tbuckley/cabot-search huggingface dataset:
Research on Gun Violence vs Other Causes of Death
Authors: David E. Stark, Nigam H. Shah
Journal: JAMA (2017)

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Retroviral replicating vector–mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity
Authors: Kei Hiraoka, Akihito Inagaki, Yuki Kato, Tiffany T. Huang, Leah A. Mitchell, Shuichi Kamijima, Masamichi Takahashi, Hiroshi Matsumoto, Katrin Hacke, Carol A. Kruse, Derek Ostertag, Joan M. Robbins, Harry E. Gruber, Douglas J. Jolly, Noriyuki Kasahara
Journal: Neuro-Oncology (2017)

Prodrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.Here we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.In both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.These results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity.
Non-Hodgkin's lymphoma in women with breast cancer: A retrospective study of 46 patients
Authors: M. Roussel
Journal: Journal of Clinical Oncology (2004)

6670 Background: Breast cancer (BC) is the first cancer in women. Improvement in screening and treatment strategies increased long-term survivors. Those women are then at risk for second malignancies, including non-Hodgkin lymphoma (NHL). Currently, no genetic or treatment-related risk factors have been demonstrated. In the Curie's Institute cohort of BC, we analyzed women with second NHL and tried to assess risk factors. Methods: More than 30000 women with invasive BC were followed at the Curie's Institute between 1969 and 2001. In the database, we recorded 57 women with NHL. 46 have been analyzed in this retrospective study. Results: Median age at diagnosis of BC was 57 yrs. More than 90% of pts had an early stage. 78.3% received radiotherapy and 41.3% systemic therapy. The median follow-up was 11.7 yrs (range 3.2–28.5) with 76% of pts in complete remission (CR). Median delay of apparition for NHL was 7.8 yrs (range 1.3–26.7). Median age was 63 yrs. B cells lymphomas were mainly represented with 50% follicular lymphoma and 30.4% large cells lymphoma. There was no recurrent cytogenetic abnormality. All pts received appropriate treatments. The median follow-up was 4.3 yrs (range 0.4–13.7). 15 pts (32.6%) were in CR. 22 (47.8%) died of the lymphoma. At 5 yrs, overall survival was 65.9% (95%CI: 51.8–80). Survival was related to histological grade. A 3/1 case control study matched on age, date of BC diagnosis and survival didn't show treatment-related risk factor. We cannot rule out a genetic predisposition. Conclusion: NHL is a second primary malignancy in women with breast cancer. There is no evidence in our cohort for treatment-induced NHL. S: surgery, RTE: external radiotherapy, CT: chemotherapy, H: hormonotherapy No significant financial relationships to disclose.
Creating a radiation oncology oriented safety culture within a large oncology practice: Lessons learned.
Authors: Ajay Dubey, Jeff Bernard, Bret Heintz, Kyle Antes, Stacy Hartman, Bernard Taylor, Brennan Scott Cheek, Jeffrey Limmer, Lalan S. Wilfong, John Russell Hoverman
Journal: Journal of Clinical Oncology (2017)

85 Background: Texas Oncology (TXO) is a dedicated oncology practice consisting of more than 400 physicians and 57 radiation oncologists at 52 sites of service. In order to enhance communications of the rad onc team, establish accountability by using metrics, and engage continuous improvement, we initiated a program to establish regional quality committees in each radiation oncology practice site. Methods: In 2015, the TXO leadership approved the formation of Regional Quality Committees (RQC) at each site. The key members of each RQC include a Physician Chair, a Physicist Co-Chair, Chief Therapist, Radiation Safety Officer, Dosimetrist, and Nurse. Meeting frequency was recommended monthly, but quarterly meetings were required. Meeting documentation reporting was required including a formal agenda, minutes for items discussed, and listing of attendees. Metrics with regard to RQC activities were reported and recorded beginning in 2016. The 2016 Action plan for the RQC at each site included documentation of timeout procedure, regular chart rounds, new patient conference, as well as a mortality and morbidity conference. Results: See table. Conclusions: Within 3 calendar quarters, a functional RQC was established in all 52 radiation oncology practice sites within TXO. Compliance with the action plan was high with regard to action items not requiring multiple physician participants (RQC committee, timeout, chart rounds, CQI projects, performance metrics). Compliance was lower in activities that required multiple physician participation. Verbal feedback was positive regarding the RQC program. Respecting time demands of physicians, education, and communication were identified as key success factors in the RQC program. [Table: see text]
Prognostic Significance of Reduced Blood Pressure Response to Exercise in Pediatric Pulmonary Arterial Hypertension
Authors: Hong-Da Zhang, Zi-Chao Lv, Li-Ting Wang, Alexander Rothman, Tian-Yu Lian, Yang-Yang He, Yan Wu, Allan Lawrie, Maurice Beghetti, Zhi-Cheng Jing
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

RATIONALE: Pulmonary arterial hypertension (PAH) is a deadly disease occurring in both adults and children.Cardiopulmonary exercise testing (CPET) has been widely used in heart failure for many years and has recently been recommended in patients with PAH, especially in younger population.This could provide more objective information on exercise capacity and right ventricular performance than six minute walking distance.It is now well established that CPET parameters are prognostic in adult patients with PAH, however, there has been very little research investigating the prognostic value in children with PAH since CPET has been proved to be safe and practical in those patients.METHODS: Thirty-seven children diagnosed with PAH were prospectively enrolled from those attending a national referral center between July 2013 and December 2015.Standard incremental CPET was performed in each participant under physician supervision.During follow-up, clinical worsening events including death, heart/lung transplantation, escalation of PAH targeted therapy, and hospitalization for PAH deterioration, were recorded.The final census date for the study was September 1, 2016.
The association of histologic grade with acute graft‐versus‐host disease response and outcomes
Authors: Mayur Narkhede, Lisa Rybicki, Donna Abounader, Brian Bolwell, Robert Dean, Aaron T. Gerds, Rabi Hanna, Brian Hill, Deepa Jagadeesh, Matt Kalaycio, Hien D. Liu, Brad Pohlman, Ronald Sobecks, Navneet S. Majhail, Betty Ky Hamilton
Journal: American Journal of Hematology (2017)

Consensus criteria are routinely used to clinically grade acute graft-versus-host disease (GVHD). A histologic grading system for acute GVHD is available, but there are limited data on its correlation with clinical grade and hematopoietic cell transplantation (HCT) outcomes. Among 503 patients who underwent allogeneic HCT from 2005 to 2013, we identified 300 biopsy episodes of the skin and gastrointestinal (GI) tract in 231 patients. Histologic grade was correlated with clinical grade of GVHD, day 28 treatment response, and outcome. Both skin (R = 0.32) and GI (R = 0.61) histologic grade correlated with clinical grade (P < 0.001). On multivariable analysis, histologic grade (HR 0.87, P = 0.011) and clinical grade (HR 0.86, P = 0.008) were significantly associated with day 28-treatment response. A histologic grade lower than its associated clinical grade predicted for better response (HR 1.26, P = 0.027), while a histologic grade higher than associated clinical grade had no correlation with response (P = 0.89). Both clinical and histologic GVHD grade were significant predictors of non-relapse mortality (HR 1.47, P = 0.04 and HR 1.67, P = 0.002, respectively) and all-cause mortality (HR 1.57, P = 0.001 and HR 1.29, P = 0.046, respectively). Histologic GVHD grade thus is correlated with clinical grading and treatment response, and may play a role in further predicting severity and treatment response of acute GVHD.
The RIST design: A molecularly targeted multimodal approach for the treatment of patients with relapsed and refractory neuroblastoma.
Authors: Selim Corbacioglu, Daniel Steinbach, Holger N. Lode, Bernd Gruhn, Michael Fruehwald, Mechthild Broeckelmann, Meinolf Suttorp, Gabriele Escherich, Gunnar Cario, Karoline Ehlert, Bernhard Meister, Thorsten Simon, Klaus-Michael Debatin, Michaela Kuhlen, Isa Feddersen
Journal: Journal of Clinical Oncology (2013)

10017 Background: The prognosis for children with recurrent or refractory neuroblastoma (rNB) remains dismal. Novel therapeutic approaches are urgently needed. Methods: Based on promising in vitro data unselected patients with rNB were treated as compassionate use according to a multimodal approach (RIST design). The treatment consisted of metronomic courses of Rapamycin/Dasatinib (R/S) for 4 days followed by 5 days of Irinotecan and Temozolomide (I/T). Twenty-one patients (median age: 38 months) with stage IV (n=19) and stage III (n=2) disease, 5 with refractory disease, 8 with 1 st and 8 with 2 nd and 3 rd relapses were included. Seven patients presented within 18 months after diagnosis (median age: 28 months). 18 patients were MIBG positive, 4 MYCN amplified. Dissemination was present in the bone in 15, bone marrow in 11 and lymph nodes in 6 patients, respectively. Results: The patients received a median of 16 courses of R/S (4 to 72) and 7 courses of I/T (4 to 65). 19 patients (90%) showed an initial response according to imaging criteria after a median of 7 R/S and 4 I/T courses (median treatment duration 12 weeks): CR in 12 (57%), a PR in 3 (14%) and a SD in 4 (19%). The median PFS was 90 weeks. The OS after a median of 148 weeks was 43% with 7 patients in CR, 1 VGPR and 1 in PR. There were no toxic deaths in this highly pretreated population. Grade III and IV toxicities (CTC 3.0) were thrombocytopenia in 81%, leukopenia in 76%, anemia in 71%, and diarrhea in 71% respectively. Conclusions: This RIST treatment design applied as a multimodal approach in a compassionate use setting exhibited very promising results considering the adequately long follow-up period of 3 years. This molecular targeted therapy design for rNB warrants confirmation in a prospective clinical trial.
Cross-talking between bone marrow-derived cells and lung cancer cells
Authors: J. Zhang, M. Liao, X. Niu, J. Xiang, Y. Zhao, H. Chen, S. Lu
Journal: Journal of Clinical Oncology (2009)

e19068 Background: Disseminated cancer cells may initially require local nutrients and growth factors to thrive and survive in bone marrow. However, data on the influence of bone marrow derived cells(BMDC, also called bone stromal cells in some publication) on lung cancer cells is largely unexplored. This study is to explore the effect from bone marrow derived cells on biological behavior of lung cancer cells. Methods: The difference among lung cancer cell lines in their abilities to bone metastasis was tested using SCID animal model. Supernatant of bone marrow aspiration(BM) and condition medium from human bone stromal cells(BSC) were used to study the activity of bone stromal factors. Affymetrix gene chip U133A 2.0 was used to study the gene expression profile of H460 cells, after exposure to secreted proteins from bone stromal cells. Results: In accordance with other literature repors, H460 was found with high bone metastasis potential, while SPC-A1 and A549 cells were low bone metastasis lung cancer cells. We found bone stromal factors significantly increased the proliferation, invasion, adhesion and expression of angiogenosis-related factors, and inhibited the apoptosis for high bone metastasis H460 lung cancer cells. These biologic effects were not seen in SPC-A1 or A549 cells, which are low bone metastasis lung cancer cells. Adhesion of H460 cells to bone stromal cells consistently up-regulated 31 genes. Ontoexpress software showed main function of 31 genes were associated with signal transduction pathways(5 genes), and adhesion molecule(5 genes), including integrin b3 and ADAMTS-1, two potential targets related with bone metastasis. Conclusions: We concluded bone marrow derived cells had a profound effect on biological behavior of lung cancers, therefore favoring the growth of lung cancer cells in bone. No significant financial relationships to disclose.
Is neoadjuvant chemotherapy a realistic alternative to primary surgery for women with advanced ovarian cancer?
Authors: H. Steed, A. Oza, J. Murphy, S. Laframboise, D. De Petrillo, J. Sturgeon, B. Rosen
Journal: Journal of Clinical Oncology (2004)

5043 Background: To compare progression free survival (PFS) and overall survival (OS) of women with advanced ovarian cancer treated with neoadjuvant chemotherapy followed by surgery to women treated with primary surgery. Methods: A retrospective analysis of 106 patients with advanced ovarian cancer was performed. Fifty women with advanced ovarian cancer diagnosed by CT scan and positive cytologic received carboplatin and paclitaxel. Most patients selected had stage IV disease (pleural effusions) or medical comorbidities. Thirty-six patients subsequently underwent cytoreductive surgery and further chemotherapy postoperative. The OS and PFS were compared to 66 women with advanced ovarian cancer who were treated conventionally with primary cytoreductive surgery followed by 6 cycles of carboplatin and paclitaxel chemotherapy. Survival analysis was also performed on a subset data, which had been selected to be comparable for stage and grade. Results: No statistical difference was observed in OS (p=0.34, HR=1.31, CI=0.76–2.55) or in PFS (p=0.30, HR=1.31, CI=0.79–2.18) between the neoadjuvant chemotherapy group and the conventional primary surgery group. Due to the small numbers, age, grade, stage, and histologic cell type were controlled for separately in bi-variate analyses and did not change the above HR's. Survival analysis matched on stage and grade controlling for age (N=28 matched pairs) also resulted in no statistical difference for OS (p=0.95, HR=1.04, CI=0.33–3.30) and PFS (p=0.79, HR=1.11,CI=0.51–2.46). The neoadjuvant chemotherapy group had less residual disease with < 1 cm at the time of surgery compared with the primary surgical group (p=0.001) and less extensive bowel surgery was performed in the neoadjuvant chemotherapy group but did not reach statistical significance (p=0.15). Conclusion: Neoadjuvant chemotherapy followed by optimal debulking surgery may be a safe alternative in women with advanced ovarian cancer. Neoadjuvant chemotherapy did not change the OS and PFS. The role of neoadjuvant chemotherapy in advanced ovarian cancer is currently being tested in larger, prospective randomized controlled trials. No significant financial relationships to disclose.
Polo-like kinase 1 as a biomarker in rectal cancers.
Authors: Stephanie Hui-Su Lim, J-S Shin, T G Tut, W T.W. Ng, Wei Chua, I U Dissanayake, Kevin Spring, Weng Ng, Les Bokey, Paul De Souza, C S Lee
Journal: Journal of Clinical Oncology (2014)

e14542 Background: Human polo-like kinase 1 (PLK1) is important in mitotic progression. It is overexpressed in many cancers including colorectal cancer. Decreased PLK1 expression has been associated with tumour regression and improved outcome. The aim of our study is to investigate PLK1 in rectal cancers and its correlation with other variables and with overall survival (OS). Methods: Tissue microarrays were constructed from formalin-fixed and paraffin-embedded (FFPE) specimens of primary rectal or rectosigmoid cancer. Samples from the cancer centre (CC), cancer periphery (CP) and involved lymph nodes (LN) were stained for PLK1 by immunohistochemistry. Percentage of positive cells and staining intensity were scored and multiplied to give weighted scores (0-12), and dichotomised [low (0-5) or high (6-12)]. CC and CP scores were also averaged (CCCP). Results: 351 cases were identified, with median age of 72 years, 36% female, 64% male, 34% pT1/2, 66% pT3/4, 45% node-positive and 7% metastatic (M1). Median follow up was 3.2 years and five year OS 58%. Twenty four percent received neoadjuvant and 31% adjuvant treatment. Median PLK1 score was three for CC and four for CP, and this was significantly different (paired t-test p<0.001). Low CP PLK1 was associated with the presence of metastases (Fisher’s exact test p=0.001). Cox regression analysis revealed low CCCP PLK1 to be borderline prognostic for improved OS (p=0.048, hazard ratio HR 0.43 to 1.00). Low CP and CCCP were significant for OS in the non-metastatic (M0) group (p=0.013, HR 0.39-0.90 and p=0.032, HR 0.38-0.96 respectively). Both remained independent prognostic factors in multivariate analyses. Low LN PLK1 expression was significant for improved OS (p=0.015, HR 0.27-0.87) in univariate and multivariate models. Age, tumor node metastasis (TNM) stage, grade, vascular invasion, perineural invasion and adjuvant chemotherapy were significant predictors of OS. Conclusions: PLK1 scores in CC and CP were significantly different. Low CP, and to a lesser extent CCCP, were predictive of OS in the M0 subgroup. In the entire cohort, only CCCP PLK1 was borderline significant for OS. There was an association between low CP PLK1 and the presence of metastases, which needs to be explored further, given low numbers in the M1 group. Low LN PLK1 was also a significant predictor of OS.
Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease
Authors: Meera Mohan, Amy Buros, Pankaj Mathur, Neriman Gokden, Manisha Singh, Sandra Susanibar, Jorge Jo Kamimoto, Shadiqul Hoque, Muthukumar Radhakrishnan, Aasiya Matin, Cynthia Davis, Monica Grazziutti, Sharmilan Thanendrarajan, Frits van Rhee, Maurizio Zangari, Faith Davies, Gareth Morgan, Joshua Epstein, Bart Barlogie, Carolina Schinke
Journal: American Journal of Hematology (2017)

Light chain deposition disease (LCDD) is characterized by monotypic immunoglobulin depositions which will eventually lead to loss of organ function if left untreated. While the kidney is almost always affected, the presence and degree of LCDD in other organs vary. Ten to thirty percent of LCDD patients have underlying Multiple Myeloma (MM), yet outcome and prognostic markers in this particular patient group are still lacking. Here, we analyzed 69 patients with MM and biopsy proven LCDD and report on renal and extra-renal involvement and its impact on prognosis as well as renal response depending on hematologic response. Coexisting light chain diseases such as AL amyloid and cast nephropathy were found in 30% of patients; those with LCDD and concurrent amyloid tended to have shorter survival. Cardiac involvement by LCDD was seen in one-third of our patients and was associated with shorter overall survival; such patients also had a significantly higher risk of treatment-related mortality (TRM) after stem cell transplant (SCT) compared to LCDD patients without cardiac involvement. This study highlights that MM patients with LCDD present with different clinical features compared to previously reported LCDD cohorts. Rapid initiation of treatment is necessary to prevent progressive renal disease and worse outcome. Coexisting light chain diseases and cardiac involvement are more common than previously reported and confer worse clinical outcome, emphasizing the need for careful patient careful patient evaluation and treatment selection.