bluuebunny/crossref_metadata_2025 huggingface dataset:
The pharmacokinetics (PK) and pharmacodynamics (PD) of ABT-751 in children with recurrent neuroblastoma or other solid tumors
Authors: Fox E. , Widemann B. C. , Maris J. M. , Cohn S. L. , Xiong H. , Krivoshik A. P. , Hagey A. E. , Adamson P. C. , Balis F. M.
Published: March 2020

9557

Background: ABT-751 is an orally administered agent that binds to the colchicine site on β-tubulin and blocks microtubule formation. We studied the PK and PD of ABT-751 and its sulfate and glucuronide conjugates in children enrolled on a phase 1 trial in solid tumors and a pilot study in neuroblastoma. Methods: Seventy-two children (2–18 yrs) received ABT-751 on a once, daily × 7d or daily × 21d schedule. Sixty had PK plasma sampling (53 sets analyzed), and 41 had a 24h urine collection after the first dose. Drug concentrations were quantified with a LC/MS/MS assay. Results: Median (range) plasma PK parameters are shown in the table . ABT-751 was rapidly absorbed (Tmax , 2h), and the Cmax and AUC0-8 increased in proportion to dose. The median molar ratio of the sulfate plasma AUC0-8 to glucuronide plasma AUC0-8 was 1.5. The median (range) percent of the administered dose excreted in urine as ABT-751, glucuronide, or sulfate conjugates was 0.09 (0–0.4)%, 10.2 (1.0–38.5)%, and 12.6 (2.3–50.9)%, respectively. The median ABT-751 AUC0-8 was higher in patients with dose-limiting toxicity (DLT) compared to those without DLT on the 7d (118 vs. 74.5 μg·h/mL; P=0.014) and 21d (73.8 vs 49.3 μg·h/mL; P=0.049) schedules. In 28 patients with neuroblastoma, the AUC0-8 did not correlate with time to progression. Apparent clearance (CL/F) did not correlate with age or gender. Conclusions: PK samples were obtained from 83% (60/72) of children enrolled. The ABT-751 AUC0-8 was dose proportional; inter- and intra-patient variability was low. Patients who experienced DLT had higher ABT-751 AUC0-8. The mean CL/F of ABT-751 was similar to that observed in adults (40 mL/min/m2) but did not correlate with age or gender. The sulfate conjugate was the primary metabolite in plasma and urine. Urinary excretion was not a major route of elimination of the parent drug.

[Table: see text]

No significant financial relationships to disclose.
A retropective analysis of colorectal cancer in adolescents and young adults: A report from the Surgical Committee of the Children's Oncology Group
Authors: La Quaglia M. P. , Morris M. , Shia J. , Idrees K. , Rosenberg S. , Ishill N. , Shamberger R. C. , Doski J. J. , Heller G. , Paty P. B.
Published: March 2020

9568

Background: The genetic origin, clinical features, and prognosis of early onset colorectal carcinomas (CRC diagnosed ≤ 30 years of age) are poorly understood. To evaluate these parameters, we performed a multi-institutional review. Methods: This is a retrospective review accomplished through a survey of Children's Oncology Group Institutions. 167 patients (median age=21yrs., range 10–30 yrs.) with adequate material were reviewed. Immunostaining for mismatch repair (MMR) proteins (MSH2, MLH1, MSH6, PMS1) was performed for 119 cases with sufficient archival tumor. Survival estimates were computed using Kaplan Meier methodology and associations assessed using a log-rank test or Cox proportional hazards. Results: The overall stage of disease at presentation: 9% stage I, 16% stage II, 34% stage III, 38% stage IV, and 4% unknown. Site of origin in the colon included: 17% right, 8% transverse, 14% left, 15% sigmoid, 37% rectosigmoid or rectum, and 9% unknown. 37% of cancers were poorly differentiated and 23% had signet ring cell features. A family history of CRC was reported in 46 (40%) of 114 patients for whom data were available. HNPCC criteria (Amsterdam II) were met in only 10 of these cases. MMR protein expression was deficient in 20 of 119 evaluable cases (17%) and was correlated to HNPCC status (P<0.0001) but not to other clinical features. R0 resection was accomplished in 115 patients. Of 159 patients with follow-up data the median survival was 44 mos. (95% CI: 31–65mos.). The 1, 3, and 5-year overall survival were 81%, 54%, and 42% respectively. Variables associated with overall survival in univariate analysis included: age (p=0.02), family history of CRC (P=0.03), HNPCC status (P=0.03), stage (P<0.0001), grade (P=0.0003), and R0 status (P<0.0001). Conclusions: CRC in this age group is associated with clinical features distinct from adult CRC, including advanced stage, high grade pathology, and poor survival. The majority of cases occur sporadically, and less than 25% can be associated with HNPCC either by clinical criteria or by MMR immunostaining. Future studies should pursue more detailed molecular characterization, improved detection strategies, and better treatment to improve outcome for these aggressive cancers.

No significant financial relationships to disclose.
Endocrine outcome for children with embryonal brain tumors treated with craniospinal irradiation on the SJMB96 trial
Authors: Gajjar A. , Merchant T. , Sklar C. , Wallace D. , Xiong Z. , Shelso J. , Broniscer A. , Fouladi M. , Kun L. , Laughton S.
Published: March 2020

9571

Background: To investigate the relationship between endocrine deficits with the radiation (RT) dose to the hypothalamic- pituitary axis (HPA) in medulloblastoma/PNET patients treated with risk-adapted craniospinal irradiation (CSI) followed by chemotherapy. Methods: 88 patients who survived at least 2 years from diagnosis were included in this analysis. CSI doses were 23.4 Gy or 36–39.6 Gy depending on clinical risk; the primary tumor site received 55.8 Gy. All pts had regular endocrine follow-up and screening to test for growth hormone (GH), thyroid hormone (TH) and adrenocorticotrophin hormone (ACTH) deficiency. Patients that had abnormal results on the screening tests underwent further evaluation by stimulation testing of the HPA. Only patients diagnosed with central hypothyroidism were included in the analysis for TH deficiency. Results: Of the 88 pts included in the study cohort, 77 pts had abnormal screening tests and underwent provocative testing. The median radiation dose to the hypothalamus was 42 Gy (26–57 Gy) and pituitary was 44 Gy (26–58 Gy). Patients receiving higher RT doses to the pituitary had a significantly higher incidence of growth hormone deficiency with 4-year estimates of 100 ±3% for those receiving = 44Gy and 82±7% for those receiving < 44 Gy (p=0.024). Four-year estimates of thyroid hormone deficiency for patients receiving = 44 Gy to the pituitary were 67±21% and 18±14% for those receiving < 44 Gy (p<0.010). There was no correlation between the dose to the pituitary with the incidence of ACTH deficiency. The estimated change in height z-score for patients receiving < 44 Gy to the pituitary was - 0.53 units per year (-0.44 to -0.63) compared with -0.70 units per year (-0.62 to -0.78) for those receiving = 44 Gy. Conclusions: Data from this prospective study demonstrate that RT to the HPA is the key determinant for developing endocrinopathies in patients with medulloblastoma/PNET.

No significant financial relationships to disclose.
BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC)
Authors: Pegram M. , Forbes J. , Pienkowski T. , Valero V. , Eiermann W. , Von Minckwitz G. , Martin M. , Crown J. , Taupin H. , Slamon D.
Published: March 2020

LBA1008

Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial in HER2-positive MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH (H with T 100mg/m2) or TCH (H with T 75mg/m2 and C AUC=6). Chemotherapy was given every 3 weeks (q3w) for 8 cycles with weekly H at 2mg/kg (loading dose of 4 mg/kg) followed by H q3w at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was Time To disease Progression (TTP). Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm Pt characteristics were well balanced in both groups. A first efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p=0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). At 39 months of median follow-up, median overall survival was 36.40 and 36.57 months in TH and TCH arms respectively. More patients on TCH received the max number of chemotherapy cycles, and numerically fewer patients on TCH discontinued treatment as a result of non hematological toxicity. The most common gr 3/4 toxicities were: Neutropenic infection that was 16.8% vs 9.2% respectively for TH and TCH, thrombocytopenia (2% vs 15%), asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 10%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline > 15 % were seen in 5.5 % vs 6.7 % of pts. One pt (0.8%) had a symptomatic CHF in TH arm. Conclusion: Both TH (T 100) and TCH (T 75) were highly effective treatment regimens in women having HER2-positive MBC, demonstrating high response rates, median TTP > 10 months, and median overall survival > 36 months in both TH and TCH. Cardiac toxicity was no significant problem with either treatment.

[Table: see text]
Preemptive versus deferred lamivudine in preventing chemotherapy (CT) interruptions in hepatitis B (HBV) carriers with non-hematological malignancy—preliminary report of a randomized phase III study
Authors: Ngan R. K. , Yiu H. Y. , Cheng H. C. , Kwan C. K. , Lam T. W. , Tsang D. , Kwok P. , Cheng W. W. , Au K. H. , Wong K. H. , Yip T. C.
Published: March 2020

LBA19684

Background: About 10% cancer patients (pts) are HBV carriers in endemic areas, who have a risk of HBV reactivation with CT preventable by Lamivudine (Lam). Methods: Pts seropositive for HBV surface antigen (HBsAg+) planned to receive ≥ 4 cycles of CT for non-hematological malignancy were randomized to receiving either preemptive Lam during and for 8 weeks after CT (arm I), or observation only and deferred Lam at biochemical hepatitis reactivation (arm II). All pts had normal liver enzymes & clotting profiles, age 18–75 & KPS >50 before entry. Serial clotting profile, liver enzyme and HBV DNA levels were monitored during CT and for 15 weeks post-CT. The endpoints include % of CT interruptions due to HBV reactivation (primary), HBV reactivation %, CT drug dose intensity levels & HBV reactivation-free survival (all secondary). 110 pts are estimated to give a power of 90% to detect the projected difference in the primary endpoint at 2-sided alpha error of 0.05. Results: Pt accrual was completed in 1/07. As at 3/07, 92 (81%) of the 114 pts randomized have completed the study or died, and were included for analysis. Breast & lung cancer constituted 71% of the cancers. There was no statistical difference in pt, cancer, CT, or viral characteristics between the 2 arms. Results are summarized in table . All 4 pts with CT interruptions and 11/14 pts with HBV reactivation had breast cancer. No difference in CT drug dose intensity levels was observed. Steroid used in the anti-emetic regimen was a significant factor in predicting viral reactivation in arm II pts in multivariate analysis. Conclusions: Although the incidence of CT interruptions was low in unselected pts without preemptive Lam, it was much higher in breast cancer pts despite deferred Lam, who also had significant rates of biochemical hepatitis & viral reactivation. Preemptive Lam should be given to breast cancer pts, & considered in other cancer pts receiving CT who are HBsAg+.

[Table: see text]

No significant financial relationships to disclose.
Final results of the EORTC Intergroup randomized phase III study 40983 [EPOC] evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases
Authors: Nordlinger B. , Sorbye H. , Collette L. , Glimelius B. , Poston G. J. , Schlag P. M. , Rougier P. , Bechstein W. , Walpole E. , Gruenberger T.
Published: March 2020

LBA5

Background: The 5-year survival after resection of colorectal cancer liver metastases is 30% but recurrence is common. This study evaluates the benefit of combining peri-operative chemotherapy and surgery for patients with initially resectable liver only metastases from colorectal cancer (LM). Methods: Between September 2000 and July 2004, 364 pts with up to 4 LM were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m2 and LV5FU2), 6 cycles before and 6 cycles after surgery, (CT), and surgery alone (S). The primary endpoint was progression free survival (PFS) with the goal to increase median PFS by 40% (HR=0.71). Safety was a secondary endpoint (already reported at ASCO 2005). PFS results are reported at the 2-sided 0.0434 significance level (adjusting for one interim analysis). Results: Baseline characteristics were similar in both arms. Eleven of 182 pts were ineligible in each arm, mostly for more advanced disease. In the CT arm, a median of 6 pre-op cycles were delivered and 151 patients were resected. 115 pts (63%) received post-op CT, with a median number of 6 cycles and a relative dose intensity of 79% to 86%. In the S arm, 152 pts were resected. Due to the nature of the trial, evaluation of resectability (relevant for eligibility) was based on pre-op imaging, but 31/182 pts (CT arm) and 30/182 pt (S arm) could not undergo resection. There were 2 (S arm) and 1 (CT arm) deaths after surgery. At a median follow-up of 3.9 years, 254 PFS events were reported (240 in eligible pts) and the results are as shown in the table . Conclusions: Peri-operative FOLFOX4 chemotherapy improved PFS over surgery alone in patients whose metastases were actually resected. The benefit was slightly diluted when also pts considered resectable on imaging but eventually not resected were taken into account. FOLFOX4 given peri-operatively is safe and does not prevent the pts from undergoing surgery. [Table: see text]

[Table: see text]
Adjuvant low-dose interleukin-2 (IL2) plus interferone-alpha (IFN) in operable renal cell cancer (RCC). A phase III, randomized, multicenter, independent trial of the Italian Oncology Group for Clinical Research (GOIRC)
Authors: Passalacqua R. , Buzio C. , Buti S. , Labianca R. , Porta C. , Boni C. , Rondini E. , Camisa R. , Sabbatini R. , Artioli F. , Caminiti C.
Published: March 2020

LBA5028

Background: For pts with non-metastatic RCC, no standard adjuvant treatment exists. Immunotherapy (IT) using IFN and/or IL2 is effective in metastatic disease setting. Low and chronically repeated doses of IL2 plus IFN induce a persistent stimulation of the immune system with no relevant toxicity. Methods: From July1994 to March 2006, surgically treated RCC pts were randomized to the following arms: A) low-dose IT; B) control arm. IT consisted of a 4-week cycle of s.c. IL2 (5 days/wk, 1 million UI/sqm bid d 1,2 and 1 million UI/sqm × 1 d 3,4,5) + IFN (1,8 million UI/sqm d 3,5 of each week). Cycles were repeated every 4 months for the first 2 years and every 6 months for the remaining 3 years. Each patient received 12 cycles in 5 years. Inclusion criteria were as follows: histological diagnosis of RCC, age <75 yrs, radical or partial nephrectomy within the past 3 months, pT1 (diameter of T > 2,5 cm), T2, T3 a-b-c; pN0-pN3, M0; good cardiac and renal function and no autoimmune disease. Based on a planned sample size of 320 pts, the trial was designed to have a 80% power to detect a 15% improvement in 5-year survival. Results: A total of 310 pts were randomized: 157 on arm A, 153 on arm B. Pts characteristics were well balanced between the two arms. At a median follow-up of 52 months, 77 pts relapsed: 35 in arm A and 42 in arm B. In the first 5 years of observation, disease free survival (DFS) curves were similar in the two arms, but diverged thereafter. DFS at 5 and 10 years was 0.73 and 0.73 in arm A vs 0.73 and 0.60 in arm B with an estimated Hazard Ratio (HR) of 0.84 (95% CI: 0.54–1.33 p=0.47). Efficacy of IT was more evident in patients with good PS (HR 0.78; 0.47–1.30 p=0.35); age<60 yrs (HR 0.61; 0.31–1.19 p=0.15), and low tumor grade (HR 0.70; 0.38–1.27 p=0.24). As for overall survival, 59 deaths were observed with no differences between the two arms. Toxicity was mild and limited to WHO grade 1 or 2 in the majority of cases. Conclusions: Low-dose adjuvant IL2+IFN is feasible in RCC and seems to reduce the risk of recurrence after 5 years from diagnosis. Follow-up update is still ongoing.

No significant financial relationships to disclose.
Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer: Updated report with survival
Authors: Fidias P. , Dakhil S. , Lyss A. , Loesch D. , Waterhouse D. , Cunneen J. , Chen R. , Treat J. , Obasaju C. , Schiller J.
Published: March 2020

LBA7516

Background: Gemcitabine (G) plus carboplatin (C) therapy is active in patients with advanced non-small-cell lung cancer (NSCLC). For nonprogressing patients, optimal timing of second-line therapy with a non-cross-resistant agent is unclear. This Phase III, randomized trial assessed the efficacy and safety of docetaxel (D) administered either immediately after GC induction therapy or upon disease progression (PD). Methods: Patients having either Stage IIIB with pleural effusion or Stage IV NSCLC were enrolled. Prior chemotherapy for NSCLC was not permitted. For GC induction, G 1000 mg/m2 was administered on Days 1, 8 followed by C AUC 5 on Day 1. After four 21-day cycles, nonprogressors were randomized to either the immediate D group (D 75 mg/m2 administered on Day 1 every 21 days, for a maximum of 6 cycles) or the delayed D group (patients given best supportive care after randomization and the same D regimen after first evidence of PD) treatment arms. Primary endpoint was overall survival (OS). Additional analyses included response rates, toxicity and progression-free survival (PFS). Results: Results are summarized in the table below. OS was not statistically different (p=0.071) between the two D arms. However, 31 patients (20.1%) in the delayed D arm and 38 patients (24.8%) in the immediate D arm were censored for OS analysis. PFS analysis (from randomization to first evidence of PD or death) showed a statistically significant (p=<0.0001) improvement in the immediate D arm. D given to NSCLS patients immediately after GC induction did not increase toxicity. Conclusions: Comparison of PFS for each D arm suggests a possible clinical benefit for immediate D therapy. However, even though OS trended in favor of immediate D therapy, the OS result did not reach statistical significance. The implications of these results will be discussed.

[Table: see text] [Table: see text]
A randomized phase III trial of active symptom control (ASC) with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma: First results of the Medical Research Council (MRC) / British Thoracic Society (BTS) MS01 trial
Authors: Muers M. , Fisher P. , Snee M. , Lowry E. , O'Brien M. , Peake M. , Rudd R. , Nankivell M. , Pugh C. , Stephens R. J.
Published: March 2020

LBA7525

Background: Although chemotherapy is widely used in the treatment of mesothelioma it has never been compared in a randomized trial with ASC alone. Two chemotherapy regimens that had shown good symptom palliation in phase II studies were chosen for investigation. Methods: Patients with malignant pleural mesothelioma were randomized to ASC alone (regular follow-up in a specialist clinic, and treatment could include steroids, analgesics, bronchodilators, palliative radiotherapy, etc), ASC+MVP (4 × 3-weekly cycles of mitomycin 6g/m2, vinblastine 6mg/m2, and cisplatin 50mg/m2), or ASC+N (12 weekly injections of vinorelbine 30mg/m2). 420 patients were required to detect a 3-month improvement in median survival with ASC+CT (both chemotherapy arms combined). Quality of Life (QL) was assessed using the EORTC QLQ-C30. Results: 409 patients were accrued (136 ASC, 137 ASC+MVP, 136 ASC+N). Median age: 65 years, male: 91%, Performance status 0: 23%, Epithelial histology: 73%, Stage III: 33%, Stage IV: 48%. In the ASC+MVP group 61% received all 4 cycles, and in the ASC+N group 49% received at least 10 weekly cycles. Good symptom palliation (defined as prevention, control or improvement) was achieved in all 3 groups, and no between-group differences were observed in 4 pre-defined QL subscales (physical functioning, dyspnoea, pain and global QL). A small (not conventionally significant) survival benefit was seen for ASC+CT (349 deaths, HR 0.89, 95%CI 0.72, 1.12, p=0.32). Median survival: ASC: 7.6 months, ASC+CT: 8.5 months. Exploratory analyses suggested a survival advantage for vinorelbine compared to ASC alone (HR 0.81, 95%CI 0.63, 1.05, p=0.11), with a median survival of 9.4 months, but no evidence of a benefit with MVP (HR 0.98, 95%CI 0.76, 1.28), p=0.91). Conclusions: This is the 2nd largest ever randomized trial in mesothelioma and the first to compare ASC with or without chemotherapy. Although the addition of chemotherapy to ASC did not result in a conventionally significant survival benefit, there was an indication that vinorelbine should be investigated further, and that MVP probably has no role in this disease.

[Table: see text]
Female fertility preservation (FP) at pediatric cancer centers: A report from the Children’s Oncology Group (COG).
Authors: Levine Jennifer , Quinn Gwendolyn P. , Klotsky James , Kelvin Joanne Frankel , Cherven Brooke , Bryson Elyse , Ahmed-Winston Sameeya , Frederick Natasha , Brackett Julienne , Meacham Lillian , Freyer David Robert , Dvorak Christopher , Chow Eric Jessen
Published: March 2020

11567

Background: Preserved fertility after cancer is a priority for female survivors and their families. Embryo/oocyte cryopreservation are standard of care (SOC) for post-pubertal females. Experimental ovarian tissue cryopreservation (OTC) is the only current option for pre-pubertal girls. We surveyed COG sites about their FP infrastructure and practices. Methods: A REDcap survey was emailed to one individual previously identified as knowledgeable about FP or the Principal Investigator at each COG site. Site specific factors associated with outcomes were determined using logistic regression. All study procedures were IRB-approved. Results: Responses were received from 144 of 220 sites (65%). Discussions about fertility at diagnosis were reported as routinely held with all females “at risk” of infertility, all post pubertal females, and all females at 113 (78%), 94 (65%), and 65 (45%) of sites respectively. Embryo/oocyte cryopreservation was offered at 95 (70%) institutions and independently associated with large (>120 new patients/year) sites (OR 6.0 95%CI 1.6-22.8) and presence of a FP navigator/team (OR 4.7 95%CI 1.7-13.5). OTC was offered at 64 (48%) sites: 34 (25%) by referral to another institution, 18 (13%) under an IRB protocol, and 12 (9%) as a clinical service. OTC accessibility was associated with large sites (OR 3.2 95% CI 1.1-8.9) and a FP navigator/team (OR 3.2 95%CI 1.4-7.0). A total of 102/133 (77%) sites use gonadotropin releasing hormone analogues (GnRHa) for any indication; 90 (68%) for menstrual suppression, 75 (56%) with the goal of ovarian suppression for fertility preservation, and 27 (20%) for contraception. Conclusions: Variation in FP services exists across COG. Discussion of infertility risk is not universal. The availability of OTC at treating institutions is limited. The presence of an FP navigator/team is a modifiable factor associated with greater likelihood of accessing SOC and experimental options. Despite conflicting evidence and lack of endorsement from professional societies, GnRHa’s are commonly used for FP. These survey results suggest FP services remain inadequate but highlight opportunities for improvement and areas of needed research.
Impact of geriatric vulnerability on outcomes of older patients in allogeneic hematopoietic cell transplantation.
Authors: Lin Richard Jirui , Elko Theresa A , Devlin Sean M. , Flynn Jessica , Jakubowski Ann Alice , Shahrokni Armin , Dahi Parastoo , Perales Miguel-Angel , Sanchez-Escamilla Miriam , Tamari Roni , Shaffer Brian Carl , Sauter Craig Steven , Papadopoulos Esperanza Bouza , Castro-Malaspina Hugo , Gyurkocza Boglarka , Barker Juliet Naomi , Maloy Molly A , Korc-Grodzicki Beatriz , Giralt Sergio
Published: March 2020

7017

Background: Older patients are at increased risk for complications and death following allogeneic hematopoietic cell transplantation (allo-HCT). Traditional transplant-specific prognostic indices such as hematopoietic cell transplant comorbidity index (HCT-CI) may not capture all underlying geriatric vulnerabilities, and in-depth evaluation by a geriatrician prior to transplant may not always be available. We hypothesize that routine pre-transplant assessments by interdisciplinary clinical providers may help uncover additional geriatric deficits. Methods: Using an institutional database of 457 adults age 60 years and older (range 60-78.7) who underwent first allo-HCT for hematological malignancies from 2010 to 2017, we retrospectively examined the prevalence and the prognostic impact of pre-transplant geriatric deficits identified by interdisciplinary clinical providers including geriatric domains of functional activity, cognition, medication, nutrition, mobility, and routine laboratory tests. Results: With a median follow-up of 37 months for survivors, the 3-year probability of overall survival (OS) was 50% (95% CI 45-55). The 2-year cumulative incidence of non-relapse mortality (NRM) was 25% (95% CI 22-28). Among pre-transplant geriatric variables, we found that impairment in instrumental activities of daily living (IADL) was associated with increased NRM and inferior PFS and OS. In multivariate analyses, mismatched donor, age-adjusted HCT-CI > 4 (aaHCTCI), and IADL impairment were associated with NRM, while high/very high disease risk index (DRI), IADL impairment, and positive CMV status were associated with OS. The combination of IADL impairment with either aaHCTCI or DRI readily stratifies NRM and OS, respectively. Conclusions: Our findings establish a simple assessment tool to risk stratify older patients prior to allo-HCT using IADL and aaHCTCI and DRI. These results may provide an entry point for prospective, interventional trials to reduce NRM and toxicities for older allo-HCT patients.
Response to brentuximab vedotin by CD30 expression: Results from five trials in PTCL, CTCL, and B-cell lymphomas.
Authors: Jagadeesh Deepa , Horwitz Steven M. , Bartlett Nancy L. , Advani Ranjana H. , Jacobsen Eric D. , Duvic Madeleine , Gautam Ashish , Rao Shangbang , Onsum Matthew , Fanale Michelle , Kim Youn H.
Published: March 2020

7543

Background: Brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, has been evaluated in multiple trials in patients (pts) with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell lymphoma. We examined the ability of CD30 expression level to predict response to BV across these patient populations. Methods: Data were integrated from 275 pts with PTCL, CTCL, and B-cell lymphoma treated with BV from 5 prospective clinical trials. Study SGN35-012 evaluated BV plus rituximab or BV monotherapy in pts with relapsed/refractory non-Hodgkin lymphoma. The ALCANZA study compared BV to physician’s choice of methotrexate or bexarotene in pts with mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL). Three investigator-sponsored trials evaluated BV monotherapy in pts with relapsed PTCL, MF, and pcALCL (35-IST-030, 35-IST-001, 35-IST-002). Exploratory analyses were conducted to examine the relationship between CD30 expression and objective response rate (ORR) for pts with CD30 expression ≥10%, <10%, or undetectable (0%) by IHC (malignant cells or lymphoid infiltrate; local review). Results: 143 pts had tumors with CD30 <10%, including 58/143 with undetectable CD30. Activity with BV was observed at all levels of CD30 expression, including CD30=0 (Table). Analysis of the interaction between CD30 and duration of response is ongoing and will be presented in the final poster. ORR by CD30 expression, n/N (%). Clinical trial information: NCT01421667, NCT02588651, NCT01578499, NCT01352520, NCT01396070. Conclusions: CD30 expression levels ≥10%, <10%, or undetectable did not predict response to BV in a range of CD30-expressing lymphomas: Clinical responses occurred in pts with CD30 low and CD30 undetectable lymphomas. Limitations of IHC, the dynamic nature and heterogeneity of cell-surface CD30 expression, and multiple mechanisms of action of BV may all contribute to this observation.[Table: see text]
NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry.
Authors: Duruisseaux Michaël , Liu Stephen V. , Han Ji-Youn , Gounant Valerie , Shih Jin-Yuan , Schram Alison M. , Schrock Alexa Betzig , Ali Siraj Mahamed , Magne Fanny , Monnet Isabelle , Moro-Sibilot Denis , Blum Torsten-Gerriet , Patil Tejas , Doebele Robert Charles , Camidge D. Ross , Muscarella Lucia Anna , Cadranel Jacques , Drilon Alexander E.
Published: March 2020

9081

Background: NRG1 fusions are potentially actionable driver events enriched in NSCLCs, particularly invasive mucinous adenocarcinomas (IMAs). These fusions activate HER3/HER2, supporting the therapeutic use of HER3 and/or HER2 inhibitors, but optimal treatment strategies remain unclear. Methods: A global, multicenter network of thoracic oncologists (6 countries, 13 institutions) identified patients with pathologically confirmed NRG1 fusion-positive NSCLCs. Anonymized clinical/pathologic features and clinical outcomes were collected retrospectively. Best response to systemic therapy was determined (RECIST v1.1). PFS was calculated (Kaplan-Meier). Results: 80 NRG1 fusion-positive NSCLCs were identified. RNA-based sequencing identified 66% (n = 53/80), DNA-based sequencing 18% (n = 14/80), and FISH 16% (n = 13/80) of cases. The most common upstream partners were CD74 (45%), SLC3A2 (31%), and SDC (9%). Most patients were female (64%) and never smokers (58%). Histology was adenocarcinoma in 95% (IMA, 91%), squamous 4%, large cell neuroendocrine 1%. At diagnosis, most patients had non-metastatic disease (stage: I 33%, II 27%, III 18%, IV 22%). The lifetime frequency of brain metastases was 15%. 12 patients received the HER2 inhibitor afatinib for stage IV disease. PD was the best response in 55% (n = 6/11) of evaluable patients with 18% PR (n = 2/11) and SD 18% (n = 2/11); median PFS was 3.5 months (range 0.6-16.5 months). 19 patients received platinum-based chemotherapy; most patients had SD as their best response (47%, n = 8); PD 41% (n = 7), PR 12% (n = 2). PD-L1 was negative in the majority of tumors (79%, n = 26/33) and none had high PD-L1 expression (range 0-20%). No responses to single-agent anti-PD-1/L1 therapy were observed (PD n = 5/6, SD n = 1/6: nivolumab/atezolizumab). No responses to chemoimmunotherapy (carboplatin, pemetrexed, pembrolizumab) were observed (SD n = 4/5, PD n = 1/5). Conclusions: RNA-based testing is an important component of NRG1 fusion detection. Novel targeted therapeutic approaches are needed as overall outcomes with afatinib are poor. NRG1 fusion-positive NSCLCs do not highly express PD-L1 and outcomes with immunotherapy ± chemotherapy are poor.
Outcomes to first-line pembrolizumab in patients with non-small cell lung cancer and a PD-L1 tumor proportion score ≥90%.
Authors: Jimenez Aguilar Elizabeth , Ricciuti Biagio , Gainor Justin F. , Nishino Mizuki , Adeni Anika E. , Subegdjo Safiya , Khosrowjerdi Sara , Peterson Rachel , Digumarthy Subba , Liu Corinne , Sauter Jennifer L. , Rizvi Hira , Arbour Kathryn Cecilia , Carter Brett W. , Heymach John , Altan Mehmet , Hellmann Matthew David , Awad Mark M.
Published: March 2020

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Background: In non-small cell lung cancers with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of ≥50%, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared to platinum-doublet chemotherapy. Whether higher PD-L1 expression levels within the TPS range of 50-100% predict for even greater benefit to pembrolizumab is currently unknown. Methods: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment for advanced NSCLC with a PD-L1 TPS of ≥50%. Results: Among 196 patients with NSCLC treated with first-line pembrolizumab, the ORR was 43.8% (95%CI: 36.8-51.1). At a median follow-up of 12.6 months (95%CI: 11.6-13.7), the mPFS was 6.2 months (95% CI: 4.2-8.2) and the mOS was not reached. The median PD-L1 TPS among patients who experienced a response to pembrolizumab was significantly higher than in patients with stable or progressive disease (TPS 90% vs 70%, P < 0.001), so a TPS cut point of 90% was chosen for further analysis. Baseline clinicopathological characteristics were well-balanced between patients with a PD-L1 TPS of 50-89% vs 90-100%. Compared to patients with a PD-L1 TPS of 50-89% (N = 114, 58.2% of the cohort), patients with a TPS of 90-100% (N = 82, 41.8% of the cohort) had a significantly higher ORR (61.0% versus 31.6%, P < 0.001), a significantly longer mPFS (13.2 versus 3.7 months, HR: 0.48 [95% CI: 0.33-0.71], P < 0.001), and a significantly longer mOS (NR versus 16.0 months, HR: 0.38 [95% CI: 0.21-0.70], P = 0.002). After adjusting for ECOG performance status and smoking history, PD-L1 TPS of 90-100% was significantly associated with improved mPFS (HR: 0.51 [95% CI: 0.34-0.75], P < 0.001) and mOS (HR: 0.38 [95% CI: 0.21-0.70], P = 0.001). Conclusions: Among patients with NSCLC and a PD-L1 TPS ≥50%, clinical outcomes are improved in the subgroup of patients with a PD-L1 TPS of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
Young Women With Breast Cancer in Mexico: Results of the Pilot Phase of the Joven & Fuerte Prospective Cohort
Authors: Villarreal-Garza Cynthia , Platas Alejandra , Miaja Melina , Fonseca Alan , Mesa-Chavez Fernanda , Garcia-Garcia Marisol , Chapman Judy-Anne , Lopez-Martinez Edna A. , Pineda Claudia , Mohar Alejandro , Galvez-Hernandez Carmen L. , Castro-Sanchez Andrea , Martinez-Cannon Bertha-Alejandra , Barragan-Carrillo Regina , Muñoz-Lozano Jose F. , Goss Paul , Bargallo-Rocha Juan E. , Aguilar Dione , Cardona Servando , Canavati Mauricio
Published: March 2020

PURPOSE

The pilot-phase report of the Joven & Fuerte prospective cohort broadly characterizes and assesses the needs of Mexican young women with breast cancer (YWBC).

PATIENTS AND METHODS

Women age ≤ 40 years with nonmetastatic primary breast cancer were consecutively accrued from 2 hospitals. Data were collected at the first/baseline oncology visit and 2 years later using a sociodemographic survey, European Organisation for Research and Treatment of Cancer Quality-of-Life (QOL) Questionnaire Core 30 (QLQ-C30) and Breast Cancer–Specific QOL Questionnaire (QLQ-BR23), Hospital Anxiety and Depression Scale (HADS), Female Sexual Functioning Index (FSFI), Sexual Satisfaction Inventory, and patients’ medical records. Pearson χ2 and 2-sided t tests were used for statistical analysis. An unadjusted P value < .05 was considered significant.

RESULTS

Ninety patients were included, all with government health care coverage. Most had low monthly household incomes (98%) and at least a high school education (59%). There was a considerable prevalence of unpartnered patients (36%) and unmet parity (25%). Patients’ most common initial symptom was a palpable mass (84%), and they were most frequently diagnosed with stage III disease (48%), with 51% having had a physician visit ≤ 3 months since detection but 39% receiving diagnosis > 12 months later. At baseline, 66% of patients were overweight/obese, and this proportion had significantly increased by 2 years ( P < .001). Compared with baseline, global QLQ-C30 had improved significantly by 2 years ( P = .004), as had HADS-Anxiety ( P < .001). However, both at baseline and at 2 years, nearly half of patients exhibited FSFI sexual dysfunction.

CONCLUSION

These preliminary findings demonstrate that YWBC in Mexico have particular sociodemographic and clinicopathologic characteristics, reinforcing the necessity to further describe and explore the needs of these young patients, because they may better represent the understudied and economically vulnerable population of YWBC in limited-resource settings.
Master Endurance Athletes and Cardiovascular Controversies
Authors: Tso Jason , Kim Jonathan H.
Published: March 2020

As interest and participation in recreational endurance exercise has steadily increased, the number of masters level recreational endurance athletes also has increased. While the benefits of regular and moderate physical activity on cardiovascular health are well established, recent data have raised concern that long-term endurance exercise participation is associated with adverse cardiovascular outcomes. In this review, we discuss the supporting evidence and limitations of prior research focused on these recent controversies. Specifically, we address the association between extreme levels of endurance exercise and longevity, risk of atrial fibrillation, accelerated coronary artery atherosclerosis, and arrythmogenic cardiac remodeling. We aim to provide sports medicine practitioners with knowledge of these contemporary controversies in sports cardiology and will highlight the importance of shared decision making in situations of clinical uncertainty.
The role and place of the General police in the system of local government of Siberia (the XVIII — beginning of XX century)
Authors: Konovalov Igor'
Published: March 2020

In the monograph developed by the scientific concept of local control of Siberia of XVIII — early XX century, according to which the military and administrative powers of the provincial government was transformed in the XVIII century in the administrative and police functions established within the framework of the Imperial legislation and implemented by the governors with extensive and specialized police apparatus. The original proposed judgment on the fact that the police from the time of its creation in the XVIII century, played a leading role in the system of local government of Siberia, in fact realizing the functions of the local administration.
For researchers and teachers, masters and bachelors, as well as anyone interested in the history of the police and local administration.
Judicial-ecological examination
Authors: Mayorova Elena
Published: March 2020

The manual includes a modern interpretation of the concept of judicial expertise, and the theoretical basis of forensic and ecological examination, containing a description of its subject, the definition of the scope of the tasks and the objects of expert research. Considered in detail the procedural and organisational issues of appointment and production of forensic-ecological expertise, order of registration of the conclusion outlined the limits of its use in the process of proof. Presents current methodological and conceptual apparatus of the system of examination of this kind, the problems of information support of expert studies.
Meets the requirements of Federal state educational standards of higher education of the last generation.
Addressed to the bachelors of science areas of training associated with the assessment of the ecological state of the environment.
The basics of anthropology
Authors: Tyumaseva Zoya
Published: March 2020

The textbook covers the relevant issues of our times: the essence of life, theories and hypotheses of the origin of life and man. For millennia, people interested in the question: where did we come from? The guide presents the views, ideas, hypotheses of philosophers, anthropologists, biologists and other specialists on the specifics of human evolution. Special attention is paid to the ontogenetic relationship of language, thought and consciousness, as well as phylogenetic stages of language development.
Addressed to teachers, students of Humanities universities, focused on independent work and advanced study courses "Social anthropology", "Anthropology and life safety", as well as teachers of biology and ecology.
Drug Abuse and the Internet: Evidence from Craigslist
Authors: Liu Jiayi , Bharadwaj Anandhi
Published: March 2020

The United States is in the midst of a drug overdose epidemic. Although the online availability of drugs has been a growing concern with considerable speculation that digital platforms are contributing to this epidemic, empirical assessments have been lacking. To quantify this impact, we rely on the phased rollout of Craigslist, a major online platform, as an experimental setup. Applying a difference-in-differences approach on a national panel data set for all counties in the United States from 1997 to 2008, we find a 14.9% increase in drug abuse treatment admissions, a 5.7% increase in drug abuse violations, and a 6.0% increase in drug overdose deaths after Craigslist’s entry. The impacts of Craigslist’s entry are larger among women, whites, Asians, and the more educated. Further, the unintended consequences of Craigslist are more likely to accrue in larger, wealthier areas with initially low levels of drug abuse. These findings raise the possibility that the marked growth in U.S. drug abuse may have partially stemmed from the wider availability of illicit drugs online at the very beginning of its evolution.

This paper was accepted by David Simchi-Levi, information systems.
On Modelling for Bias-Aware Sentiment Analysis and Its Impact in Twitter
Authors: Mahmood Ahsan , Khan Hikmat Ullah , Ramzan Muhammad
Published: March 2020

Sentiment Analysis (SA) is an active research area for the last ten years. SA is the computational treatment of opinions, sentiments, and subjectivity of text. Twitter is one of the most widely used micro-blog and considered as an important source for computation of sentiment and of data analysis. Therefore, companies all over the world analyze Twitter data using SA and extract knowledge which has potential applications in diverse areas. Although SA is the successful way of finding the people’s opinion, the bias in the tweets affects the results of the SA and reflects inaccurate analysis that may mislead users to take erroneous decisions. The biased tweets are shared by valid, but biased human users as well as the social bots to propagate the biased opinions on certain topics. To counter this, this research study proposes a statistical model to identify such users and social bots who share the biased content in the form of tweets in the Twitter social media. For experiment purpose, we use annotated twitter dataset and argue the results of SA with and without the biased tweets and explored the effects of biased users at micro-level and macro level. The empirical results show that the proposed approach is effective and properly identifies the biased users and bots from other authentic users using sentiment analysis.
Quantitative inspection of coating thickness by flash-pulse thermography and time-power transformation evaluation
Authors: Švantner M. , Muzika L. , Houdková Š.
Published: March 2020

Thermographic testing is an inspection method that primarily indicates the presence of discontinuities in a tested sample. Its application to coatings can indicate a presence of local thickness variations; however, it mostly does not bring any quantitative information about the thickness of the coatings. This contribution is focused on a quantification of the thermographic inspection, which would make possible an evaluation of coating thickness differences. Flash-pulse thermographic testing was applied to thermally sprayed coatings. The importance of a precise synchronization of flash source and thermographic recording was determined. Different evaluation methods were analyzed, and their comparison showed that a time-power transformation method is the most suitable for quantification of the inspection results.
Flexible Optical Network Enabled Hybrid Recovery for Edge Network with Reinforcement Learning
Authors: Lian Meng , Gu Rentao , Qu Yongyao , Wang Zihao , Ji Yuefeng
Published: March 2020

The proposed hybrid recovery utilizes flexible optical network with reinforcement learning to recover IP fault for edge network. The testbed experiments indicate, the recovery time is 20% of rerouting-based strategy for a heavy-loaded network.
Deep Reinforced Energy Efficient Traffic Grooming in Fog-Cloud Elastic Optical Networks
Authors: Zhu Ruijie , Li Shihua , Wang Peisen , Li Lulu , Samuel Aretor , Zhao Yongli
Published: March 2020

We propose a novel energy efficient traffic grooming algorithm based on deep reinforcement learning in fog-cloud elastic optical networks. Simulation results show that it can achieve much lower energy consumption than the state-of-art algorithm.
Single-shot detection time-stretched interferometer with attosecond precision
Authors: Xian Tianhao , Zhan Li , Zhang Wenchao , Zhang Wenyan , Gao Lirun
Published: March 2020

A single-shot time-stretched interferometer for femtosecond and picosecond time detection is proposed and demonstrated. The time precision is ~40 attosecond. This technique succeeds in charactering the motion of delay-line and in fabricating vibrating sensor.
50 Gbit/s silicon modulator operated at 1950 nm
Authors: Li Wenxiang , Li Miaofeng , Zhang Hongguang , Zhang Yuguang , Xie Hucheng , Xiao Xi , Xu Ke
Published: March 2020

We have experimentally demonstrated an integrated silicon Mach-Zehnder modulator which operates at 1950 nm wavelength range. 50 Gbit/s intensity modulation is achieved with bit error rate below 3.8×10−3.
High Output Power and Compact LAN-WDM EADFB Laser TOSA for 4 × 100-Gbit/s/λ 40-km Fiber-AmplifierLess Transmission
Authors: Kanazawa Shigeru , Shindo Takahiko , Chen Mingchen , Fujiwara Naoki , Nada Masahiro , Yoshimatsu Toshihide , Kanda Atsushi , Nakanishi Yasuhiko , Nakajima Fumito , Sano Kimikazu , Ishikawa Yozo , Mizuno Kazuyo , Matsuzaki Hideaki
Published: March 2020

We achieved the world’s first demonstration of 4 × 100-Gbit/s/λ 4-PAM signals 40-km fiber-amplifier-less transmission featuring a power budget over 18 dB using a 4-channel high output power LAN-WDM EADFB laser TOSA and APD ROSA.
16-QAM Probabilistic Constellation Shaping by Learning the Distribution of Transmitted Symbols from the Training Sequence
Authors: Fallahpour A. , Alishahi F. , Minoofar A. , Zou K. , Almaiman A. , Liao P. , Zhou H. , Tur M. , Willner A. E.
Published: March 2020

A technique for probabilistic constellation shaping based on distribution learning from a training sequence is investigated. In this approach, the probability distribution is optimized such that it can maximize the mutual information. The effectiveness of this approach is verified by shaping 10 Gbaud 16QAM in simulation and experiment.
Applications of Machine Learning in Optical Communications and Networks
Authors: Khan Faisal N. , Fan Qirui , Lu Jianing , Zhou Gai , Lu Chao , Lau Pak Tao
Published: March 2020

OFC 2020 Tutorial presentation
Optically Controlled Beam-steering Wireless Systems
Authors: Koonen Ton , Mekonnen Ketemaw , Cao Zizheng , Huijskens Frans , Pham Ngoc-Quan , Tangdiongga Eduward
Published: March 2020

Wavelength-controlled 2D steering of mm-wave beams and infrared beams provides high communication capacity, privacy and energy efficiency. Using diffractive elements and accurate user localization, delivery of multiple 10GbE video streams by infrared beams is demonstrated.
Uncooled Operation of 53-Gbaud PAM4 EA-DFB Lasers in the Wavelength Range of 1510-1570 nm for 800-GbE Applications
Authors: Nakai Yoshihiro , Hayakawa Shigenori , Yamauchi Syunya , Yamaguchi Yoriyoshi , Takamure Tetsuyoshi , Asakura Hideaki , Nakajima Ryosuke , Hamada Shigetaka , Naoe Kazuhiko
Published: March 2020

53-Gbaud EA-DFB lasers—with four wavelengths in the 1500-nm region—for 800-GbE applications were developed. They demonstrated uncooled 53-Gbaud PAM4 operation with a TDECQ of lower than 2.5 dB over a wide temperature from 20 to 85°C.