are needed to better understand the impact of initial therapy on short- and long-term outcomes.

[Table: see text]
Serum levels and pharmacokinetic of rituximab in Bi-weekly R-CHOP in elderly patients with DLBCL treated in the RICOVER-60 trial:
Authors: Reiser M. , Wenger M. , Nickenig C. , Peter N. , Metzner B. , Pfreundschuh M.
Published: March 2020

7537

Background: The combination of Rituximab (R) and CHOP is considered the standard of treatment for DLBCL in elderly patients (pts) but there is hardly any data on the pharmacokinetic of Rituximab in aggressive lymphoma pts. The RICOVER-60 trial using Rituximab + bi-weekly CHOP-14 resulted in improved TTF in 828 elderly DLBCL pts (Blood 106:9a, 2005). Objective: To study serum levels and pharmacokinetic properties of Rituximab when combined with CHOP-14 in elderly DLBCL pts. Methods: Blood samples of 20 pts were taken before and after Rituximab infusion at each chemotherapy cycle. Additional samples were taken after the end of treatment and at the following time points: after 1 week, 1 month, 2 months, 3 months, 6 months and 9 months, respectively. Peak serum samples were taken within a maximum of 30 min, all samples were centrifuged at 1000 g for 10 min (room temperature) and stored at −20 degrees C. Batch samples were shipped to Xendo Laboratories, Groningen, The Netherlands, and analysed. Results: Samples from 20 pts were evaluable for this analysis with 16/20 pts having completed all 8 cycles of treatment, yet. The median (range) of serum Rituximab levels (μg/ml) before each cycle were: #1 0 (0–0); #2 39 (13–62); #3 74 (47–109); #4 95 (40–136); #5 111 (55–157); #6 114 (12–518); #7 125 (72–207);#8 116 (75–304). After therapy median (range) of serum Rituximab levels were: 163 (67–248) at 1 week; 101 (44–163) at 1 month; 55 (1–123) at 2 months; 34 (1–577) at 3 months; 5 (0–103) at 6 months; 1 (0–128) at 9 months. At 9 months samples from 7 pts were evaluable with detectable serum Rituximab levels in 4/7 pts. Conclusion: In the dose dense regimen R+CHOP-14 Rituximab levels increased after each subsequent cycle for the first 4 cycles. During cycle 5- 8 the serum Rituximab levels reached a plateau and decreased constantly after the end of treatment with detectable levels even after 9 months. Based on this data the German High Grade NHL Study Group (DSHNHL) further investigates a densification of Rituximab in the first cycles in order to improve treatment outcome. A final analysis of all 20 pts and a pharmacokinetic model of Rituximab distribution and elimination phase will be presented at the meeting.

[Table: see text]
Clarithromycin, lenalidomide and dexamethasone combination therapy as primary treatment of multiple myeloma
Authors: Niesvizky R. , Jayabalan D. S. , Furst J. R. , Cho H. J. , Pearse R. N. , Zafar F. , Lent R. W. , Tepler J. , Schuster M. W. , Leonard J. P. , Coleman M.
Published: March 2020

7545

Background: Lenalidomide (Revlamid [R]) is the leading clinical compound in a new group of drugs called IMiDs. Our group demonstrated that clarithromycin (Biaxin [Bi]) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or dexamethasone (D). We report the results of the combination of Bi plus R plus D (BiRD) in newly diagnosed MM. Methods: A phase II trial designed to accrue 50 pts. A 2-stage design rejects a CR rate of < 10% (alt >30%). Between Nov. 2004 and Jan. 2006, 46 pts have been accrued of which 40 pts are eligible for evaluation. R is given po at 25 mg daily on days 1–21 of a 28-day cycle. D is given po at 40 mg once weekly. Bi is given po at 500 mg bid. Pts receive low dose aspirin (ASA)(81mg) qd as thrombosis (TE) prophylaxis. Responses are defined according to modified EBMTR criteria. Analysis is by intent-to-treat. Patient Selection: Median age: 62.5 years (36–80), Male/Female 25/15, Hgb: 10.6 g/dL (7.2–15.1), Plt 234 k/uL (51–526), β2m: 3 mg/L (0.8–12.8), CRP: 0.6 mg/dL (0.12–14.2), creat: 1.1 mg/dL (0.6–3.1), albumin 3.5 g/dL (2.3–4.9). SD stage IIIa: 48%, stage IIIb: 10% and IIa: 42%. ISS stage I: 50%, stage II: 25% and stage III: 25%. Cytogenetics and FISH: trisomy 11 (10 pts), tetrasomy 11 (3 pts), del13q14 (14 pts), t (4,14) (1pt), t (11,14) (3 pts). Results: Of the 40 evaluable pts, 38 (95%) have achieved an objective response (>PR) within 3–4 months of Rx with the remaining pts continuing to respond. Seventeen pts (43%) had a >90% reduction of the initial paraprotein. Nearly one third of pts have achieved either a CR (10/40) or a nCR (2/40-continuing on Rx). CR has been confirmed in all pts by normalization of free light chain levels and ratio. The remaining 26 pts (65%) achieved a PR. Of those pts who achieved a PR, 5/26 pts (19%) had >90% reduction in the initial paraprotein. Nineteen pts have experienced grade ≥3 adverse events. Heme toxicities: anemia (11%), neutropenia (9%) and thrombocytopenia (9%). Non-heme toxicities (NHT) include TE in 7 patients (15%) 2 of them fatal. Four of the TE events were while off ASA. Other NHT include myopathy (6%), GI (4%), and mood (4%). Conclusions: BiRD therapy is a safe and highly effective primary therapy for symptomatic, treatment-naïve MM.

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Salvage chemotherapy with rituximab DHAP (RDHAP) for relapsed non-hodgkin lymphoma (NHL): A phase II trial in the North Central Cancer Treatment Group
Authors: Witzig T. E. , Geyer S. M. , Kurtin P. J. , Colgan J. P. , Inwards D. J. , Micallef I. N. , Michalak J. C. , Salim M. , Nikcevich D. A. , Dakhil S. R. , Fitch T. R.
Published: March 2020

7574

Background: Patients (pts) with relapsed aggressive NHL are usually treated with intensive platinum-based chemotherapy regimens prior to stem cell transplant (SCT). This study was designed to learn the toxicity and efficacy of adding 4 doses of rituximab to the standard DHAP salvage chemotherapy regimen. Methods: Eligible pts had biopsy-proven relapsed CD20+ NHL and were eligible for platinum-based chemotherapy. Pts were treated with rituximab 375 mg/m2 d1,8,15, and 22 as well as cis-platinum 100 mg/m2 d3, cytosine arabinoside 2 g/m2 IV q 12 hours x two doses d4, dexamethasone 40 mg PO/IV d3–6, and G-CSF d5–14. Pts were restaged after 1 and 2 cycles; responding pts could proceed to SCT or further cycles of DHAP at MD discretion. There was no provision for rituximab maintenance. The goal was to achieve an overall response rate (ORR) of ≥ 75%. Results: Fifty-eight pts were enrolled between 10/29/00 and 6/20/03. The median age was 63 years (range, 43–83). One pt was ineligible because the tumor was CD20-. All 57 eligible pts completed one cycle; 48 pts completed 2 cycles. The ORR was 70% (40/57) with 16 (28%) CR/CRu and 24 (42%) PR. For all 57 pts, the median TTP was 13.1 months (mos) (95% CI: 7.3–18.2) and the median OS 30.5 mos (95% CI: 17.8–52.5). Seventeen pts (30%) proceeded to SCT. The median duration of response (DR), time to progression (TTP) and overall survival (OS) for the SCT pts were 41.6, 42.3, and 43.6 mos, respectively. The median DR, TTP, and OS for the 25 pts who responded to RDHAP but did not proceed to SCT were 12.4, 13.1, and 38.8 mos, respectively. The incidence of grade 3 and 4 thrombocytopenia was 53% and 39%, respectively. The incidence of grade 3 and 4 neutropenia was 11% and 68%, respectively. Six pts (11%) had nephrotoxicity–five grade 3 and two grade 4 (one pt had both) and one pt required dialysis. Conclusions: The addition of rituximab to standard DHAP is safe with similar toxicity profile to DHAP alone. Despite a high ORR, the CR rate and the % pts proceeding to SCT in this cooperative group setting remain low. New agents are needed that can be added to these regimens to increase the effectiveness and reduce toxicity to allow more pts to proceed to SCT.

No significant financial relationships to disclose.
A phase I trial of PS-341 and fludarabine for relapsed and refractory indolent non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
Authors: Snell M. , Koc O. N. , Bahlis N. J. , Liu L. , Lazarus H. M. , Gerson S. L. , Laughlin M. J. , Jacobberger J. , Horvath N. , Remick S. , Cooper B. W.
Published: March 2020

7580

Background: The safety and efficacy of PS-341 (bortezomib) as a single agent in relapsed and refractory hematologic malignancies has been well documented. Fludarabine is known to be active in indolent non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). PS-341 may potentiate fludarabine activity by inhibiting DNA repair and inducing apoptosis in Bcl-2 over-expressing cells. The safety of this combination was evaluated in an ongoing phase I study. An additional dose level including rituxumab has been added to potentially improve efficacy without significant additional toxicity. Methods: Dose levels were as outlined in the table below. Each cycle was 21 days. Results: To date, 13 patients have received at least one cycle of treatment and are evaluable for toxicity. Diagnoses of patients included CLL, Waldenstom’s macroglobulinemia and MALT, lymphoplasmacytoid, mantle cell and follicular lymphomas. Patients received a median of 3 prior treatments (range 1–6). DLT’s were not observed in the first 4 dose levels, however the first patient on dose level 5 experienced grade 4 neutropenia. Three patients had doses of PS-341 held due to toxicity (2 due to neuropathy and one leukopenia; doses were held during cycles 3, 4 and 2 respectively) and two required dose reductions for grade 2 neuropathy (on cycles 2 and 3). One CRu has been documented (follicular lymphoma), 1 PR (mantle cell) and 6 patients with SD for 1.5 to 3 months. One patient was taken off the study with disease progression after 1 cycle (CLL) and two discontinued treatment due to prolonged cytopenias (MCL) and patient decision. The most 2 most recent patients are not yet evaluable for response. Conclusions: Combination PS-341 and fludarabine appears to be well-tolerated and active in relapsed and refractory NHL and CLL. Enrollment and follow-up of patients on level 5 (addition of rituxan) continues. Initiation of a phase II study of this regimen is anticipated shortly.

[Table: see text]

No significant financial relationships to disclose.
High expression of nucleoside transporter hENT1 predicts a worse event-free survival in relapsed/refractory Hodgkin lymphoma patients treated with gemcitabine, vinorelbine, and liposomal doxorubicin—A CALGB 59804 correlative study
Authors: Lai R. , Hsi E. D. , Mackey J. , Jung S. , Johnson J. L. , Cook J. R. , Jones D. , Said J. W. , Cheson B. D. , Bartlett N. L.
Published: March 2020

7581

Background: CALGB 59804 was a phase I/II trial of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) for pts with relapsed Hodgkin lymphoma (HL). Overall response rate (RR) was 70% (manuscript in review). Plasma membrane nucleoside transporters such as hENT1 are important in transporting nucleoside analogs into cells to exert their pharmacologic effects. We hypothesized high hENT1 expression would predict better RR and outcome in pts treated with GVD. Methods: 58 of 91 pts enrolled in CALGB 59804 had sufficient tissue for study; 31 relapse biopsies and 27 initial diagnosis biopsies. Expression of hENT1 was evaluated by immunohistochemistry in formalin fixed tissue and scored independently by two hematopathologists (RL and EH) blinded to the clinical outcomes. Positivity for hENT1 was defined as >25% of Reed-Sternberg (RS) cells expressing hENT1. Expression was correlated with clinical factors, including IPS at relapse, as well as the overall (OS) and event-free survival (EFS). Results: Expression of hENT1 in RS cells was heterogeneous among cases. 28/58 cases (48%) were hENT1-positive. hENT1-expression was not associated with age, gender, stage, IPS (≤2 or >2), or maximum toxicity grade (≤2 or >2). Compared to hENT1-negative pts, hENT1-positive pts were less likely to have complete or partial response (19/30, 63% versus 22/28, 76%, P=0.20, chi square). hENT1 expression was not significantly associated with OS (P=0.18). Univariate log-rank analysis showed hENT1 positivity and IPS >2 correlated significantly with a lower EFS (P=0.05, and P=0.03, respectively). Multivariate Cox regression analysis confirmed that IPS >2 and hENT1 positivity were independent predictors of EFS (Hazard ratio 2.16, 95%CI 1.08–4.35, P=0.03; and Hazard ratio 2.10, 95% CI 1.06–4.19, P=0.03, respectively). P-values are two-sided. Conclusions: Contrary to our hypothesis, there is an inverse relationship between EFS and hENT1 expression in relapsed HL pts treated with GVD. High expression of hENT1 did not identify gemcitabine-sensitive disease, but may identify a biologically aggressive and/or treatment refractory subtype of HL.

No significant financial relationships to disclose.
Novel model to evaluate changes in gene expression profile of myeloma cells in vivo following interaction with human BM microenvironment
Authors: Neri E. P. , Tassone P. , Shammas M. , Tai Y. , Blotta S. , Prabhala R. , Catley L. , Tagliaferri P. , Venuta S. , Anderson K. C. , Munshi N. C.
Published: March 2020

7613

Background: Interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a critical role in promoting MM cell growth, survival, migration and development of drug resistance. This interaction within the bone marrow milieu is unique and its understanding is important in evaluating effects of novel agents in vitro and in vivo. We here describe a novel murine model that allows us to study the in vivo expression changes in MM cells within the human BM milieu. Methods: In our model, BM stromal and IL-6-dependent human MM cell line, INA-6, tranduced with green fluorescent protein (INA-6 GFP+) was injected in human fetal bone chip implanted into SCID mice. At different time points the bone chip was retrieved, cells flushed out and GFP+ MM cells were separated by flow cytometry or purified by CD138 MACS microbeads. Similar isolation process was used on INA-6 GFP+ cells cultured in vitro and used as control. Total RNA was isolated from these cells and gene expression profile analyzed using the HG-U133 array chip (Affymetrix). Results: We report that interaction between INA-6 cells and the BM microenvironment in vivo induced significant changes in expression profile; specifically, we observed up-regulation of genes implicated in cell growth; DNA transcription; chromosome structure; cell-cell signaling and adhesion. We also observed down-regulation of genes involved in apoptosis and cell death. To determine which biological pathways are modulated by interaction between MM cells and human stroma, all genes were subjected to Ingenuity Pathway Analysis. Our results indicate that the most relevant pathways modulated by the interaction between MM cells with BMSCs are involved in cell-cycle regulation, apoptosis and integrin signaling, as well as with IL-6, IGF1 and PI3K/AKT, p38-MAPK and ERK/MAPK-mediated pathways. These results are consistent with previously observed in vitro cell signaling studies. Conclusions: Taken together these results highlight the ability of BM microenvironment to modulate the gene expression profile of the MM cells in vivo. This model now provides us with an opportunity to study in vivo effects of novel agents on MM cells expression profile, to pre-clinically characterize their activity.

No significant financial relationships to disclose.
Autologous stem cell transplant for primary CNS lymphoma results in prolonged progression free and overall survival
Authors: Johnston P. B. , O’Neill B. P. , Ansell S. M. , Inwards D. J. , Porrata L. F. , Micallef I. N.
Published: March 2020

7623

Background: Survival for patient with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now report on outcomes of patients who have had at least 1 year follow up post ASCT. Methods: Between June, 2000 and September, 2004, 11 patients underwent ASCT for PCNSL. The medical records of consenting patients were abstracted for the following information. Median age at transplant was 47 years old (range 30–67). Median number of prior treatments 1 (range 1–3). Median time from diagnosis to transplant was 7.5 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0–3). Disease status at transplant: First CR 5 patients, later CR or PR 6 patients. Results: Eleven patients underwent ASCT for PCNSL and have a minimum of 1 year follow-up. All patients received BEAM conditioning. Median follow up was 28.3 months. Four patients have relapsed at a median of 200 days (range 40–523). Of the patients who relapsed, one has died of disease progression and the remaining three are alive after additional therapy. Median overall survival and progression free survival from transplant have not been reached. Two year overall and event free survival are 89% and 61%, respectively. Conclusions: Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2–3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline.

No significant financial relationships to disclose.
Genomewide single nucleotide polymorphism microarray mapping for prediction of outcome of neuroblastoma patients
Authors: Hiyama E. , Yamaoka H. , Kamimatsuse A. , Onitake M. , Sueda T. , Nishiyama M. , Hiyama K.
Published: March 2020

9010

Background: Neuroblastoma is a biologically and genetically heterogeneous tumor and demonstrates favorable or unfavorable outcomes. However, the number of subgroups in neuroblastoma and natural history of each subgroup remain unclear. In Japan, nation-wide neuroblasotma mass-screening (MS) project had been performed on 6-month-old babies for 20 years that might have detected almost all neuroblastomas including regressing/ maturing tumors developed in this period. We surveyed more than 3,600 neuroblasotma cases including approximately 2,000 MS detecting cases. In this study, we examined genetic alterations in the representative cases using genome-wide SNP array and compared with the clinical courses. Methods: Genomic DNA was extracted from 198 neuroblastoma samples. SNP array (Affimetrix GeneChip Human mapping Array100K) was used to determine genome-wide aberrations. Chromosome aberrations were confirmed by BAC array and FISH examination. Expression profiles of these tumors were also examined using whole genome microarray (Codelink and Affimetrix Array U133 plus2). Results: SNP arrays could frequently identify chromosomal aberrations and allelic imbalances including 1p and 11q loss and MYCN amplification in unfavorable tumors. Then, we broadly classified the chromosome aberrations in neuroblastoma into four types: whole gain/loss type, partial gain/loss type, MYCN amplified type, and silent type with no large alterations. Almost all tumors with whole gain/loss type showed favorable prognosis, while MYCN amplified type and partial gain/loss type showed unfavorable outcome. In 32 tumors with silent type, 18 unfavorable tumors had small deletions and/or gains in 1p, 2p, 3p, 11q, and/or 17q but the remaining 16 favorable cases did not. The expression analysis of the unfavorable tumors showed high expression of several genes (DDX1, NAG, NME1, MAC30) in these loci. Conclusions: Genome-wide genetic analysis classified neuroblastoma into four types, which are useful to predict the outcome of patients. In the silent type, unfavorable tumors revealed several genes to predict the outcome of the patients. These data provided important candidates of indicators for risk assessment and of therapeutic targets for unfavorable neuroblastoma.

No significant financial relationships to disclose.
Clinical predictors and risk of optic pathway glioma (OPG) in Neurofibromatosis-1 (NF-1)
Authors: Mian A. R. , Schorry E. , Chakraborty R. , Chakraborty B. , Perentesis J. P.
Published: March 2020

9016

Background: NF-1 is a progressive disease with wide spectrum of phenotype and unpredictability in clinical course. NF-1 patients are at significantly increased risk for development of a variety of neoplasms that cause morbidity and limited mortality, including OPG. There are limited data identifying risk factors predictive of subsequent OPG development. Objective: To identify key early clinical features which predict subsequent risk for development of OPG. Methods: Case-control study of NF-1 patients with and without OPG from Cincinnati Children’s Hospital NF-1 and Cancer Registries. Predictor variables were clinical risk factors (age at diagnosis of NF-1, race/ethnicity, gender, and history of familial NF-1, macrocephaly, plexiform neurofibroma, developmental delay, seizure disorder,), and the dependent variable was development of OPG by imaging. Patients received screening head MRI at the time of presentation with NF-1. Odds ratios (O.R.) were calculated with 75 cases (NF-1 and OPG) and 215 controls (NF-1 only) and statistically/clinically significant factors were further analyzed by logistic regression method. Results: Prevalence of OPG in NF-1 was 15.6%. Almost half had familial NF-1. Median age at diagnosis of NF-1 was 1.6 yrs (cases) and 2.4 yrs (controls). OPG was diagnosed at median age 4 yrs. Patients with T2 hyperintense lesions on imaging (UBOs) and age 4 years or less at diagnosis of NF-1 were at significantly increased risk of developing OPG (O.R=3.1, p=0.006 and O.R=3.1, p=0.002 respectively). In addition, presence of seizure disorder and developmental delay were borderline significant (O.R=2.8, p=0.07 and O.R=1.7, p=0.04 respectively). Race (Caucasian) appeared to have disease modifying effect on development and progression of OPG. Conclusions: Patients with T2 lesions on presentation MRI, developmental delay, seizures, and age 4 years or less at NF-1 diagnosis appear to be at an increased risk of developing OPG. Caucasian race appears to have a modifying effect on disease progression. Patients with these risk factors may be stratified as “high risk” and may benefit from close surveillance for early detection of OPG. The association of developmental delay and seizures may suggest a pathophysiologic relationship.

No significant financial relationships to disclose.
Cardiac status predicts quality of life in Hodgkin’s disease survivors
Authors: Adams M. J. , Ng A. K. , Mauch P. M. , Lipshultz S. E.
Published: March 2020

9029

Background: Long-term survivors of Hodgkin’s disease (HD) treated with mediastinal radiotherapy suffer from a variety of subclinical cardiac abnormalities including valvar defects and findings suggestive of restrictive cardiomyopathy. Their clinical importance has not been definitively demonstrated in longitudinal studies, but they may be related to the reduced quality of life reported by many HD survivors. Methods: The overlapping participants in two independent studies of HD survivors were identified in order to form a longitudinally studied cohort. In the first study, 48 survivors of childhood and young adulthood HD were evaluated by multiple cardiac testing modalities and quality-of-life assessment including the SF-36, a mean of 16 years after diagnosis. In the second performed about 5 years later, 511 survivors took part in a survey study, which also included the SF-36 instrument. A total of 23 patients participated in both studies and formed the current study population. Correlations were performed between key cardiac abnormalities uncovered during the first study and the physical component score (PCS) of the SF-36 measured in the second study, and the changes in PCS during the time between the 2 studies. Results: Average PCS was 44.05 at time of the second study, about 6.0 points lower than at time of cardiac testing. Maximum oxygen consumption correlated with PCS at time 2 (r=0.50, p=0.029). Univariate regression suggested that for every unit decrease in maximum oxygen consumption, the PCS decreased by 0.45 units. The higher the baseline PCS, the greater the negative change in PCS. Left ventricular fractional shortening correlated with PCS at time 2 (r=−0.579, p=0.0094) but not change in PCS. Conclusions: The study suggests that objective measures of reduced cardiac function are predictive of future quality of life in HD survivors. These results however need to be verified in a larger longitudinal study that allows for multivariate analysis.

No significant financial relationships to disclose.
Immunological recovery in children with ALL at the end of intensive therapy, at the completion of therapy, and up to one year off therapy. A follow-up study
Authors: Kosmidis S. P. , Baka M. , Bouhoutsou D. , Kallergi C. , Doganis D. , Douladiris N. , Varvoutsi M. , Pourtsidis A. , Sotiropoulou A. , Papageirgiou P. S. , Kosmidis H. V.
Published: March 2020

9031

Background: Children undergoing therapy for ALL are known to have impaired immune function. (ASCO 2005, abstract #8541). Methods: We prospectively evaluated the humoral and cellular immunity in children with ALL at the end of intensive therapy (Evaluation 1 -E1) and values were compared to those at the completion of therapy (E2), at 6 months (E3) and at 12 months thereafter (E4). Investigations among others included CBC, lymphocyte subpopulation by flow cytometry (CD3, CD4, CD8, CD16, CD19, CD3 DR, CD45RO and CD45RA), immunoglobulin levels by nephelometry, antibody titers to MMR immunization and skin tests to Candida, Trichophyton, diphtheria toxin and tetanus toxoid. Seventy three children with ALL, 48 boys, 25 girls (median age 4 years on diagnosis) treated according to BFM 95 protocol were evaluated. Of the 139 evaluations, 41 were E1, 43 E2, 37 E3, 18 E4 and data were analyzed with a non parametric Mann Whitney test. Results: Immunoglobulin levels at E1 were low in the majority of children and were increasing at E2 and E3 and E4 for IgA and IgM (median values of parameters studied are shown in the table in mg/dl for immunoglobulins and % for CD’s). Of the 70 children immunized with MMR only 11 had absent IgG antibodies. Also, skin tests were positive for tetanus toxoid in 93/139 evaluations, for candida in 41/139 and negative for trichophyton and diphtheria toxin. Conclusions: Children with leukemia experience severe immunological damage after intensive therapy which is gradually improving overtime although some values remain abnormal 6 months after the completion of therapy. It is worth mentioning that despite impaired immune function serious infections were not documented after the first six months of intensive therapy.

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No significant financial relationships to disclose.
Metabolic syndrome traits in long-term survivors of pediatric sarcoma at a single institution
Authors: Hoffman K. E. , Derdak J. , Bernstein D. , Reynolds J. C. , Steinberg S. M. , Chrousos G. , Gerber L. , Mackall C. L. , Mansky P. J.
Published: March 2020

9041

Multi-modality therapy (MMT) for pediatric sarcoma (SARC) may result in late endocrine abnormalities and increased cardiovascular morbidity. Metabolic syndrome (MS; NCEP ATPIII definition), a cluster of obesity, dyslipidemia, hyperglycemia and hypertension, conveys an increased risk of type 2 diabetes and cardiovascular disease. This cross-sectional study investigated the prevalence of the MS traits (MST) in long-term survivors of MMT for SARC. 32 survivors of SARC (predominantly Ewing’s; median age 36.5 years, range 17–54; f:m = 15:17; median age at MMT of 15 years, range 7–34; median time since completion of MMT 18 years, range 3–33) completed CT evaluation of abdominal obesity, DEXA scan for body mass composition, fasting serum lipid profile (FLP), the Human Activity Profile (HAP) and PAI and beta 2 microglobulin (B2M) analysis. Results, compared to appropriate controls were considered statistically significant if the p-value < 0.01. SARC survivors were more likely to have one or more MST (common OR 4.04, CI:[1.52, 13.55], p=0.0045). Subjects aged 20–39 had a higher pooled prevalence of the MS (common OR 4.29 [1.50, 11.21], p=0.0077), defined as 3 or more traits, compared to controls stratified by gender. Analysis of individual MST demonstrated higher prevalence of hypertension (common OR 2.61,[1.20, 5.59], p=0.015), hypertriglyceridemia (common OR 3.63, [1.75, 7.60], p=0.0006), and male abdominal obesity (common OR 4.52, [1.57, 13.39], p=0.0046). SARC survivors had a higher prevalence of hypercholesterolemia than healthy adults (p=0.012). PAI antigen (p=0.043), PAI activity (p=0.018) and B2M levels (p=0.043) increased with an increasing number of MST. In male subjects, total testosterone declined (p=0.008) as the number of MST increased. Average (p=0.028) and maximum (p=0.041) activity levels decreased as the number of MST increased. After a median follow up of 18 years, adult SARC survivors of MMT have an increased prevalence of MST, especially between ages 20–39 years. The development of MST may be associated with decreased testosterone and decreased activity level. Younger male adult SARC survivors may be at particular risk for type 2 diabetes and cardiovascular disease and should be monitored.

No significant financial relationships to disclose.
Online pediatric oncology education: A novel teaching tool for oncology residents
Authors: Gfeller P. , Harrison R. , Goddard K. J.
Published: March 2020

9048

Background: Deficiencies in pediatric oncology training for residents have been identified internationally. A lack of training in pediatric oncology during residency is correlated with impaired outcomes for pediatric patients. There is a clear need for novel teaching tools to supplement training in pediatric oncology. Purpose: The goal of this project was to develop a series of multimedia web-based learning modules for the interactive instruction and review of pediatric oncology. A needs-based assessment of pediatric oncology training in Canadian radiation oncology residency programs was used to guide web-site development. Methods: A needs-based analysis was conducted via a web-based survey sent to all Canadian radiation oncology program directors and residents. The survey was designed to identify the limitations of current training curriculum in pediatric oncology. A multidisciplinary team, including pathologists, radiologists, medical physicists, radiation and medical oncologists, developed the web site curriculum. The site was designed using teaching modules to focus on pediatric tumour sites. Modules were developed using a common format, divided into chapters detailing specific tumour types. Each chapter reviewed relevant epidemiology, anatomy, pathology, radiology, and treatment for the tumor type. A self-assessment tool was included at the end of the modules. User satisfaction surveys were used for feedback. Results: 100% (10/10) of Canadian radiation oncology program directors and 66% (69/106) of Canadian residents responded to the survey. 56% (59/106) of resident respondents felt that teaching in pediatric radiation oncology was inadequate and 56% (20/36) of senior residents felt unprepared for questions in pediatric oncology on qualifying board exams. 90% (105/116) of respondents felt that a web-based teaching tool would be useful. The first module, pediatric neuro-oncology, has been completed. Results indicate users find this module useful for supplementing traditional training. Conclusions: There are no other interactive teaching tools in pediatric oncology. This unique web-based educational program will allow self-directed study in the area of pediatric oncology, providing more effective learning of this challenging yet essential area of study.

No significant financial relationships to disclose.
Micro-RNA deletion in neuroblastoma: A possible alternative mechanism of MYCN overexpression
Authors: Yaniv I. , Reshef-Ronen T. , Ash S. , Goshen Y. , Jeison M. , Stark B. , Nordenberg J. , Avigad S.
Published: March 2020

9052

Background: Micro-RNAs (miRNAs) are small noncoding RNAs of 18 to 25 nucleotides that regulate protein expression. The biological functions of miRNAs are not yet fully understood. miRNA genes were recently found to be abnormally expressed in several types of cancer. By negatively regulating proto-oncogenes, miRNAs could act as tumor suppressors and conversely, by inhibiting tumor suppressors function as oncogenes. Neuroblastoma (NB) is the most common solid tumor in children under 5 years of age. Major adverse prognostic factors include: age over 1 year, advanced stages, adrenal primary site, MYCN amplification, diploid or tetraploid DNA content (DI), and chromosomal aberrations - including 1p deletions. We studied a possible involvement of miRNAs in neuroblastoma. Methods: The cohort consisted of 72 patients: 65% of them were above 1 year of age, 72% with advanced stages, 33% of the patients progressed. Median follow up was 60 months (ranging 1–221). Genomic DNA from 72 tumors were analyzed for the presence of 7 miRNAs located on chromosome 1p, ranging from 1p36.33 to 1p31.1 by PCR. Results: Deletion of one or more of the miRNAs was identified in 50% of the tumors.The most prevalent deletions were of two miRNAs: miR 30e located on 1p34.2 (29%) and miR 34a on 1p 36.23 (22%), accounting for 40% of the patients with a deletion of one or both of these miRs. Interestingly, miR 30e and miR 34a are known to negatively regulate the oncogene MYCN. MYCN protein expression is currently being evaluated in this cohort. Conclusions: The deletions of these miRNAs in neuroblastoma tumors suggest their involvement as tumor suppressor genes. This implies a new mechanism for the overexpression of MYCN. Discovery of the miRNAs and their targets involved in neuroblastoma has a therapeutic potential, for the development of new targeted therapies.

No significant financial relationships to disclose.