bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of a randomized phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small cell lung cancer who failed one or two chemotherapy regimens
Authors: Niho S. , Ichinose Y. , Tamura T. , Yamamoto N. , Tsuboi M. , Nakagawa K. , Shinkai T. , Jiang H. , Nishiwaki Y. , Fukuoka M.
Published: March 2020

LBA7509

Background: This phase III study (V-15–32) compared gefitinib vs docetaxel on overall survival (OS) in Japanese patients (pts) with pretreated advanced NSCLC. Methods: Pts with advanced or metastatic (Stage IIIb or IV) NSCLC who failed 1 or 2 chemotherapy regimens were randomized to gefitinib (250 mg/day) or docetaxel (60 mg/m2 every 3 weeks). Non-inferiority of the primary endpoint, OS, was assessed by the confidence interval (CI) of the hazard ratio (HR; gefitinib/docetaxel) derived from an unadjusted Cox proportional hazard model. Results: 489 eligible pts were recruited. Non-inferiority in OS was not achieved (HR 1.12; 95.24% CI 0.89, 1.40) according to predefined criterion (upper CI limit for HR <1.25); however, no significant difference in OS (p=0.330) or PFS (p=0.335) was apparent between treatments. Post study, 36% of gefitinib-treated pts received subsequent docetaxel and 40% received no other therapy apart from gefitinib; 53% of docetaxel-treated pts received subsequent gefitinib and 26% received no other therapy apart from docetaxel. Gefitinib significantly improved ORR (22.5% vs 12.8%; p=0.009), TTF (HR 0.63; 95% CI 0.51, 0.77; p<0.001), and QoL (FACT-L trial outcome index 20.5% vs 8.7%; p=0.002; FACT-L 23.4% vs 13.9%; p=0.023), vs docetaxel. Additional subgroup analyses will be presented. Grade 3/4 AEs occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of pts. Incidence of interstitial lung disease (ILD) was 5.7% (n=14) and 2.9% (n=7), respectively. There were 4 deaths due to AEs in the gefitinib arm (3 possibly treatment-related due to ILD; 1 due to pneumonia that was not considered treatment-related) and none in the docetaxel arm. Conclusions: Whilst non-inferiority in OS between gefitinib and docetaxel was not demonstrated according to predefined criteria, there was no statistically significant difference in survival between the two arms. Secondary endpoints largely unaffected by subsequent therapy provide further evidence of clinical efficacy of gefitinib in these pts. AEs were consistent with those previously observed for both treatments.

[Table: see text]
Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704
Authors: Manegold C. , von Pawel J. , Zatloukal P. , Ramlau R. , Gorbounova V. , Hirsch V. , Leighl N. , Mezger J. , Archer V. , Reck M.
Published: March 2020

LBA7514

Background: The ECOG 4599 phase III trial demonstrated that the addition of bevacizumab (B) to carboplatin/paclitaxel improved overall and progression-free survival (PFS) in patients (pts) with advanced NSCLC [Sandler et al. NEJM 2006]. Cisplatin/gemcitabine (CG) is a common combination in regions outside of the US. Methods: This randomised, placebo-controlled phase III study compared two doses of B plus CG versus CG plus placebo. The primary endpoint was PFS; secondary endpoints include overall survival, response rate (RR) and safety. Eligibility criteria: histologically or cytologically documented previously untreated advanced or recurrent non- squamous NSCLC; ECOG PS 0–1; no brain metastases. Between 2/05 and 8/06 1,043 pts were randomised to: C 80mg/m2 on d1 and G 1,250mg/m2 on d1 and d8 every 3 wks for up to 6 cycles plus B continued to progression at 7.5mg/kg every 3 wks, or 15mg/kg every 3 wks or placebo. The study was designed to include the number of patients required to observe a 30% reduction in the risk of a PFS event in the B arms compared with control using a two-sided logrank test (a=2.5%) with 80% power. Results: PFS was significantly prolonged as analysed both in a primary analysis (without censoring for non-protocol anti-neoplastic therapy [NPT] prior to progression) and in a prespecified analysis with censoring for NPT. The RR and response duration were also increased. Overall survival is immature due to short duration of follow up. Conclusions: Both doses of B significantly improved PFS and RR, consistent with the results of the earlier phase III trial E4599. No unexpected safety signals were detected.

[Table: see text] [Table: see text]
Ten-year results of a German Hodgkin Study Group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9)
Authors: Diehl V. , Franklin J. , Pfistner B. , Engert A.
Published: March 2020

LBA8015

Background: The HD9 trial was designed to compare standard and dose escalated versions of a novel chemotherapy BEACOPP in advanced Hodgkin lymphoma. The previous analysis in 2004 showed improved tumor control and overall survival due to dose escalation. The present 10 year analysis in March 2007 aimed to update and confirm these results and to monitor late effects. Methods: Patients aged 16–65 years with untreated Hodgkin lymphoma stage IIB/IIIA and risk factors or stage IIIB/IV were randomized to (A) 4 double cycles COPP/ABVD, (B) 8 cycles standard-dose BEACOPP or (C) 8 cycles increased-dose BEACOPP (doxorubicin, cyclophosphamide and etoposide at 140%, 192% and 200% of standard doses, respectively), each followed by irradiation of initial bulky and residual disease. Accrual of at least 900 patients was planned so as to detect a 9–10% improvement in the primary endpoint, freedom from treatment failure (FFTF), with a power of 80% (alpha=5%). Results: 1196 of 1201 eligible, randomized patients were evaluable (261, 469 and 466 in arms A, B and C, respectively). Median follow-up times were 122, 111 and 107 months in arms A, B and C respectively (29–32 months longer than in 2004). Corresponding 10-year FFTF rates were 64%, 70% and 82% respectively (p<0.0001). FFTF was significantly better in the increased-dose arm than in the standard-dose arm (p<0.0001). 10-year overall survival rates were 75%, 80% and 86% respectively (p=0.0005). Overall survival was also significantly better in the increased-dose arm than in the standard-dose arm (p=0.0053). Death due to HL was 11.5%, 8.1% and 2.8% in arms A, B and C respectively. 74 second malignancies were documented: 1, 7 and 14 acute myeloid leukemias (AML); 7, 8 and 5 non-Hodgkin lymphomas; 7, 16 and 9 solid tumors/others in arms A, B and C respectively. The corresponding overall secondary malignancy rates were 6.7% , 8.9% and 6.8%. Conclusions: Even after 10 years, dose escalation of BEACOPP chemotherapy results in a stabilized significant improvement in long-term FFTF and OS rates. The risk of secondary AML, although increased in this study after increased-dose BEACOPP, amounts to 0.9% in the succeeding study with increased BEACOPP with 1502 patients and 4 years median follow-up.

No significant financial relationships to disclose.
Pexidartinib for advanced tenosynovial giant cell tumor (TGCT): Long-term efficacy and safety from the phase 3 ENLIVEN and phase 1 PLX108-01 (TGCT cohort) studies.
Authors: Gelderblom Hans , Tap William D. , Palmerini Emanuela , Stacchiotti Silvia , Wainberg Zev A. , Desai Jayesh , Healey John H. , van de Sande Michiel , Bernthal Nicholas M. , Peterfy Charles , Shuster Dale Edward , Wang Qiang , Hsu Henry , Wagner Andrew J.
Published: March 2020

11042

Background: TGCT is a rare, locally aggressive neoplasm of the joint/tendon sheath linked to colony-stimulating factor 1 (CSF1) overexpression. Pexidartinib (pex), a selective inhibitor of CSF1 receptor, KIT, and FLT3-ITD, had a compelling tumor response rate in the TGCT cohort of a phase 1 study (NCT01004861) and significant tumor response vs placebo by RECIST v1.1 (39% vs 0%, P< 0.0001) and tumor volume score (TVS) (56% vs 0%, P< 0.0001) in the randomized, 2-part, crossover phase 3 ENLIVEN study (NCT02371369). Updated efficacy and safety with longer treatment are reported. Methods: Patients (pts) were ≥18 y with TGCT that was inoperable or for which surgery would likely be associated with worsening functional limitation or severe morbidity. Best overall response (complete or partial [CR/PR]) and duration of response (DOR) by RECIST and TVS were assessed by independent central review. Data cutoff was Jan 31, 2018, 16-67 mo after pts’ first dose. Results: In both studies 130 pts received pex, 61 ongoing at data cutoff. Median treatment duration was 17 mo (1, 60+). CR/PR rates were high and consistent and, together with DOR, improved with prolongation of treatment (Table). Most frequent adverse events were hair color change (75%), fatigue (60%), nausea (45%), arthralgia (38%), AST increase (30%), and diarrhea (30%). In ENLIVEN part 1, 3 of 61 (5%) pts had reversible ALT and AST ≥3 × ULN with TBil and ALP ≥2 × ULN; all started in the first 8 weeks of treatment, and no new cases emerged with continuation of treatment. Conclusions: Tumor response rate increased with continuation of pex treatment. The safety profile remained similar, with no new mixed or cholestatic hepatotoxicity. Clinical trial information: NCT01004861 and NCT02371369. [Table: see text]
A phase II study of epacadostat and pembrolizumab in patients with advanced sarcoma.
Authors: Kelly Ciara Marie , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Qin Li-Xuan , Adamson Travis , Condy Mercedes M. , Biniakewitz Matthew , Phelan Haley , Singer Samuel , Crago Aimee Marie , Yoon Sam S. , Ariyan Charlotte Eielson , Hwang Sinchun , Erinjeri Joseph Patrick , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: March 2020

11049

Background: Tumors express IDO1, an intracellular enzyme involved in the degradation of tryptophan to kynurenine, in order to evade immunosurveillance. Epacadostat inhibits IDO1 and shifts the tumor microenvironment from an immunosuppressive state to an immune-stimulated state. Pembrolizumab previously demonstrated activity in select sarcoma subtypes. We performed an open-label, single-center, phase II study of epacadostat and pembrolizumab in patients with advanced sarcoma. Methods: Patients received the recommended phase II dose of oral epacadostat (100mg) twice per day and intravenous pembrolizumab (200mg/dose) every 3 weeks. The primary endpoint was best objective response rate (ORR) (complete response and partial response [PR]) at 24 weeks by RECIST 1.1. Secondary endpoints included adverse events (AEs), ORR by irRECIST, progression free survival (PFS) and overall survival (OS). Correlative studies performed on pre/on-treatment biopsy specimens included PD-L1, IDO1, and kynurenine expression and characterization of tumor infiltrating lymphocytes by IHC, whole exome and RNA sequencing. Results: Twenty-nine patients were enrolled [median age 53 years (range, 24-78), 57% male, ECOG PS 0 83%]. Histological subtypes included leiomyosarcoma (17%), UPS (17%), myxofibrosarcoma (7%), liposarcoma (10.5%), EHE (10.5%), angiosarcoma (3%), “other” sarcoma subtype (35%). Patients were refractory to 0 (21%), 1 (38%), 2 (24%) and ≥ 3 (17%) prior lines of therapy. The most common ( > 20% of pts) grade (G)1 or 2 treatment related AEs (TRAEs) observed included fatigue (31%), rash (31%) and ALT elevation (24%). G3 TRAEs included AST elevation (10%), ALT elevation, anemia, hypophosphatemia and increased lipase each occurred in 3% of pts. Three patients discontinued therapy due to G3 immune mediated hepatitis. Among the 29 evaluable patients 1 (3%) confirmed PR (leiomyosarcoma), 13 stable diseases (45%) and 15 progressions (52%) were observed by RECIST 1.1. The median PFS was 8.0 weeks (two-sided 95% CI: 6.9 ~ 26.7) and the PFS rate at 24 weeks was 27.9% (two-sided 95% CI: 15.0% ~ 52.2%). The median OS was not estimable (two-sided 95% CI: 40.9 weeks ~ NE). The OS at 24 weeks was 85.2% (95% CI: 72.8%, 99.7%). Conclusions: Epacadostat in combination with pembrolizumab was generally well tolerated. Limited anti-tumor activity was observed among advanced sarcoma patients. Correlative analyses including determination of adequacy of IDO1 inhibition will be reported. Clinical trial information: NCT03414229.
Impact of cancer on physical and mental activities of daily living in young adult (YA) survivors.
Authors: Ketterl Tyler Garrett , McCabe Mary S. , Rosenstein Donald L. , Jacobs Linda A. , Palmer Steven C , Ganz Patricia A. , Casillas Jacqueline N. , Risendal Betsy C , Overholser Linda , Partridge Ann H. , Syrjala Karen L , Baker Kevin Scott
Published: March 2020

11517

Background: Young Adult (YA) survivors face challenges unique from those survivors of childhood cancer or of middle and older age adults. The potential impact of cancer, its treatment or the lasting effects on daily mental and physical tasks are not fully understood. Methods: Eligibility included diagnosis of malignancy between ages 18-39, 1-5 years from diagnosis and ≥1 year from therapy completion. Participants were randomly selected from tumor registries of 7 academic institutions. Enrolled participants were asked to complete an online patient reported outcomes (PRO) survey related to the effects of cancer and its treatment on daily functionality, finances, and cancer-related distress. All enrolled subjects had diagnostic and treatment information abstracted by a standardized protocol and entered into a database. Results: Enrollment and the online PRO survey was completed by 872 survivors (43.5% of eligible survivors). Survivors were 72.3% female, 90% non-Hispanic or Latino and the most common cancer for males and females were testicular and breast cancer respectively. Cancer, its treatment or the lasting effects limited the kind or amount of instrumental activities of daily living (IADLs) in 649 (76.3%) of survivors. Exposure to chemotherapy was associated with a 3.2-fold increased odds of interference with IADLs (CI 2.08-4.83, p < 0.01) after controlling for diagnosis, age, gender, radiation and surgery exposure. This impairment lasted longer than 1 year in 268 (41.3%) of survivors. Cancer, its treatment or the lasting effects interfered with their ability to perform any mental tasks as part of their IADLs in 454 (53.3%) of survivors. Exposure to chemotherapy was associated with a 2.8-fold increased odds of interference with mental impairment of IADLs (CI 1.94-3.96, p < 0.01) after controlling for diagnosis, age, gender, radiation and surgery exposure. Exposure to radiation was also associated with an increased odds of interference with mental impairment of daily activities (CI 1.05-1.91, p < 0.01) after controlling for diagnosis, age, gender, chemotherapy and surgery exposure. Conclusions: In YA cancer survivors, cancer, its treatment or the lasting effects of treatment commonly impact the daily physical and mental IADLs and many survivors report ongoing limitations > 1 year from therapy completion.
Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML).
Authors: Dinardo Courtney Denton , Stein Anthony Selwyn , Stein Eytan M. , Fathi Amir Tahmasb , Frankfurt Olga , Schuh Andre C. , Martinelli Giovanni , Patel Prapti Arvind , Raffoux Emmanuel , Tan Peter , Zeidan Amer Methqal , de Botton Stéphane , Kantarjian Hagop M. , Stone Richard M. , Lam Du Hung , Gong Jing , Zhang Vickie , Winkler Thomas , Wu Bin , Vyas Paresh
Published: March 2020

7011

Background: IVO, a mutant IDH1 (mIDH1) inhibitor, is approved for the treatment of relapsed/refractory mIDH1 AML. We report results from an ongoing phase 1b study of patients (pts) with mIDH1 ND AML ineligible for intensive treatment who received combination IVO+AZA (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m2 on D1–7 in 28-d cycles. ORR comprised CR + CRi/CRp + PR+ MLFS. CR with partial hematologic recovery (CRh) was defined as CR with ANC > 0.5×109/L and platelets > 50×109/L. Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of 9Oct2018, 23 pts received IVO+AZA (11 male; median age 76 yrs [range 61–88]). Median duration of exposure was 11 mo (0.3–25.3); 12 pts remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% pts were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% pts were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18): CR 57%, CRi/CRp 13%, and MLFS 9%. CR+CRh rate was 70% (n = 16). Median time to response was 1.8 mo (0.7–3.8) and to CR 3.5 mo (0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10/16 pts (63%) with CR/CRh, including 9/13 (69%) with CR. Conclusions: IVO+AZA was well tolerated with a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other non-intensive therapies. CR and ORR rates exceeded those of AZA alone (Dombret et al., Blood 2015) and most responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO +AZA (AGILE, NCT03173248) is actively enrolling pts. Clinical trial information: NCT02677922.
Results of the PI3Kδ inhibitor ME-401 alone or with rituximab in relapsed/refractory (R/R) follicular lymphoma (FL).
Authors: Zelenetz Andrew David , Jagadeesh Deepa , Reddy Nishitha M. , Stathis Anastasios , Salman Huda S. , Asch Adam Steven , Kenkre Vaishalee Padgaonkar , Jhangiani Haresh S. , Iasonos Alexia , Soumerai Jacob D. , Llorin Judith , Pagel John M.
Published: March 2020

7512

Background: ME-401, a potent and selective oral PI3kδ inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938). 70 pts were treated; we report here results in FL. Methods: Pts with ECOG ≤2, no prior PI3K therapy and progression of disease (POD) after ≥1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg) then in 60 mg expansion cohorts as monotherapy or in combination with rituximab. ME-401 was given initially on a daily continuous schedule (CS) until POD or unacceptable toxicity. An intermittent schedule (IS) on days 1-7 of a 28-day cycle was then evaluated after 2 cycles (n = 18) or ≥3 cycles (n = 9) of CS. Toxicity on CS managed by switch to IS. POD on IS managed by switch to CS. Results: 48 FL pts received ME-401 alone (n = 39) or with rituximab (n = 9). Median age 64.5 yrs. (range 38-81), median prior therapies 2 (range 1-10), 30 had ≥3 prior therapies and 25 were POD24. 28 pts remain on therapy with median follow-up of 9.3 months (range 0.5-22.5) and 20 discontinued: 9 POD, 4 adverse events (AEs), 4 withdrew consent, and 3 for stem cell transplant. Delayed (> Cycle 2) grade 3 immune related AEs (irAEs), primarily diarrhea/colitis and rash, reported in 9/30 (30%) on CS and 2/18 (11%) switched to IS after 2 cycles, with irAEs noted 15 and 18 days after switch. 4 pts with grade 3 irAEs had a drug holiday and corticosteroids then resumed ME-401 on IS without AE recurrence. Objective responses in 34/43 pts (79%) with follow-up disease assessment: 79% with ME-401 alone (including 26% morphologic/metabolic CR), 78% with ME-401 plus rituximab, 91% in POD24, and 75% in ≥3rd line therapy. 24/27 (89%) IS pts continue therapy, 20 on IS and 4 who switched to CS due to POD on IS, and 3 pts discontinued due to persistent POD after switch to CS. Conclusions: ME-401 achieves a high rate of durable responses in R/R FL. IS appears to reduce the incidence of irAEs and maintains responses. POD on IS can be salvaged by reverting to CS. A randomized study to evaluate ME-401 given by IS or CS is enrolling pts with R/R FL, with switch to IS for irAEs and switch to CS if POD on IS. Clinical trial information: NCT02914938. [Table: see text]
Randomized phase II study of adjuvant afatinib for three months versus two years in patients with resected stage I-III EGFR mutant NSCLC.
Authors: Chaft Jamie E. , Costa Daniel Botelho , Muzikansky Alona , Shrager Joseph B , Lanuti Michael , Huang James , Ramchandran Kavitha , Rangachari Deepa , Huberman Mark , Piotrowska Zofia , Kris Mark G. , Azzoli Christopher G. , Sequist Lecia V. , Neal Joel W.
Published: March 2020

8507

Background: EGFR tyrosine kinase inhibitors are superior to chemotherapy in patients with advanced EGFR+ lung cancers. In the adjuvant setting, erlotinib for two years improves recurrence free survival (RFS) compared to historical controls. The optimal duration of adjuvant TKI is unknown. Methods: Patients with completely resected Stage I-III NSCLC with a sensitizing EGFR mutation were enrolled after standard adjuvant therapy. Pts were randomly assigned to 3 months (3m) or 2 years (2y) of adjuvant afatinib. Afatinib was started at 30 mg by mouth daily. Patients without toxicity after 28 days were allowed to escalate to 40 mg daily. Patients were imaged with CT every 6 months for 3 years and then annually or as clinically indicated. RFS was measured from the date of randomization. The primary study endpoint was recurrence rate at 2 years. 60 randomized patients would provide 82.5% power to detect a 26% difference in 2y-recurrence rate. Results: Patient characteristics are in the Table. The study was terminated for slow accrual after 46 of the planned 60 patients. Planned treatment was completed by 92% (22/24) pts in the 3m arm and 41% (9/22) of pt in the 2y arm. 22 patients required ≥1 dose modification due to toxicity including expected GI, mucosal, and skin AEs. With a median follow-up of ≥38 months there were 10 recurrences and 3 deaths in the 3m arm and there were 5 recurrences (2 on treatment) and 2 deaths in the 2y arm. Median RFS has not been reached in either arm, but recurrence was more common in the 3m arm at every landmark. 2y-recurrence rates were 29% for 3m and 15% for 2y. Conclusions: Recurrences at 2 years were 14% less common with 2y versus 3m of adjuvant afatinib. This difference did not meet the primary study endpoint. The RFS curves show a durable and clinically meaningful separation with substantial follow-up. Failure to meet significance was likely influenced by under-accrual and early drug discontinuation on the 2y arm. In the era of TKIs with improved tolerance, duration of adjuvant therapy remains an important question. Clinical trial information: NCT01746251. [Table: see text]
ml-RECIST: Machine learning to estimate RECIST in patients with NSCLC treated with PD-(L)1 blockade.
Authors: Arbour Kathryn Cecilia , Anh Tuan Luu , Rizvi Hira , Yala Adam , Hellmann Matthew David , Barzilay Regina
Published: March 2020

9052

Background: Real-world evidence (RWE) is increasingly important for discovery and may be an opportunity for regulatory approval. Effective use of RWE relies on determining treatment-specific outcomes, such as overall response rate (ORR) and progression-free survival (PFS), which are challenging to accurately evaluate retrospectively and at scale. We hypothesized the use of machine learning of text radiology reports from patients with NSCLC treated with PD-1 blockade could be used to train a model that estimates RECIST-defined outcomes. Methods: 2753 imaging reports from 453 patients with advanced NSCLC treated with PD-1 blockade were collected and separated into independent training (80%, n = 362) and validation (20%, n = 92) cohorts. Reports were limited to interval of PD-1 blockade. RECIST reads performed by thoracic radiologists on all patients served as “gold standard” to determine ORR, occurrence of, and date of progression. Baseline reports were compared to all follow up reports to determine machine-learning RECIST (ml-RECIST). A four layers neural-network model for classification was proposed to solve the three above tasks. Results: In the training cohort, ml-RECIST best estimated ORR by RECIST (accuracy CR/PR 84%, SD 82%, POD 91%). ml-RECIST estimated PFS by RECIST accurately predicting progression occurred at any time (86%) and exact progression date (65%). Date of progression was closely correlated (Pearson’s r coefficient = 0.91, 95% CI:0.89-0.94, p < 0.001) in patients determined to have progressed by both methods. Similar accuracy of ml-RECIST was observed in the validation cohort (accuracy CR/PR 84%, SD 80%, POD 90%; progression occurred 86%, progression date 72%). Accuracy was consistent when RECIST reads were performed prospectively as part of clinical trials vs retrospectively for standard of care treatment (e.g. CR/PR 82% vs 88%, respectively). ml-RECIST-defined response similarly determined improvement in overall survival compared to RECIST (HR = 0.19, p < 0.001 vs HR = 0.26, p < 0.001 respectively). Conclusions: Machine learning-RECIST ("ml-RECIST") accurately estimates outcomes using imaging text reports. ml-RECIST may be tool to determine outcomes expeditiously and at scale for use in RWE studies, enabling more useful and reliable applications of large clinical databases.
Late cholecystectomy in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Dieffenbach Bryan V , Li Nan , Madenci Arin L , Barnea Dana , Murphy Andrew J , Tonorezos Emily S. , Gibson Todd M. , Liu Qi , Leisenring Wendy , Howell Rebecca M. , Diller Lisa , Armstrong Gregory T. , Yasui Yutaka , Oeffinger Kevin C. , Weldon Christopher Bertero , Weil Brent
Published: March 2020

e21525

Background: Cholecystectomy (CCY) is among the most common operations performed in the developed world and is offered as a cure for symptomatic gallbladder disease. Whether survivors of childhood cancer undergo CCY at a higher rate than the general population is unknown. Methods: We identified 5-year survivors diagnosed between 1970 and 1999 who self-reported late (> 5 years after cancer diagnosis) CCY. Rates of CCY were determined among the entire cohort and in association with various risk factors and treatment exposures. Adjusted rate ratios (ARR) were estimated with multivariable piecewise exponential models. Results: Among 24,248 survivors (median follow-up 22.3, interquartile range [IQR] 16.2-30.1 years) and 5,038 siblings (median follow-up 26.4, IQR 19.3-33.7 years), the unadjusted cumulative incidence of CCY at age 50 was 7.2% (n = 757) in survivors and 6.5% (n = 168) in siblings. After adjusting for age, sex and race/ethnicity, survivors underwent CCY at higher rates compared to siblings (ARR = 1.3, 95% CI = 1.1-1.5). Relative to siblings, acute lymphoblastic leukemia survivors underwent CCY at a higher rate (ARR = 1.6, 95% CI = 1.3-2.0), all other diagnoses were not independently associated with higher rates of CCY. Among survivors, risk factors for late CCY included female sex, increasing body mass index (BMI) class, exposure to platinum agents and total body irradiation (TBI) (Table). Conclusions: CCY is performed more commonly among childhood cancer survivors relative to siblings. In addition to known risk factors for gallbladder disease, cancer treatment exposures may further enhance risk for CCY. Awareness and education regarding this observation may ensure timely diagnosis and treatment of symptomatic disease. [Table: see text]
References for Ultrasound Staging of Breast Maturation, Tanner Breast Staging, Pubic Hair, and Menarche in Norwegian Girls
Authors: Bruserud Ingvild Særvold , Roelants Mathieu , Oehme Ninnie Helén Bakken , Madsen Andre , Eide Geir Egil , Bjerknes Robert , Rosendahl Karen , Juliusson Petur B
Published: March 2020

Context

Discriminating adipose and glandular tissue is challenging when clinically assessing breast development. Ultrasound facilitates staging of pubertal breast maturation (US B), but has not been systematically compared to Tanner breast (Tanner B) staging, and no normative data have been reported.

Objective

To present normative references for US B along with references for Tanner B, pubic hair (PH), and menarche.

Design, Setting, and Participants

A cross-sectional sample of 703 healthy girls aged 6 to 16 years were examined.

Main Outcome Measures

Breast development was determined with US B and Tanner B staging. Tanner PH and menarcheal status were recorded. The age distributions of entry in US B, Tanner B, and PH stages and menarche were estimated with generalized linear and generalized additive models with a probit link. Method agreement was tested with weighted Cohen’s kappa.

Results

The median (±2SD) ages for thelarche, US B2 and Tanner B2, were 10.2 (7.7, 12.8) and 10.4 (8.0, 12.7) years. The median (±2SD) ages at Tanner PH2 and menarche were 10.9 (8.5, 13.3) and 12.7 (11.0, 16.2) years. Cohen’s kappa of agreement (95% confidence interval) between US B and Tanner B was 0.87 (0.85–0.88). When the methods disagreed, US B was usually more advanced.

Conclusion

Thelarche occurred at a slightly younger age when assessed with ultrasound compared to clinical Tanner staging, although the 2 methods had a very good agreement when determining pubertal breast maturation. A significant decrease of 2.8 months in age at menarche was observed during the past decade in Norwegian girls.
Service Product Design and Consumer Refund Policies
Authors: Huang Xiao , Zhang Dan
Published: March 2020

This paper studies joint quality and refund policy design for service products in the presence of customer valuation uncertainty.
Frontiers: In-Consumption Social Listening with Moment-to-Moment Unstructured Data: The Case of Movie Appreciation and Live Comments
Authors: Zhang Qiang , Wang Wenbo , Chen Yuxin
Published: March 2020

This research proposes a new approach for in-consumption social listening and demonstrates its value in the context of online movie watching and live comments.
Transparency and Fairness in Organizational Decisions: An Experimental Investigation Using the Paired Ultimatum Game
Authors: Nai Jared , Kotha Reddi , Narayanan Jayanth , Puranam Phanish
Published: March 2020

Organizations often keep secret their decisions about what employees receive (e.g., salary, budgets, benefits) to manage fairness concerns. We propose that this can be counterproductive because of a mechanism we call the “escalation of deservingness under secrecy,” where the existence of peers can inflate one’s own sense of deservingness, even when the actual allocations to peers are unknown. Building on the ultimatum game, we developed a paired ultimatum game (PUG) in which a player and a peer respondent engage with the same offeror simultaneously but with no direct competition between respondents. Across three experiments—a live interaction study as well as two scenario studies—using the PUG, we analyze the conditions under which transparency may be better than secrecy in preventing the escalation of deservingness perceptions.
Patients with metabolic syndrome have a greater rate of complications after arthroplasty
Authors: Guofeng Cui , Chen Yue , Rong Wei , Ruiyu Liu , Kunzheng Wang
Published: March 2020

Aims

Patients with metabolic syndrome (MetS) are known to be at increased risk of postoperative complications, but it is unclear whether MetS is also associated with complications after total hip arthroplasty (THA) or total knee arthroplasty (TKA). Here, we perform a systematic review and meta-analysis linking MetS to postoperative complications in THA and TKA.

Methods

The PubMed, OVID, and ScienceDirect databases were comprehensively searched and studies were selected and analyzed according to the guidelines of the Meta-analysis of Observational Studies in Epidemiology (MOOSE). We assessed the methodological quality of each study using the Newcastle-Ottawa Scale (NOS), and we evaluated the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Data were extracted and meta-analyzed or qualitatively synthesized for several outcomes.

Results

Ten cohort studies involving 1,352,685 patients were included. Qualitative analysis suggested that MetS was associated with a higher incidence of cardiovascular events, and meta-analysis showed that MetS increased the risk of all-cause complications (risk ratio (RR) 1.55, 95% confidence interval (CI) 1.28 to 1.89), surgical site infection (SSI; RR 2.99, 95% CI 1.30 to 6.90), urinary tract infection (UTI; RR 2.58, 95% CI 1.03 to 6.43), and 30-day readmission (RR 1.45, 95% CI 1.33 to 1.59). There was insufficient evidence for assessing an association between MetS and venous thromboembolism events, pulmonary or gastrointestinal complications, or mortality.

Conclusion

Patients with MetS undergoing THA and TKA are at increased risk of all-cause complications, cardiovascular complications, SSI, UTI, and 30-day readmission. Surgeons should be aware of the increased risk of these complications in MetS, and presurgical protocols for these complications should give special consideration to MetS patients. Cite this article: Bone Joint Res. 2020;9(3):120–129.
Analysis of the caustics of partially coherently combined truncated Gaussian beams
Authors: Jabczynski Jan K. , Gontar Przemyslaw
Published: March 2020

A theoretical model of the caustics of partially coherently combined beams (CBCs) was derived to model CBCs in the case of truncated Gaussian beams. The model enables the analysis of different lattice structures and partial coherence effects, including incoherent beam combining. The impacts of the coherence state, geometry of the array and truncation losses were analyzed. An optimal truncation level of about 6% was found and a maximum CBC efficiency of 62% was determined for this CBC system. With an increase in the beam numbers in the lattice, the relative caustics length decreases, which is consistent with the general rules of diffraction theory.
Forward multiple scattering dominates speckle decorrelation in whole-blood flowmetry using optical coherence tomography
Authors: Ferris Natalie G. , Cannon Taylor M. , Villiger Martin , Bouma Brett E. , Uribe-Patarroyo Néstor
Published: March 2020

Quantitative blood flow measurements using optical coherence tomography (OCT) have a wide potential range of medical research and clinical applications. Flowmetry based on the temporal dynamics of the OCT signal may have the ability to measure three-dimensional flow profiles regardless of the flow direction. State-of-the-art models describing the OCT signal temporal statistics are based on dynamic light scattering (DLS), a model which is inherently limited to single scattering regimes. DLS methods continue to be applied to OCT despite the knowledge that red blood cells produce strong forward multiple scattering. Here, we postulate that forward multiple scattering is the primary mechanism causing the rate of speckle-decorrelation derived from data acquired in vivo to deviate from the rate of decorrelation determined in phantom experiments. We also postulate that multiple scattering contributions to decorrelation are only present when the sample exhibits velocity field inhomogeneities larger than the scale of a resolution volume and are thus absent in rigid bulk motion. To test these hypotheses, we performed a systematic study of the effects of forward multiple scattering on OCT signal decorrelation with phantom experiments under physiologically relevant flow conditions and relative bulk motion. Our experimental results confirm that the amount of forward multiple scattering affects the proportionality between lateral flow and decorrelation. We propose that multiply scattered light carries information from different locations in the sample and each location imprints scattering dynamics on the scattered light causing increased decorrelation rates. Our analysis confirms that the detection of forward scattered light inside the vessel lumen causes an increase in the rate of decorrelation which results in an overestimation of blood flow velocities at depths as shallow as 40 µm into whole blood for OCT systems with typical numerical apertures used in retinal imaging.
Hybrid Learning Assisted Abstraction for Service Performance Assessment Over Multi-Domain Optical Networks
Authors: Wang Rui , Chen Xi , Gao Zhengguang , Yan Shuangyi , Nejabati Reza , Simeonidou Dimitra
Published: March 2020

This paper demonstrates the field-trial validation for a novel machine learning-assisted lightpath abstraction strategy in multi-domain optical network scenarios. The proposed abstraction framework shows high accuracy for dynamic optical networks with 0.44 dB estimation error.
Real-time structured-light depth sensing based on ultra-compact, non-mechanical VCSEL beam scanner
Authors: Li Ruixiao , Taknohashi Masashi , Hu Shanting , Gu Xiaodong , Koyama Fumio
Published: March 2020

We realized real-time scanning structured-light depth sensing with accuracy of less than 270μm for distance of 35cm using ultra-compact (<0.5mm2) non-mechanical beam scanner. The peak output power can be as low as 1mW.
Experimental Demonstration of PAM-4 Transmission through Microring Silicon Photonic Clos Switch Fabric
Authors: Dai Liang Yuan , Hung Yu-Han , Cheng Qixiang , Bergman Keren
Published: March 2020

We present the first experimental demonstration of a 25 Gbps optical PAM4 signal transmission through a microring-based Clos topology under realistic operating conditions. We observe a 1.1-dBm power penalty at the bit error rate of 1.03 × 10−7.
Phase Reconstruction Scheme Using Dispersive Media in Direct Detection
Authors: Matsumoto Masayuki
Published: March 2020

A non-iterative reconstruction scheme of phase-modulated signals using dispersive media in direct detection is described. The phase retrieval is performed by solving the temporal transport-of-intensity equation. Required carrier-to-signal power ratio and allowable carrier location in frequency are numerically studied.
Superior Temperature Performance of Si-Ge Waveguide Avalanche Photodiodes at 64Gbps PAM4 Operation
Authors: Yuan Yuan , Huang Zhihong , Wang Binhao , Sorin Wayne , Liang Di , Campbell Joe C. , Beausoleil Raymond G.
Published: March 2020

We demonstrate a low voltage Si-Ge waveguide avalanche photodiode with extremely high temperature performance. It exhibits high temperature stability from 30 °C to 90 °C, and achieves excellent operation with 64 Gb/s PAM4 modulation.
Compact Tunable DBR/Ring Laser Module Integrated with Extremely-high- Δ PLC Wavelength Locker
Authors: Nishita Masayoshi , Higa Yasutaka , Matsubara Noritaka , Hasegawa Junichi , Yamaoka Kazuki , Ariga Maiko , Inaba Yusuke , Kimura Masayoshi , Wakaba Masaki , Yoshida Masahiro , Maruyama Kazuomi , Okuyama Shunsuke , Suzuki Toshihito , Ishii Hiroyuki , Mikhailov Vitaly , Sefel Richard , Kawakita Yasumasa
Published: March 2020

A compact tunable laser module integrating a newly developed DBR/Ring laser and an extremely-high- Δ PLC wavelength locker is demonstrated with narrow spectral linewidth of <100 kHz across the full C-band.
In-Phase/Quadrature Modulation by Directly Reflectivity Modulated Laser
Authors: Dong Po , Melikyan Argishti , Kim Kwangwoong , Kaneda Noriaki , Stern Brian , Baeyens Yves
Published: March 2020

We report a directly reflectivity modulated laser that generates a 50-Gbaud QPSK signal with a BER of 2.2×10−5. We believe this is the first demonstration of a coherent transmitter made from a directly driven laser.
Metro-haul Project Vertical Service Demo: Video Surveillance Real-time Low-latency Object Tracking
Authors: Dochhan Annika , Fischer Johannes K. , Lent Bodo , Autenrieth Achim , Shariati Behnam , Berenguer Pablo Wilke , Elbers Jörg-Peter
Published: March 2020

We report on the EU H2020 project METRO-HAUL use-case demonstration, including flexible allocation of storage and computing resources in different network locations and deployment of a network slice instance through a programmable multi-layer optical network.
Leveraging Photonic Flexibility in Multi-layer Resilient Networks
Authors: Oltman Jack
Published: March 2020

Planning and operation of large-scale deployments of photonic networks and working with a variety of constraints to offer a resilient photonic layer.
Demonstration of Pattern Division Multiple Access with Message Passing Algorithm in MMW-RoF Systems
Authors: Shen Shuyi , Chen You-Wei , Zhou Qi , Chang Gee-Kung
Published: March 2020

Implementing PDMA with MPA, ambiguous symbol recovery and 4-dB sensitivity improvement was achieved compared to conventional PD-NOMA-SIC. Experimental results show that PDMA enhances application flexibility by pattern variants tailored for different scenarios including grant-free uplinks.
Hybrid W-Band/Baseband Transmission for Fixed-Mobile Convergence Supported by Heterodyne Detection with Data-Carrying Local Oscillator
Authors: Shen Shuyi , Zhou Qi , Chen You-Wei , Yao Shuang , Zhang Rui , Alfadhli Yahya , Su Shang-Jen , Finkelstein Jeffrey , Chang Gee-Kung
Published: March 2020

A novel architecture with data-carrying local oscillator was proposed and demonstrated, supporting co-transmission of 35.39-Gbps W-band OFDM at 85-GHz and 10.9-Gbps OOK signals. Sensitivity penalty induced by interference as low as 0.5 dB was experimentally validated.
A Co-integrated Silicon-Based Electronic-Photonic Wideband, High-Power Signal Source
Authors: Zeinolabedinzadeh Saeed , Goley Patrick , Frounchi Milad , Rao Sunil , Bottenfield Christian G. , Ralph Stephen E. , Kaynak M. , Zimmermann Lars , Lischke Stefan , Mai Christian , Cressler John D.
Published: March 2020

A novel co-integrated electronic-photonic distributed photo-mixer-amplifier is presented that improves the bandwidth and gain of the system. An RF signal with an output power of 10 dBm across the bandwidth of 50 GHz was achieved.
Self-adaptive over-the-air RF self-interference cancellation based on signal-of-interest driven regular triangle algorithm
Authors: Zheng Lizhuo , Liu Zhiyang , Xiao Shilin , Zhang Zhiyi , Liu Qidi , Fok Mable P.
Published: March 2020

A signal-of-interest driven self-adaptive RF self-interference cancellation system has been proposed based on regular-triangle algorithm. A weak 16-QAM OFDM signal-of-interest at 18.35GHz has been successfully retrieved with small converge steps in an in-band full-duplex transmission.
Experimental Comparisons between Machine Learning and Analytical Models for QoT Estimations in WDM Systems
Authors: Fan Qirui , Lu Jianing , Zhou Gai , Zeng Derek , Guo Changjian , Lu Linyue , Li Jianqiang , Xie Chongjin , Lu Chao , Khan Faisal Nadeem , Lau Alan Pak Tao
Published: March 2020

We experimentally compare QoT estimations for WDM systems using Machine Learning(ML) and GN-based analytical models. ML estimates the side channels with better accuracy but is temporally less stable and less generalizable to different link configurations.
Fast BER Distribution and Neural Networks for Joint Monitoring of Linear and Nonlinear Noise-to-Signal Ratios
Authors: Salehiomran Ali , Jiang Zhiping
Published: March 2020

Experimentally observed long-tail fast BER (10ns–1µs) histogram (FBH) in presence of NLIN is explained through simulation. Features from FBHs are applied to train an ANN to estimate linear and nonlinear NSRs with <5% error.
Machine Learning Based Fiber Nonlinear Noise Monitoring for Subcarrier-multiplexing Systems
Authors: Liu Xiaomin , Lun Huazhi , Fu Mengfan , Yi Lilin , Hu Weisheng , Zhuge Qunbi
Published: March 2020

We propose a set of correlation features for machine learning based fiber nonlinear noise monitoring in subcarrier-multiplexing systems. Improved accuracy is demonstrated by adding correlations between subcarriers and data fusion processing across subcarriers.
The Real Time Implementation of a Simplified 2-Section Equalizer with Supernal SOP Tracking Capability
Authors: Zeng Tao , He Zhixue , Meng Liheng , Li Jie , Li Xiang , Yu Shaohua
Published: March 2020

We propose a 2-section equalizer architecture, two adaptive multi-tap 1×1 equalizer updated by proposed joint-CMA, followed by a feedforward 1-tap 2×2 MIMO. We implement it in 10G coherent transceiver and achieve 20Mrad/s SOP tracking speed.
1.6Tbps Coherent 2-Channel Transceiver Using a Monolithic Tx/Rx InP PIC and Single SiGe ASIC
Authors: Lal V. , Studenkov P. , Frost T. , Tsai H. , Behnia B. , Osenbach J. , Wolf S. , Going R. , Porto S. , Maher R. , Hodaei H. , Zhang J. , Di Giovanni C. , Hoshino K. , Vallaitis T. , Ellis B. , Yan J. , Fong K. , Sooudi E. , Kuntz M. , Buggaveeti S. , Pavinski D. , Sanders S. , Wang Z. , Hoefler G. , Evans P. , Corzine S. , Butrie T. , Ziari M. , Kish F. , Welch D.
Published: March 2020

We present a 1.6Tbps coherent transceiver delivering 800Gbps/wave transmission using integrated Tx/Rx functions with 50GHz bandwidth and 50kHz linewidth tunable lasers on a single 2-channel InP PIC, paired with a SiGe Driver and TIA ASIC.
Chip-Scale, Optical-Frequency-Stabilized PLL for DSP-Free, Low-Power Coherent QAM in the DCI
Authors: Brodnik Grant M. , Harrington Mark W. , Bose Debapam , Netherton Andrew M. , Zhang Wei , Stern Liron , Morton Paul. A. , Bowers John E. , Papp Scott B. , Blumenthal Daniel J.
Published: March 2020

We demonstrate a DSP-free 16-QAM/50GBd link based on independent transmit and LO frequency-stabilized ultra-narrow-linewidth SBS lasers, with ~40Hz integral linewidths and 7x10-14 fractional frequency stability. The low-BW optical-frequency-stabilized-PLL with 3×10-4 rad2 phase error operates within 1% of DSP and self-homodyne.
Nonlinear Impairment Scaling in Multi Mode Fibers for Mode Division Multiplexing
Authors: Krummrich Peter M. , Brehler Marius , Rademacher Georg , Petermann Klaus
Published: March 2020

The scaling of nonlinear effects in multi mode transmission fibers with mode count has been investigated. Results indicate that transmission reaches comparable to standard single mode fibers are achievable for at least 100 modes.
Large-optical-aperture Top-illuminated 50-Gbaud PIN-PD with High 3-dB Bandwidth at a Low Bias of 1.5 V
Authors: Toyonaka Takashi , Hamada Hiroshi , Tanaka Shigehisa , Arasawa Masatoshi , Washino Ryu , Sakuma Yasushi , Naoe Kazuhiko
Published: March 2020

High 3-dB bandwidth of 28 GHz at 1.5 V was demonstrated by introducing a capacitance-control layer into a high-responsivity top-illuminated PIN-PD with large optical-aperture diameter of 20 µm for 50-Gbaud operation.
Recent Progress on Wavelength Selective Switch
Authors: Ma Yiran , Clarke Ian , Stewart Luke
Published: March 2020

WSS application scenarios have been illustrated from network core to edge. WSS in core network is focused on higher port count and outstanding performance, while cost is the key factor for WSS in edge network.
SDM Power-Efficient Ultra High-Capacity Submarine Long Haul Transmission Systems (Tutorial)
Authors: Pilipetskii Alexei , Bolshtyansky Maxim , Foursa Dmitri , Sinkin Oleg
Published: March 2020

Submarine long-haul systems have a unique set of challenges to address the capacity demand. The tutorial will examine the need for power efficiency, SDM solutions for capacity and greater economy, and ways to move forward.
20.09-Gbit/s Underwater WDM-VLC Transmission based on a single Si/GaAs-substrate Multichromatic LED array chip
Authors: Hu Fangchen , Li Guoqiang , Zou Peng , Hu Jian , Chen Shouqing , Liu Qingquan , Zhang Jianli , Jiang Fengyi , Wang Shaowei , Chi Nan
Published: March 2020

We demonstrated a record-breaking 20.09-Gbit/s WDM-VLC transmission over 1.2 m underwater link with PS-bitloading-DMT modulation. A silicon-substrate multichromatic LED array chip and a feasible optical-filter scheme are proposed for future LED-based WDM-VLC system.
Transmission of 36-Gbaud PAM-8 Signal in IM/DD System Using Pairwise-Distributed Probabilistic Amplitude Shaping
Authors: Kim Daeho , He Zonglong , Bo Tianwai , Yu Yukui , Kim Hoon
Published: March 2020

We experimentally demonstrate the transmission of 36-Gbaud probabilistically-shaped PAM-8 signal over 10-km link. The performance measured after FEC decoding and inverse distribution matcher shows that the receiver sensitivity is improved by >1 dB compared to uniform-distributed signals.