tbuckley/cabot-search huggingface dataset:
Autophagy and Apoptosis Cross Talk: Cross Talk Between Autophagy and Apoptosis Contributes to ZnO Nanoparticle‐Induced Human Osteosarcoma Cell Death (Adv. Healthcare Mater. 17/2018)
Authors: Guanping He, Yunlong Ma, Ye Zhu, Lei Yong, Xiao Liu, Peng Wang, Chen Liang, Chenlong Yang, Zhigang Zhao, Bao Hai, Xiaoyu Pan, Zhongjun Liu, Xiaoguang Liu, Chuanbin Mao
Journal: Advanced Healthcare Materials (2018)

In article 1800332 by Xiaoguang Liu, Chuanbin Mao, and co-workers, ZnO nanoparticles can induce interrelated apoptosis and autophagy to destroy cancer cells. These findings provide a mechanistic understanding of the NP-directed autophagy and apoptosis in osteosarcoma cells.
Breast cancer specific survival in patients with node-positive hormone receptor positive invasive breast cancer and Oncotype DX recurrence score results in the SEER database.
Authors: Megan Roberts, Valentina I. Petkov, Dave P. Miller, Steven Shak, Nadia Howlader, Kathleen Cronin, Lynne Penberthy
Journal: Journal of Clinical Oncology (2016)

6575 Background: The 21-tumor gene expression assay has been shown to predict breast cancer recurrence and adjuvant chemotherapy benefit in lymph node positive (LN+), hormone receptor positive (HR+), HER2- breast cancer (BC). We assessed 5-year breast cancer specific survival (BCSS) in LN+ patients with Oncotype DX Recurrence Score (RS) in SEER data. Methods: SEER breast cancer cases (diagnosed 2004-2012) were linked to Oncotype DX tests performed by the Genomic Health Clinical Laboratory during 2004-2013. The analysis was restricted to single primary invasive BC, LN+, no distant metastases, HR+ (per SEER), HER2- (per RT-PCR). BCSS was assessed by Oncotype DX RS category and by the number of positive lymph nodes using the actuarial method in SEER*Stat. Results: The proportion of women with LN+, HR+ BC who had a Recurrence Score (n = 7695) , increased between 2004 (0.3%, n = 33) and 2012 (13.8%, n = 2010), and decreased as lymph node involvement increased from micrometastases only (36.0%, n = 792) to 4+ lymph nodes (2.6%, n = 81) in 2012. 5-year BCSS outcomes for those with RS < 18 ranged from 99.4% (95%CI = 97.4-99.9) in those with micrometastases to 85.7% (95%CI = 33.4-97.9) among those with 4+ lymph nodes. Similar patterns were found for those with RS = 18-30 and RS ≥ 31 (see Table). Conclusions: Overall, 5-year survival is excellent in patients with RS < 18 and fewer positive lymph nodes and worsens as the number of involved lymph nodes increases. Further analyses that account for treatment are warranted. Annual updates will be important to better characterize utilization of Oncotype DX and survival outcomes. # of Positive Lymph Nodes RS < 18 RS 18-30 RS ≥ 31 BCSS (95% CI)N BCSS (95% CI)N BCSS (95% CI)N Micro-metastasis only 99.4 (97.4-99.9) 1207 99.3 (98.2-99.7) 732 84.2 (69.2-92.2) 135 1 99.2 (97.2-99.8) 1084 96.3 (91.8-98.4) 675 91.3 (79.5-96.4) 135 2 97.9 (92.7-99.4) 300 96.0 (84.6-99.0) 192 73.2 (20.4-94.1) 36 3 94.7 (77.4-98.9) 103 94.0 (75.9-98.6) 70 85.4 (51.6-96.3) 22 4+ 85.7 (33.4-97.9) 82 79.5 (58.0-90.8) 93 75.1 (39.2-91.6) 31
A new concept to target the proteasome: disrupting protein-protein interactions in the proteasome super-assembly as a way to stop the growth of cancer cells.
Authors: Maria E Gaczynska, Pawel A. Osmulski, Karolina Wlodyga, Tim Huang
Journal: Journal of Clinical Oncology (2016)

e14113 Background: The ubiquitin-proteasome pathway is responsible for the most of regulated intracellular protein degradation in human cells. The proteasome, a major protease of the pathway, is a recognized anti-cancer drug target. Proteasome inhibitors such as bortezomib and carfilzomib revolutionized the treatment of aggressive blood cancers, most notably refractory/relapsed multiple myeloma and lymphomas. Despite the successes many cancers are refractory to the treatment or develop resistance, and solid cancers are generally poor responders. All proteasome inhibitors currently used in clinics share the competitive mechanism: they block active sites and stop enzymatic actions. Here we present a drug lead with a novel molecular mechanism, potentially bypassing limitations of the available drugs. Methods: We rationally designed a small compound B1 and tested its potency in vitro and in cultured cells, alone or in combination with bortezomib. We tested toxicity of the drug lead and its pharmacokinetics/pharmacodynamics in mice. Results: Proteasome is a multifunctional protease with a common catalytic core able to assume distinct functions upon attachment of several modules. B1 disrupts the protein-protein interactions essential for functionality of the 26S proteasome, the most common proteasome super-assembly. These actions, apparent in vitro and in cellulo, leave part of the proteasome-dependent degradation intact, allowing better selectivity toward proteasome-addicted cancers. Moreover, the compound presents uncompetitive/ noncompetitive mode of action, a rare but very effective mechanism of targeting enzymatic activities. Indeed, B1 in nanomolar concentrations stops proliferation of a variety of cultured cancer cells while not affecting non-cancerous cells. Addiitionally, B1 synergizes with bortezomib in cellulo. Preliminary tests revealed no detectable toxicity and a favorable PD/PK in mice. Conclusions: The new molecular mechanism of the drug lead promises to extend the use of the proteasome as a drug target. B1 based compounds may work alone or in combination, to eliminate cancerous cells resistant to competitive proteasome inhibitors.
Changes in ovarian hormonal status in cervical cancer patients under the influence of combined HPV/chlamydia trachomatis infection.
Authors: Valeria Bandovkina, Elena Mikhaylovna Frantsiyants, Nailya Guskova, Tatiana Moiseenko, Marina Vovkochina, Natalia D. Cheryarina, Yulia A. Pogorelova, Elena I. Agarkova, Marina I. Vereskunova, Ekaterina Guskova, Kristina Avanesova, Irina V. Tselishcheva, Svetlana V. Abakumova, Nadezhda Golomeeva, Viktoria Zakharchenko, Svetlana V. Belgova, Anastasia Nozdricheva, Ekaterina Gornostaeva
Journal: Journal of Clinical Oncology (2017)

e17019 Background: The purpose of the study was to analyze hormonal disorders in tissues of histologically unchanged ovaries of patients with cervical cancer infected with HPV/Chlamydia trachomatis. Methods: We studied levels of estrone (E1), estradiol (E2), free estriol (E3), free (fT) and total (T) testosterone, progesterone (P4), steroid-binding globulin (SBG) and prolactin (PRL) by the ELISA in intact ovaries of 25 patients aged 53.4±3.2 years with cervical cancer T1b-2aN0M0. HPV presence was determined by Е7 protein expression, Chlamydia trachomatis (Ch. tr.) – by IgG and IgА to Ch. tr. and antigen/DNA by ELISA and Real-time PCR. Tissues of intact ovaries obtained during hysterectomy from 22 non-infected women of similar age with endometrial cancer T1N0M0 were used as the control. Results: The data demonstrated a sharp decrease in E2 level by 9.3 times and increase in E1 by 2.3 times in intact ovaries of cervical cancer patients infected with HPV and Ch. tr., compared with the values in controls. Changes were noted in the balance between some estrogen fractions: E1 percentage increased by 5 times, E3 – by 2.4 times and E2 percentage decreased by 4 times. Androgenic status in intact ovaries in cervical cancer was characterized with increased levels of T (by 5.1 times) and fT (by 1.6 times). We noted an increase in SBG concentration by more than 3 times in response to the release of androgens registered in ovarian tissue, as well as significant (by 4.4 times) increase in PRL and decrease in P4 by 1.5 times compared with non-infected tissues. Estrogens to P4 ratio in co-infected patients reduced by 1.6 times, while the PRL to P4 ratio increased by 6.4 times, mainly due to disorders in hormone-producing ovarian function. Conclusions: The development of malignant process in the cervix in a combined HPV and Chlamydia trachomatis infection is accompanied by disorders of the endocrine status in tissues of intact ovaries and shows the undeniable role of consequences of HPV/Chlamydia trachomatis coinfection in this process.
P01.096 Hypofractionated radiotherapy and temozolomide in patients with glioblastoma and poor prognostic factors other than age - is it worth it?
Authors: P A Jablonska, M Gimeno, A García-Consuegra, L Arbea, M Moreno, D Azcona, B Barbés, L Ramos, J M Aramendía, A Gúrpide, J Guridi, R Díez Valle, A Tomás-Biosca, P Domínguez, J Arbizu, M A Idoate, J J Aristu
Journal: Neuro-Oncology (2018)

The impact of hypofractionated radiation therapy (HFRT) in elderly glioblastoma patients has recently been investigated, aiming to reduce the overall treatment time in this poor-prognosis group. There is evidence supporting that HFRT is comparable to conventional radiotherapy in terms of outcome and safety. The purpose of our study was to determine whether HFRT was satisfying in regard to disease control and feasibility in primary glioblastoma patients with other poor prognostic factors, such as high tumor burden, unresectability and/or low KPS. Inclusion criteria were defined based on tumor and surgery-related characteristics, KPS/RPA score, patient’s comorbidities, rapidly progressive disease and social or family factors that could influence the treatment adherence. Patients with KPS lower than 50% and brain stem tumors were excluded. Radiation treatment planning involved image fusion with brain CT-scan, MRI and 11C-Methionine PET. GTV included the surgical cavity plus macroscopic disease visible in T1WI MRI, Flair-MRI and the PET MET-uptake. Fourty grays were prescribed to 95% of PTV, in 15 fractions. Treatment was delivered using IMRT or VMAT techniques. Simultaneously, 75mg/m2/day of temozolomide were administered. Between January 2010 and November 2017, 17 patients were enrolled. MGMT-methylation status was negative in 5 patients and 8 tumors were IDH wild type. The median KPS at diagnosis was 70%, with a median age of 68-years. Median tumor volume was 26,95cc with a median PTV volume of 321,75cc. Biopsy was performed in 4 patients and 5 lesions underwent a subtotal resection. With a median follow up of 52 months, median OS was 7 months and the PFS was 60% at 6 months, 33% at 1-year and 13% at 2-years. Acute grade 2 toxicity was documented in 2 patients. One patient presented a symptomatic radionecrosis five months after the radiation therapy. Patients with poor clinical factors other than advanced age could be selected for HFRT and temozolomide. The OS and PFS rates observed in our series are similar to the results obtained in patients treated with standard fractionation. HFRT is an option that assures good treatment adherence, low rates of toxicity and probably improves the cost-effectiveness. These data should be tested in a larger prospective trial.
Allogeneic stem cell transplantation following relapse post autologous stem cell transplantation in adult patients with acute myeloid leukemia: A retrospective analysis of 537 patients from the Acute Leukemia Working Party of the EBMT
Authors: Maximilian Christopeit, Myriam Labopin, Norbert‐Claude Gorin, Francesco Saraceni, Jakob Passweg, Edouard Forcade, Johan Maertens, Maria Teresa Van Lint, Alberto Bosi, Dietger Niederwieser, Gerhard Ehninger, Emmanuelle Polge, Mohamad Mohty, Arnon Nagler
Journal: American Journal of Hematology (2018)

Patients with acute myeloid leukemia (AML) who relapse after autologous stem cell transplantation (ASCT) can be rescued by allogeneic SCT. We identified 537 adult patients with AML allografted in second complete remission (CR2) or first relapse after ASCT in the European Society for Blood and Marrow Transplantation (EBMT) registry. At 3 years post allograft, leukemia free survival (LFS) was 31.4% [95%CI 27.3-35.6], overall survival (OS) 39.5% [95%CI 35.1-43.9], relapse incidence (RI) 34.6% [95%CI 30.4-38.8], and nonrelapse mortality (NRM) 33.7% [95%CI 29.6-37.9]. RI was higher in patients transplanted in relapse in comparison to those transplanted in CR2 (HR 1.76, P = .004) and in patients who relapsed later after ASCT (HR 0.97 per month, P < 10-3 ), both translating into better LFS/ OS. Relapse was also lower in patients undergoing allogeneic stem cell transplantation (allo-HSCT) from an unrelated donor (UD) in comparison to those transplanted from a matched sibling donor (MSD) (HR 0.49, P < 10-3 ). NRM was increased in patients who received total body irradiation (TBI) pre-ASCT (HR 2.43; P < 10-4), translating into worse LFS/OS. LFS/OS did not differ between patients allotransplanted with reduced intensity (RIC) or myeloablative (MAC) conditioning. In conclusion, one third of adult patients with AML relapsing post ASCT can be rescued with allo-HSCT, with better LFS/OS in patients who relapsed later post ASCT, those transplanted in CR2 and those who had not received TBI pre-ASCT.
Activity and tolerabilty of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: Initial phase 1b/2 results.
Authors: Ranjana H. Advani, Ian Flinn, Leslie Popplewell, Andres Forero-Torres, Nancy L. Bartlett, Nilanjan Ghosh, Justin Paul Kline, Thu Tran, Judith Lynn, James Y Chen, Balaji Agoram, Jenny Huang, Chris H.M. Takimoto, Mark Chao, Sonali M. Smith
Journal: Journal of Clinical Oncology (2018)

7504 Background: Targeted non-cytotoxic therapies are needed in relapsed/refractory (r/r) NHL. Hu5F9-G4 (5F9) is a first-in-class humanized antibody targeting CD47, a protective “don’t eat me” signal on cancers, that stimulates tumor cell phagocytosis and an anti-tumor T cell response. Pre-clinically, 5F9 synergizes with rituximab to eliminate lymphoma by enhancing Fc receptor-mediated antibody-dependent cellular phagocytosis. This trial is the first to explore clinical activity of an anti-CD47 antibody+rituximab. Methods: This Phase 1b/2 enrolled r/r NHL patients in a 3+3 dose escalation design (NCT02953509). A 1 mg/kg 5F9 priming dose with higher weekly maintenance doses was used to mitigate on-target toxicities, specifically anemia. Maintenance doses were escalated from 10 to 30 mg/kg with standard dose rituximab. Results: 22 heavily pre-treated patients with r/r DLBCL (n = 15) and FL (n = 7) were enrolled in Phase 1b. Patients had a median of 4 prior therapies (range 2-9), 90% were rituximab-refractory. 5F9+rituximab was well-tolerated. Common treatment-related AEs were chills (41%), headache (36%), anemia (32%), and fever (27%). All were grade 1-2 except 3 G3 AEs (chills, fever, anemia). Prime/maintenance 5F9 dosing significantly mitigated on-target anemia, a mostly first dose effect with spontaneous recovery. Only 2 patients required a one-time transfusion. The MTD was not reached up to 30 mg/kg weekly of 5F9 dosing. > 90% CD47 receptor occupancy was achieved on peripheral blood cells, showing high target saturation. A Phase 2 dose of 30 mg/kg 5F9 Q2 weeks after cycle 1 was selected. Across all doses, the ORR was 50%, 32% achieved CR. %ORR/CR was 40/27 in DLBCL and 71/43 in FL, respectively. As of 1/16/2018, 90% of responding patients continued in response (4.4 month median follow up), including 1 patient for 13+ months. Conclusions: 5F9 + rituximab is a novel immunotherapy that inhibits a key macrophage/cancer checkpoint. It is well tolerated with no MTD reached and has promising clinical activity in rituximab-refractory DLBCL and FL patients including multiple CRs. Phase 2 cohorts are ongoing in indolent lymphoma and DLBCL Clinical trial information: NCT02953509.
The radiation sensitization effect of newly discovered EGFR specific inhibitor HS-10182 in human lung cells.
Authors: Ningbo Liu, Yang Chen, Lujun Zhao, Youyou Wang, Chenghai Li, Rudi Bao, Ping Wang
Journal: Journal of Clinical Oncology (2016)

e20635 Background: Although EGFR overexpression is associated with radioresistance in cancer, the underline mechanism for the combination of EGFR TKI and irradiation regarding the radiosensitivity in NSCLC with mutant EGFR are inconclusive. Our study was to investigate the newly discovered EGFR specific inhibitor, HS-10182(Hengrui Pharmacy, China), on the sensitization of lung cells and its molecular mechanism. Methods: Three human lung cells, A549(EGFR wild type); PC-9(exon 19 deletion) and H1975 (L858R/T790M double mutant) were selected. MTS assay was used to detect the inhibitory effects. Clonogenic assay was used to detect the combined effect and the radiation dose enhanced ratio (DER) was calculated. The activation of caspase, phosphorylation of EGFR and AKT, expression level of DNA-PK and RAD were detected by Western Blot. Flow Cytometry assay was used to detect apoptosis and immunofluorescence was used to detect the formulation of γ-H2AX foci. The Synergistic effect of HS-10182 and irradiation in vivo was verified in nude mice xenograft tumors. Results: We found that HS-10182 can greatly inhibit PC-9 cells proliferation while a relatively moderate inhibition of H1975 cells when compared to A549 cell. The experimental results showed that HS-10182 can increase the sensitivity of H1975 cells after irradiation (DER 2.36) compared to A549 cells (DER 1.43). The phosphorylation level of EGFR and AKT were significantly decreased after HS-10182 treatment in all cells. HS-10182 can also induce more apoptosis of PC-9 and H1975 cells when being synchronously exposed to ionizing radiation. Except the modification of cell cycle, the cleaved of PARP, caspase 8, caspase 3 and caspase 6 were significantly increased when HS-10182 combined with irradiation. The radiosensitization effect of HS-10182 was further proved in H1975 xenograft tumors in vivo. Conclusions: NSCLC cell lines with EGFR mutation exhibit characteristics of radiosensitive phenotype, such as increased apoptosis and delayed DNA repair. Newly discovered EGFR TKI HS-10182 can act as a radiotherapy sensitization agent while its mechanism of radiation sensitivity is still needed to be further studied.
Health plan budget impact of introducing elotuzumab in combination with lenalidomide and dexamethasone for relapsed/refractory multiple myeloma in the United States.
Authors: Ravi C. Potluri, Hitesh Bhandari, Sandip Ranjan, Manan Shah, Clara Chen
Journal: Journal of Clinical Oncology (2016)

e18244 Background: Elotuzumab was recently approved in combination with lenalidomide and dexamethasone (ELd) for the treatment (Tx) of multiple myeloma (MM) patients who have received 1–3 prior therapies, based on a significant increase in progression-free survival (PFS) over the combination of lenalidomide and dexamethasone. A budget impact model (BIM) was developed to assess the impact of adding ELd to a formulary of a health plan in the United States. Methods: The BIM estimated the 3-year costs of adding ELd to a plan’s formulary. Patients under Tx each year included patients new to therapy in that year and those continuing with Tx from previous years as per the Tx regimen’s PFS and duration of Tx. Incidence and Tx data for relapsed/refractory (RR) MM were obtained from published and market research data. ELd was projected to have a share of 3%, 8%, and 11% of incident RRMM patients in Years 1–3, respectively. The following costs were included: MM medications, concomitant medications, adverse event management, lab tests, and monitoring. Costs were adjusted to 2016 values using the medical component of the Consumer Price Index. The model output is expressed in terms of absolute annual budget impact, and budget impact per plan member per month (PMPM) and per year (PMPY). Results: For a plan of 1 million members, incidence of RRMM was estimated to be 80. The model estimated a budget increase of $159,659 in Year 1, $567,642 in Year 2, and $1,139,054 in Year 3. The PMPM budget impact was $0.013 in Year 1, $0.047 in Year 2, and $0.095 in Year 3 (Table). The largest percent increase in budget was associated with MM Tx. Sensitivity analyses of varying RRMM incidence and market shares of ELd showed the model results to be robust. Conclusions: Our model predicts that treating RRMM patients with elotuzumab will have a quite gradual and modest budget impact on US health plans, estimated at about $0.16 PMPY in Year 1 to $1.14 in Year 3. Inputs Plan population 1 million RRMM incidence rate 8 per 100,000 Patients on drug Tx 90% Year 1 Year 2 Year 3 Elotuzumab share 3% 8% 11% Outputs BI $159,659 $567,642 $1,139,054 PMPM BI $0.013 $0.047 $0.095 PMPY BI $0.16 $0.57 $1.14
Impact of cervical cancer care volume on clinical outcomes of laparoscopic radical hysterectomy: A systematic review and meta-analysis.
Authors: Banghyun Lee, Kidong KIM
Journal: Journal of Clinical Oncology (2017)

e17013 Background: This study investigated the impact of hospital and physicain cervical cancer case volume on clinical outcomes of laparoscopic radical hysterectomy (LRH) to clarify the hypothesis that clinical outcome of cervical cancer may depend on experience of hospital and physician performing radical hysterectomy (RH). Methods: In January 2017 the PubMed search identified 556 articles. A combination of the following key words was used in the search: (cervical cancer and laparoscopy and RH) and (cervical cancer and LRH). When filtered for studies presenting operative outcomes and/or perioperative complications of LRH 59 studies including 4,367 patients met the selection criteria: high volume hospitals (HVH) (≥15 cases/year; 13 studies, 2227 patients) and low volume hospitals (LVH) (&lt;15 cases/year; 46 studies, 2140 patients); high volume physicians (HVP) (≥10 cases/year; 7 studies, 1167 patients) and low volume physicians (LVP) (&lt;10 cases/year; 35 studies, 1258 patients). Linear regression analysis which is weighted by the number of patients per year in each study was performed to evaluate differences between the groups using Stata/SE 14. Results: Analyses according to hospital volume showed following outcomes in HVH compared with LVH: tendency of lower operative time and blood loss; the higher number of lymph nodes (LN) retrieved; older age; and lower frequency of stage IA. Moreover, hospital stay, intra- and post-operative complications, adjuvant therapy, 5-year overall survival, disease free survival and recurrence rate, stage IB1, IB2, and IIA, LN metastasis, and lymphovascular space, parametrial and surgical margin invasion were not different between the groups. Analyses according to physician volume showed following outcomes in HVP compared with LVP: the higher number of LN retrieved; longer hospital stay; higher 5-year recurrence rate; and lower frequency of stage IA and surgical margin invasion. Moreover, other factors were not different between the groups. Conclusions: Higher hospital and physician volumes are associated with better operative outcomes. However, those might not be favorable prognostic factors for cervical cancer.