tbuckley/cabot-search huggingface dataset:
Total marrow irradiation (TMI) combined with treosulfan and fludarabine conditioning regimen for chemosensitive advanced multiple myeloma (MM) patients undergoing matched allogeneic stem-cell transplantation: First results of a phase I/II prospective monocentric study (TrRaMM TMI).
Authors: Andrea A. Assanelli, Francesca Lorentino, Magda Marcatti, Anna Chiara, Maria Teresa Lupo Stanghellini, Fabio Giglio, Daniela Clerici, Raffaella Greco, Sara Broggi, Mauro Cattaneo, Jacopo Peccatori, Andres J. Ferreri, Fabio Ciceri, Nadia Di Muzio
Journal: Journal of Clinical Oncology (2018)

e19019 Background: Recent data support the use of Helical Tomotherapy to deliver radiation to target tissues, such as bone marrow, sparing vital organs in an effort to reduce toxicities. We report the results of feasibility and efficacy of a myeloablative Treosulfan-based conditioning combined with dose-escalating TMI in pts affected by chemosensitive advanced MM (TrRaMM-TMI Eudract 2013-002479-16). Methods: Eleven pts (7 females and 4 males, median age 59 yrs) affected by advanced MM were treated from Dec 2012 to Jul 2017. Most had received Bortezomib and IMIDs and all relapsed after autologous SCT; active disease was present in 30%. Median HCT-comorbidity index was 2. All received myeloablative conditioning (Treosulfan 14 g/mq d -6 to -4; Fludarabine 30 mg/mq d -6 to-2) combined with TMI (8 to 14 Gy) using Helical Tomotherapy. Each pt had a personalized immobilization device and a mega-voltage CT scan assured the correct set-up. 4 pilot cases received 8 Gy, while the others received as scheduled: 3 10 Gy, 3 12 Gy, 1 14 Gy. PBSC was the stem cell source: 4 MRD and 7 MUD (10/10 match in 6 and 9/10 in 1). A median 5x10e6 Cd34+/kg and 317x10e6 Cd3+/Kg were infused. GVHD prophylaxis consisted of Sirolimus and MMF; ATG d -4 to -2 and Rituximab d -1 were added in all MUDs and one MRD. Results: All pts received the planned TMI dose and achieved engraftment with no secondary graft failure. There was no grade 4 extra-hematological toxicity in the first 30 days. Five deaths have occurred, 2 due to TRM, 3 due to progressive disease. With a median follow-up time of 39 months, 3-yr PFS was 38% and 3-yr OS 48%. Day +100 incidence of grade II-IV aGVHD was 36%; grade III-IV 9%; 1-year incidence of cGVHD was 39%. 3-year relapse incidence was 39%. Conclusions: From our preliminary data, the addition of TMI to Treosulfan-based chemotherapy has not demonstrated an excess of short-term toxicities, confirming its safety and feasibility. Moreover efficacy outcomes and an acceptable TRM suggest that TMI is promising in the context of MM even with advanced and heavily pretreated disease. Clinical trial information: TrRaMM-TMI Eudract 2013-002479-16.
Phase I study of recombinant human interleukin-18 (IL-18) in combination with ofatumumab after autologous peripheral blood stem cell transplantation (PBSCT) for lymphoma.
Authors: Michael J. Robertson, Lijun Ni, Jill Weisenbach, David Pelloso, Nagendra K. Prasad
Journal: Journal of Clinical Oncology (2016)

e19066 Background: IL-18 is an immunostimulatory cytokine that is well-tolerated in combination with the CD20 mAb rituximab. Ofatumumab is a CD20 mAb that is more potent than rituximab in preclinical models. Methods: The safety and biological activity of IL-18 in combination with ofatumumab after PBSCT for lymphoma were assessed. Patients with CD20+ non-Hodgkin lymphoma (NHL) were given ofatumumab 1000 mg IV weekly for 4 consecutive weeks in combination with IL-18 IV weekly for 8 weeks. Results: 9 patients were enrolled on study at a median of 133 days after PBSCT, including 7 patients with relapsed (5) or primary refractory (2) diffuse large B cell lymphoma (DLBCL), 1 patient with indolent follicular NHL with transformation to aggressive lymphoma (relapsed), and 1 patient with mantle cell lymphoma (MCL) in first response. 3 patients each were enrolled in the 3, 10, and 30 mcg/kg dose cohorts, respectively. The combination of IL-18 and ofatumumab was well-tolerated with a safety profile similar to that observed with IL-18 plus rituximab given for NHL. No dose-limiting toxicity has been seen. Absolute natural killer (NK) cell counts transiently decreased by a median of 95% (range, 89%-99%) after the first infusion of IL-18. Activated T and NK cells were detected by flow cytometry in most patients after IL-18 infusions. Plasma interferon-gamma levels are being measured. Based on prospectively defined biomarker criteria, the optimal biologic dose of IL-18 was determined to be 10-30 mcg/kg and escalation to a 100 mcg/kg dose of IL-18 will not be pursued. The patient with MCL was taken off study for disease progression after receiving 6 doses (at 1 mcg/kg) of IL-18. One patient with DLBCL is on active treatment with IL-18 (30 mcg/kg). At a median follow-up of 19.3+ months post-PBSCT (range, 6.9+ to 31.4+ months), the 7 patients with aggressive NHL (5 DLBCL, 1 transformed lymphoma) who completed study drug treatment are alive and free of disease progression. Conclusions: The combination of IL-18 and ofatumumab is safe, well-tolerated, and induces expected biological activity after PBSCT. Further studies of IL-18 plus CD20 mAb in patients with B cell NHL are warranted. Clinical trial information: NCT01768338.
Safety and efficacy of combining pembrolizmumab and dose escalation/fraction de-escalation SRS for melanoma and NSCLC brain metastasis: Preliminary results from arm a of a prospective pilot trial.
Authors: Mohammad Khurram Khan, Tahseen Nasti, Lily Masoumy, Alice O. Kamphorst, Melinda I Yushak, Taofeek Kunle Owonikoko, Ragini Reiney Kudchadkar, Suresh S. Ramalingam, David H. Lawson, Rafi Ahmed
Journal: Journal of Clinical Oncology (2018)

e21542 Background: Brain metastases occur in 15–40% of patients (pts) with systemic cancers, such as lung and melanoma. The standard of care for brain metastases is radiation therapy. Methods to minimize radiation toxicity, and improve efficacy include conformal, focused single fraction stereotactic radiation surgery (SRS), and hypofractionation (2-5 fractions) for larger lesions and for lesions located near critical areas. Methods: We evaluated the safety, efficacy, and tolerability of concurrent stereotactic radiosurgery (SRS) with pembrolizumab for brain metastasis (MBM); safety was assessed based on CTCAE toxicity criteria. Clinical response to anti PD-1 therapy was classified according to RECIST 1.1. We characterized the effect of radiation fractionation (Arm A: 6 Gy x 5) on response rates, tumor control rates within the brain as well as outside the brain, and overall survival rates in six patients. The tumor burden in brain was assessed by MRIs before and after treatments, while systemic burden was evaluated by serial CT scans. We also evaluated the immunological response in these patients using PBMCs at different time points during treatment. Results: Six patients have been enrolled; median age- 65y, 4 males and 2 females, primary tumor type` melanoma (4 pts), and Non-small cell lung cancer (NSCLC) (2 pt). A dose of 200 mg IV every 3 weeks of pembrolizumab was administered. No significant increases in baseline toxicity were noted when pembrolizumab was combined with pembrolizumab. Additionally, no increases in baseline radiation necrosis was noted within the radiated lesions. One patient experienced treatment related grade 2 dizziness. Out of 6 patients, one patient showed complete response to therapy and 2 had partial responses. Combination therapy induced immunological responses in 4 patients (66.6%) assessed by increases in PD1+Ki67+ CD8+ T cells in peripheral blood. Conclusions: Our preliminary data suggest that using fractionated radiation dose with pembrolizmumab is well tolerated, and induces immunological responses in patients with brain metastasis. Clinical trial information: NCT02858869.
TCT-392 A First-in-Man Study of the Bioheart Sirolimus-Eluting Bioresorbable Scaffold in Patients with Coronary Artery Disease: One-Year Clinical and Imaging Outcomes
Authors: Changdong Guan, Lijian Gao, Zhongwei Sun, Shubin Qiao, Haibo Liu, Fenghuan Hu, Yongjian Wu, Bo Xu
Journal: Journal of the American College of Cardiology (2018)
Reader disagreement index (RDI) as an indicator of reader performance.
Authors: Manish Sharma, Anitha Singareddy, Michael O'Connor, A. Kassel Fotinos-Hoyer, Sayali Karve, Nicholas Enus, Daniel Clark
Journal: Journal of Clinical Oncology (2018)

e18592 Background: Blinded independent central review utilizing double read with adjudication is a preferred model by regulatory authorities to minimize reader bias in clinical trials. Monitoring of reader performance is critical to trial outcome. Adjudication rate, percent cases triggering adjudication, is commonly used for monitoring read quality. However, this does not consider how often the adjudicator agreed with a given reader (adjudicator agreement rate) or when no adjudication is required. We propose an innovative RDI to more accurately monitor reader quality. Methods: A retrospective review of adjudication data was performed for 20 clinical trials with a total of 7163 subjects (32,536 visits) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or 1.1. The adjudication rate, adjudication agreement rate and RDI were generated per reader per study. RDI for each reader was calculated as below, with high RDI indicating high % disagreement overall: RDI = (# cases where adjudicator disagreed with given reader ÷ Total # of all cases read) × 100 Each RDI was used to identify the discordant reader (ie, reader with the highest level of cases disagreed by the adjudicator). Results: RDI identified the discordant reader in all 20 studies, whereas adjudication rate and adjudication agreement rate identified the discordant reader in 13 and 12 of the 20 studies, respectively. In 3 studies, the reader with highest % adjudicator disagreement had neither the highest adjudication rate nor lowest adjudicator agreement rate. This reader could have been missed without the RDI. Conclusions: Though adjudication and adjudicator agreement rates are widely used to assess reader quality, these rates, individually, do not give full insight into reader performance. A high adjudication rate may not always mean poor reader performance if associated with high adjudicator agreement. Similarly a low adjudicator agreement rate may not always mean poor reader performance if associated with low adjudication rate. RDI proves to be a composite quality indicator by effectively combining adjudication and adjudication agreement rates in identifying potential outliers, and can serve as an excellent tool for identifying the discordant reader for timely intervention.
Phase 1 multicenter trial of CUDC-907 in children and young adults with relapsed or refractory solid tumors, CNS tumors, and lymphoma.
Authors: David Stephen Shulman, Clay Gustafson, Kieuhoa Tran Vo, Elizabeth Fox, Jodi Ann Muscal, Jeffrey G. Supko, Andrew E. Place, Susan N. Chi, Suzanne Shusterman, Gina Hanna, Jane O'Brien, Suzanne Ezrre, Cecilia Carlowicz, Wendy B. London, Steven G. DuBois
Journal: Journal of Clinical Oncology (2017)

TPS10576 Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.
Clinical characteristics and prognosis of nasopharyngeal carcinoma patients: A report of 479 cases.
Authors: Jingjing Zhang, Min Ying Li, Hong Chen
Journal: Journal of Clinical Oncology (2018)

e18082 Background: Nasopharyngeal carcinoma (NPC) is also known as Guangdong cancer. Zhong Shan City has the highest incidence of NPC in Guangdong Province of China. This study was to explore clinical characteristics and prognoses of NPC patients. Methods: Clinical data of 479 NPC patients confirmed by pathology, received radical treatment as a first-line treatment and hospitalized in the cancer center of Zhongshan City’s People’s Hospital from Jan. 1, 2011 to March 31th, 2014, were analyzed. Of the 479 patients, 364 were men and 115 were women. 356 patients received concurrent chemoradiotherapy; 434 patients received neoadjuvant chemotherapy. The survival rate was calculated by Kaplan-Meier method, and compared by log-rank test. Prognosis was analyzed by Cox regression model. Results: With a median follow-up of 60 months, the 3- and 5-year local-regional progression-free survival rate, distant metastases-free survival rate and overall survival rate of all the NPC patients were 92.9%, 92.1%, 97.3% and 87.5%, 81.5% , 89.8%, respectively. Clinical stage, T stage, N stage, cranial nerve invasion, radiation dose on the nasopharynx and interval time were significant prognostic factors of survival (P = 0.035), whereas only clinical stage was independent prognostic factor (P = 0.007). No concurrent chemotherapy was the adverse independent prognosis factor of nasopharyngeal recurrence after treatment (P = 0.003). Conclusions: UICC 8th staging and 2017 Chinese staging can predict prognosis of NPC patients properly. Radiotherapy is an effective way to cure NPC patients, while the protocol with concurrent chemotherapy may be effective for the prevention of recurrence.
Evaluation of tolerability and reactions of immune checkpoint inhibitors.
Authors: Ozlem Nuray Sever, Ozlem Sonmez, Osman Gokhan Demir
Journal: Journal of Clinical Oncology (2017)

e14605 Background: Immunotherapies have revolutionized the treatment of cancer, especially in recent years. Today, there are anti-CTLA-4 antibodies and PD-L1 monoclonal antibodies which are active in use as checkpoint inhibitors. Side effects of these agents have a different spectrum in the form of immuno-related side effects. Methods: In this study, we aimed to evaluate the side effect and tolerability in patients treated with immune checkpoint inhibitors in our clinic. Results: 32 patients who were treated with PD-L1 monoclonal antibodies between August 2015 and January 2017 were screened retrospectively in our clinic. Six of the cases had immuno-related side effects (18.75%). 2 patients had a elevated liver function test. Both patients were diagnosed with NSCLC. In both of them, elevation was detected in the second course of nivolumab treatment, and the USG and hepatitis markers of the patients were normal. Enzymes returned to normal after treatment interruption. In a patient diagnosed with malignant melanoma that receiving pembrolizumab colitis was developed after 3th cycles of the therapy. The treatment of the patient who recovered after steroid administration and treatment interruption continued until the 8th cure. In the third cure of the patient with NSCLC, when nivolumab was used pneumonitis was diagnosed. Steroid treatment was applied for 2 weeks. Our patient continued to use nivolumab for up to 22 cycles. In our patient with malign melanoma that treated with pembrolizumab autoimmune thyroiditis developed. We started prednisolone treatment. After recovery our patient's treatment continued. In one of our patient who was diagnosed with malign melanoma, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. Control ejection fractions normalized. Conclusions: İmmuno-related side effects were regarded as manageable side effects and no treatment change was needed. Immune Checkpoint inhibitors, which have been shown to be useful for survival every day, are proceeding to take a favorable position in the treatment of cancer with ease of use and lack of side effects.
Prognostic impact of PD-L1 expression in correlation with HLA class I expression status in stage I adenocarcinoma of the lung.
Authors: Kazue Yoneda, Ayako Hirai, Shohei Shimajiri, Takeshi Hanagiri, Fumihiro Tanaka
Journal: Journal of Clinical Oncology (2017)

8548 Background: Programmed death-ligand 1 (PD-L1) and human leukocyte antigen (HLA) class-I, expressed on tumor cells (TCs), are important regulators in cancer immunity. The current study was conducted to assess prognostic impact of PD-L1 status in correlation with HLA class-I status in lung adenocarcinoma. Methods: A total of 94 patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. PD-L1 expression on TCs was evaluated with immunohistochemistry, in correlation with several clinicopathological and molecular features including HLA class-I expression on tumor TCs. Results: Seventeen patients (18.1%) had tumor with positive PD-L1 expression (percentage of TCs expressing PD-L1, ≥ 5%), and the incidence was higher in smokers with higher smoking index and in poorly differentiated tumor. There was no significant correlation between HLA class-I expression and PD-L1 expression. PD-L1-positivity was a significant factor to predict a poor survival (5-year survival rate, 66.7% versus 85.9%; P = 0.048), which was enhanced in tumor with normal HLA class-I expression (p = 0.029) but disappeared in tumor with reduced HLA class-I expression. Conclusions: The prognostic impact of PD-L1 expression on TCs in early-stage resectable lung adenocarcinoma was distinct according to HLA class-I expression on TCs.
Novel ex vivo patient-derived 3D model as a powerful tool to apply precision medicine.
Authors: Kayla Simeone, Robin Guay-Lord, Muhammad Abdul Lateef, Benjamin Péant, Euridice Carmona, Jennifer Kendall-Dupont, Adriana Mari Orimoto, Thomas Gervais, Anne-Marie Mes-Masson, Fred Saad
Journal: Journal of Clinical Oncology (2018)

12086 Background: Among the several therapeutic options available to treat Castrate-Resistant Prostate Cancer (CRPC), choosing the most suitable option for an individual patient remains a clinical challenge. For this, our group has developed a novel ex-vivo model based on patient-derived micro-dissected tissues (MDT) cultivated in microfluidic devices to determine patient sensitivity profile in the presence of therapeutic agents. Methods: MDTs (~400 µm in diameter) derived from PC cell line xenografts (DU145 and LnCaP) were exposed to docetaxel (10 nM for 12 hours) or enzalutamide (10 µM for 24 hours) and analyzed after a 12-hour recovery period or immediately after exposure time. Cell fate was measured using flow cytometry techniques (Annexin V for apoptotic cells and DRAQ7 for dead cells) and by a technique based on formalin fixed paraffin embedding of MDTs within a microfluidic device creating a high-density MDT-Array (MDTA). Using MDTA we can monitor MDT viability (cleaved caspase-3), proliferation (Ki-67) and epithelial composition (CK 8/18) by immunohistochemistry (IHC) and immunofluorescence (IF). MDTs were also separately treated with TNF-α at a concentration of 10 ng/mL for 30 minutes and analyzed by MDTA. Results: We show that the microfluidic device does not affect the viability ( > 85% by flow cytometry) or proliferative capacity (60% by IHC) of the MDTs during a culture period of 15 days in PC cell line xenograft models (N = 3 for LNCaP, N = 2 for DU145). Pharmacological responses to docetaxel showed 50% increase in caspase-3 activity by IF and 20% increase in cell death by flow cytometry compared to control MDTs. Enzalutamide response was dependent on the cells 2D hormone sensitivity profile. The nuclear translocation of p65 was also monitored in 80% of MDTs treated with TNF-α. Conclusions: Within less than 5 days, we can obtain treatment response analysis using our ex vivo drug response model, appropriate for clinical decision-making, The precise techniques developed within our lab, allows the characterization of molecular responses of cancerous cells in the presence of various therapeutic agents while conserving the natural tumor microenvironment.
Combination of biomarker and clinicopathologic characters to circle out beneficiaries through second-line immunotherapy: A meta analyse.
Authors: C Zhang, Wenzhao Zhong, Zhong yi Dong, Yi-Long Wu
Journal: Journal of Clinical Oncology (2017)

e14535 Background: Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of non-small cell lung cancer (NSCLC). Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown. Methods: We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1. Results: Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR = 0.64, 95%CI = 0.56-0.73, P &lt; 0.00001) and PD-L1 negative (HR = 0.88, 95%CI = 0.78-1.00, P = 0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR = 0.70, 95%CI = 0.63-0.79, P &lt; 0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR = 0.67, 95%CI = 0.60-0.76, P &lt; 0.00001). Both KRAS mutation (HR = 0.60, 95%CI = 0.39-0.92, P = 0.02) and wild type/unknown (HR = 0.81, 95%CI = 0.67-0.97, P = 0.02) were apt to anti PD-1/L1. Conclusions: Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.
MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation
Authors: Sandra R. Bacman, Johanna H. K. Kauppila, Claudia V. Pereira, Nadee Nissanka, Maria Miranda, Milena Pinto, Sion L. Williams, Nils-Göran Larsson, James B. Stewart, Carlos T. Moraes
Journal: Nature Medicine (2018)