tbuckley/cabot-search huggingface dataset:
Preliminary results of phase I clinical trial of high doses of seleno-L-methionine (SLM) in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.
Authors: Rohan Garje, James A. Brown, Kenneth Gerard Nepple, Laila Dahmoush, Andrew Bellizzi, Jaime Bonner, Sarah L Mott, Gideon Zamba, Douglas Earl Laux, Mohammed M. Milhem, Youcef M. Rustum, Yousef Zakharia
Journal: Journal of Clinical Oncology (2019)

660 Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3 rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.
Inferior Vena Cava Filters in the Management of Venous Thromboembolism—Reply
Authors: Tobias Tritschler, Noémie Kraaijpoel, Philip S. Wells
Journal: JAMA (2019)

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Serum tumor marker utilization in patients with advanced solid tumors.
Authors: Melissa Kate Accordino, Jason Dennis Wright, Sowmya Vasan, Alfred I. Neugut, Ana Isabel Tergas, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2015)

6599 Background: Despite data on the sensitivity and specificity of serum tumor marker tests, there is no evidence to suggest that early changes in therapy related to rising tumor markers have an effect on survival. Studies have failed to show benefit of surveillance testing in patients with limited disease. We performed a retrospective analysis in patients with advanced cancer to evaluate trends in utilization of tumor marker testing and the associated costs. Methods: Patients at Columbia University Medical Center with advanced or metastatic cancer were identified by ICD9 codes and confirmed with tumor registry and medical record review. Between 7/1/2013-6/30/2014 for each patient, the dates each of the following tumor markers were recorded: alpha fetoprotein (AFP), CA 125, CA 15-3, CA 19-9, CA 27-29 and carcinoembryonic antigen (CEA). Subjects who had > 1 of any single tumor marker over the time-frame were included. We evaluated the maximum number of tests per month and the average number of tests per-month the patient was alive. Costs of each tumor marker were determined using 60% Medicare reimbursement rates. Results: Over the 12 month time frame 996 patients were included in the analysis. The mean number of any individual test per-patient was 7 and the maximum was 35; and the mean number of total tests per-patient was 12 and the maximum was 70. CEA and CA-19-9 were the most commonly ordered tests with an average of 1.94 and 2.18 times per-month, per-patient. On average the number of patients that had > 1 of any individual test per month was 33%. The most common tests were CA-125, CEA and CA-19-9 (25.3%, 38.2% and 45.6% respectively). Overall 21.9% of patient had ≥ 3 of any individual marker per-month (38% CA19-9 and 25.6% CEA). The mean per-patient annual cost of testing was $421, with a maximum $2,567. Costs per-patient were highest for those with breast cancer (mean $755, max $1,787) and pancreatic cancer (mean $643, max $2,567). Conclusions: Tumor marker testing is frequent, with a large number of patients being tested multiple times per month, every month. Given the rising costs of cancer care, the large number of serum tests, and the frequency of use, efforts should be made to determine the clinical utility of tumor marker testing in metastatic cancer patients.
Quality of life assessment in glioblastoma patients with irradiation of periventricular and subgranular zones.
Authors: Monica Malik, Akram Kothwal Syed, Deepa M Joseph, Deepthi Valiyaveettil, Fayaz Ahmed Syed
Journal: Journal of Clinical Oncology (2015)

e13054 Background: Recent data suggests that glioblastomas are organized hierarchically with a small number of cancer stem cells, with the ability to self-renew. Retrospective evidence links irradiation of potential stem cell niches in the periventricular and subgranular zones to improved outcomes. However prospective studies are lacking and the impact of irradiation of these stem cell niches on quality of life is not known. Methods: We conducted a prospective study on patients of Glioblastoma with irradiation of potential stem cell niches. The CTV included the preoperative tumor bed with 1-1.5 cm margin, peritumoral edema, and ipsilateral stem cell niches. The periventricular zone (PVZ) was contoured as a 5 mm expansion around the ventricles. The subventricular zone (SVZ) was defined as a 5 mm expansion from the lateral wall of lateral ventricle. The subgranular layer (SGL) was contoured as per RTOG guidelines. The prescribed dose was 60 Gy at 2 Gy per fraction. The ipsilateral PVZ was planned to receive ≥ 50 Gy. All patients received concurrent and adjuvant chemotherapy with temozolomide. Quality of life was assessed using the SF-36 questionnaire at three time points: before radiation and at one and six months post radiation. Results: 15 patients were analysed. Median age was 45 years. RPA class was III, IV and V/VI in 40%, 53% and 7% cases respectively. Mean doses received by the ipsilateral PVZ, SVZ and SGL were 57.5, 58.4 and 53.4 Gy respectively. QOL was assessed in all patients at baseline and one month post radiation. Six months post radiation QOL data was available for 10 patients. Paired t-test showed a significant improvement in Physical Component Summary (PCS), Mental Component Summary (MCS) at one month. Sub components such as Physical functioning, General Health, Social Functioning and Mental Health also showed significant improvement while components Vitality, Role Physical, Bodily Pain, Role Emotional did not improve significantly. At six months, there was a significant improvement in PCS (p < 0.001), MCS (p < 0.001) as well as all sub components. Conclusions: Irradiation of ipsilateral PVZ and SGL to doses of ≥ 50 Gy was well tolerated. There was improvement in all QOL parameters post treatment.
L-arginine depletion by PEG-arginase I, a new potential therapy for acute lymphoblastic leukemia.
Authors: Ofelia Crombet Ramos, Claudia Hernandez, Kevin Morrow, John T. Cole, Paulo Rodriguez
Journal: Journal of Clinical Oncology (2012)

6580 Background: Advances in therapies have resulted in an overall complete remission rate of approximately 85% for childhood acute lymphoblastic leukemia (ALL). In contrast, the overall remission rate of adults with leukemia continues to be poor, only about 40% in cases of T cell-ALL (T-ALL). Therefore, it is imperative to generate new therapies that alone or in combination with other treatments could potentially increase the percentages of complete responders or be used to treat the refractory ALL population. Our published results show that a pegylated form of human arginase I (peg-Arg I) prevented T-ALL cell proliferation in vitro and in vivo through the induction of tumor cell apoptosis. Interestingly, the anti-leukemic effects induced by peg-Arg I did not affect the anti-tumor activity of normal T cells, suggesting an anti-tumor specific effect. Our hypothesis states that peg-Arg I has an anti-tumoral effect on B-ALL and T-ALL cells in vitro and that the sensitivity of ALL cells to peg-Arg I depends on their expression of argininosuccinate synthase (ASS) and their ability to produce L-arginine de novo from citrulline. Methods: Malignant T cell proliferation was tested using nonradioactive cell proliferation yellow tretrazolium salt kit. Apoptosis studies were based on the expression of annexin V. Western blot assays were conducted to determine enzymatic expression in different cell lines. Results: The results of our in vitro experiments showed that peg-Arg I had a pro-apoptotic and anti-proliferattive effect on B-ALL cells similar to the one previously seen on T-ALL cells. These effects can be overcome in cell lines able that express ASS and therefore to produce L-arginine de novo. Conclusions: Our results suggest the role of ASS in the ALL-apoptosis induced by peg-Arg-I. Our next steps include: _Understand why ASS-expressing ALL cells do not undergo apoptosis when cultured with peg-Arg-I_Determine the role of ASS in the anti-leukemic effect induced by peg-Arg-I in vivo. Completion of this research is expected to lead to a better understanding of how peg-Arg-I kills ALL cells and could provide the foundation for a novel therapy for ALL patients.
Sarcoma: A Lynch syndrome (LS)-associated malignancy?
Authors: John M. Kaczmar, Jessica Everett, Karen Ruth, Elena Martinez Stoffel, Jessica Stoll, Sonia Kupfer, Heather Hampel, Zsofia Kinga Stadler, Pragna Gaddam, Christina Rybak, Thomas Paul Slavin, Jonathan P. Terdiman, Amie Blanco, Michael J. Hall
Journal: Journal of Clinical Oncology (2015)

1516 Background: Lynch syndrome (LS) is a well characterized hereditary cancer syndrome caused by mismatch repair (MMR) deficiency of epithelial tumors. Uncertainty remains as to whether several less common non-epithelial cancers such as sarcomas may also be associated with LS. We sought to describe the incidence and characteristics of sarcomas within a sample of LS families assembled through a multi-institutional collaboration. Methods: Participating sites (n = 7) queried their databases for molecularly proven and clinical LS families with sarcoma reported in a close relative (1st, 2nd, 3rd-deg). Information on the familial underlying MMR gene mutation (MLH1, MSH2, MSH6, PMS2, or EPCAM) was collected, as was age, sex, and tumor histology of all familial cancers from LS-sarcoma pedigrees (if available). Vague sarcoma diagnoses ("bone") were considered possible, while a documented category/histology ("rhabdosarcoma") was considered likely. Results: In total, from 958 LS families, 55 LS-sarcoma families (5.7%) contained 58 individuals with possible (n = 16) or likely (n = 42) sarcomas. Mean age of sarcoma diagnosis was 47.1 years (age range 4-87 years), with a 1:1 male to female ratio. Nearly two-thirds (62%, 36/58) of sarcomas were in MSH2+/EPCAM+ families, in contrast to the ~40% of all LS that are MSH2+. Other LS-sarcoma families were: MLH1+ (n = 12), MSH6+ (N = 3), PMS2+ (n = 3) and unknown (n = 4). Sarcoma histologies were diverse and included pleomorphic, synovial, myxofibroid, DFSP, liposarcoma, rhabdomyosarcoma, and osteosarcoma. Recurrent MSH2 mutations in presumed unrelated LS-sarcoma families included 2 known founder mutations del exon 1-6 and c.942+3A > T as well as c.1216C > T, c.2135insT and c.1906G > C. Other pedigree findings included: Muir-Torre variant LS in 14/38 (37%) evaluable families, 7 thyroid cancers (2 early-onset, 29 and 31 yrs), an adult retinoblastoma, and an MSI-H thymoma in a 55 year-old woman with 2 soft tissue sarcomas. Conclusions: From a large sample of nearly 1000 LS families, our findings suggest sarcomas may be a rare manifestation of LS, especially MSH2+ LS. More research of genotype-phenotype correlations in LS is needed.
Abstract P216: Plant-Based Diets Are Associated With a Lower Risk of Cardiovascular Disease, Cardiovascular Disease Mortality, and All-Cause Mortality
Authors: Hyunju Kim, Laura E Caulfield, Vanessa Garcia-Larsen, Lyn M Steffen, Josef Coresh, Casey M Rebholz
Journal: Circulation (2019)

Introduction: Previous studies of plant-based diets and chronic diseases have limited generalizability because most have been conducted among vegetarians or Adventists who may have healthier lifestyles than the general population. Hypothesis: We hypothesized that plant-based diets are associated with lower risk of cardiovascular disease and all-cause mortality in a community-based US cohort. Methods: We used data from middle-aged adults (n=12,168) in the Atherosclerosis Risk in Communities (ARIC) study who were followed from 1987 to 2016. We classified participants’ diet using a plant-based diet index (PDI) and a provegetarian diet index. For the PDI, higher intakes of all plant foods were scored higher. For the provegetarian diet index, higher intakes of selected plant foods were scored higher. Higher intakes of animal foods were scored lower for both indices. We used Cox proportional hazards models to evaluate associations between plant-based diet indices and incident cardiovascular disease, cardiovascular disease mortality, and all-cause mortality, adjusting for several potential confounders. Results: On average, participants in the highest quintiles of PDI and provegetarian diet index consumed 4.8 servings of fruits and vegetables (FV) and 0.9 servings of red and processed meat per day. Participants in the lowest quintiles consumed 2.8 servings of FV and 1.5 servings of red and processed meat. Higher adherence to PDI was associated with 16% lower risk of cardiovascular disease, 31% lower risk of cardiovascular disease mortality, and 24% lower risk of all-cause mortality (all P -trend&lt;0.001, Table ). Similarly, higher adherence to provegetarian diet index was associated with a 15% lower risk of cardiovascular disease, 32% lower risk of cardiovascular disease mortality, and 18% lower risk of all-cause mortality (all P -trend&lt;0.001). Conclusions: Diets high in plant foods and low in animal foods were associated with lower risk of cardiovascular disease outcomes and all-cause mortality in a general population.
Medtronic subsidiary pays $17m to settle allegations of kickbacks to US doctors
Authors: Owen Dyer
Journal: BMJ (2019)

A subsidiary of the device maker Medtronic will pay $17.5m (£13.2m; €15.4m) to resolve allegations from the US Department of Justice that it offered doctors kickbacks in the form of free or discounted services to encourage them to buy its devices and bill the cost to Medicare or Medicaid.

The doctors received no money from the company, called Covidien, but the support it gave them in developing their practices and finding new patients nevertheless counted as an illegal inducement to bill the government for services that involved the company’s products, US attorneys warned.

“Today’s settlement serves as an important reminder to those in the healthcare …
Expression and significance of the co-regulatory ligands B7-H4 and PD-L1 in triple negative breast cancer.
Authors: Mehmet Altan, Kurt Alex Schalper, Matthew Silver, David L. Rimm
Journal: Journal of Clinical Oncology (2015)

1087 Background: B7-H4 is a member of the CD28/B7 family of immune co-inhibitory molecules and is upregulated in various tumors. It has been postulated that it functions as a negative regulator of effector T-cells. Here, we measured the levels of B7-H4 and PD-L1 protein in triple negative breast cancers (TNBC) using objective methods and determined their relationship with tumor infiltrating lymphocytes (TILs) and patient outcome. Methods: We used automated quantitative immunofluorescence (QIF) to assess the levels of B7-H4 (clone D1M8I, CST) and PD-L1 (clone E1L3N, CST) in 96 stages I-IV TNBC represented in tissue microarray format [YTMA149]. B7-H4 and PD-L1 were measured in the tumor and stromal compartments by simultaneous staining of pancytokeratin (Dako) and DAPI. The proportion of stromal TILs was assessed in H&E stained preparations by a pathologist using 10% increments, as recently reported. Cases with more than 50% stromal TIL content were considered as lymphocyte predominant breast carcinomas (LPBC). Results: B7-H4 expression was detected in 83 % of cases (80/96) and PD-L1 in 9% (9/96). In samples with high B7-H4 levels, the signal was predominantly located in the tumor compartment. Elevated PD-L1 was seen both in tumor and stromal cells. LPBC corresponded to 28% of cases (26/96) and were significantly associated with tumor and stromal PD-L1 expression (Table). Expression of B7-H4 was not associated with LPBC or PD-L1 positivity. Regression analysis of PD-L1 and B7H4 is suggestive of an inverse relationship. In univariable survival analysis expression of B7-H4 and PD-L1 were not significantly associated with overall survival. Conclusions: B7-H4 is expressed in the majority (~80%) of TNBC, but is not associated with the lymphocyte infiltrates. PD-L1 expression occurs in a lower proportion of TNBC (~10%) and shows strong association with LPBC. Most cases that are high for B7H4 are low for PD-L1, suggesting that expression of these checkpoints may be specific to tumor regions or types. Futures studies are required to better understand the relationship between these two immune checkpoints. Protein Expression High TILs Low TILs P value Tumor stroma PD-L1 194 ± 18 324 ± 28 <0.0005 Tumor PD-L1 219 ± 15 299 ± 30 <0.012
The features and management of late relapse of non-seminomatous germ cell tumors: The Royal Marsden Experience.
Authors: Robert A Huddart, Erik Mayer, Alexander Jay, Adam Pearce, Alison Helen Reid, David Nicol
Journal: Journal of Clinical Oncology (2019)

529 Background: Late relapses (LR) of non-seminomatous germ cell tumours (NSGCT), defined as those occurring after a disease free interval of 2 years, are increasingly recognised. We reviewed the features of LR in NSGCT within a tertiary referral testicular cancer service. Methods: 3,064 patients (pts) were referred to the testis multi-disciplinary team (January 2005 to Dec 2017). Pts who experienced a LR where initial pathology demonstrated NSGCT were identified. Data of their original and late presentation and management was reviewed from patient electronic records. Results: Of the 3,064 pts, 101 (3.3%) had a LR, with 43 pts (43%) relapsing after 10 years. 36 were symptomatic and 39 had raised markers (AFP 29, HCG 9, both 1). Table 1 shows stage at initial presentation and time to relapse. As regards treatment before late relapse, 13 CS1 patients had received prior chemotherapy (Cht) (8 as adjuvant and 5 Cht for early relapse). 59/60 CS2/3 patients received Cht as primary treatment and 41 had a post chemotherapy retroperitoneal lymph node dissection(PC-RPLND (bilateral template in 12). 20 of these 41 men who had a PC-RPLND experienced a LR in the retroperitoneum (6 after bilateral template) Patient management at relapse is summarised in table.Time to recurrence was longer in CS2/3 patients (p&lt;0.001). 84 surgical procedures were [performed in 82 patients; histology was TD in 43, Yolk sac 14, De-differentiated in 7 and viable GCT in 12, benign 8. To date 22 patients have died, 13 of these patients relapsed at multiple sites. Conclusions: LR of NSGCT frequently occurs after an extended interval and typically occurs earlier in CS1 disease compared to higher stages. Aggressive surgery +/- chemotherapy can cure most patients. [Table: see text]
Abstract 14753: A Novel Quadripolar Lead with a Narrow-Spaced Bipole Allows for Effective LV Pacing While Avoiding Phrenic Nerve Stimulation - Attain Performa LV Lead Study Primary Results
Authors: George H Crossley, Maurio Biffi, W. Ben Johnson, Albert C Lin, Daniel Gras, Azlan Hussin, Shelby Li, Angela Smedberg, Derek V Exner
Journal: Circulation (2014)

Introduction: The Medtronic Attain Performa™ Model 4298 Quadripolar left ventricular (LV) Lead has 4 electrodes, provides 16 different polarities &amp; includes a short bipole (1.3 mm between 2nd &amp; 3rd electrodes). A prospective clinical study was conducted to investigate the safety and effectiveness of this new lead in 20 countries worldwide. Methods: Cardiac resynchronization therapy defibrillator (CRT-D) patients were enrolled &amp; implanted with the Model 4298 LV lead &amp; a Quad CRT-D device. All implanted subjects(SUB) were followed at 1, 3, 6 and every 6 months (M) post-implant. Pacing capture thresholds (PCTs) were measured manually or with automated testing methods. Adverse events (AEs) were reported upon occurrence &amp; reviewed by an independent committee. Events requiring invasive intervention or resulting loss of CRT were considered to be complications. Results: Of 499 SUB (68 + 11 yr, 71% male) who underwent an LV lead implant attempt, 487 (97.6%) had an LV lead implanted, Most (73%) had NYHA Class III or IV symptoms, average LV ejection fraction was 25 ± 7%, QRS duration was 155 ± 24ms &amp; most (71%) had LBBB. There were 20 LV lead related complications in 19 SUB over 6M (LV lead related complication free survival rate = 96%). Phrenic nerve stimulation (PNS) occurred in 31 SUB (6.3%) &amp; resolved with no treatment (N=1) or noninvasive reprogramming (N=29). The average PCT at 6M was 1.1 + 0.7 V at the programmed vector and 93.9% of SUB had a PCT≤ 2.5V. The vast majority (97.7%) of SUB had &gt; 1 additional selectable pacing vector with a PCT ≤ 4V and no PNS. Non-standard pacing polarities (i.e., vectors other than LV1 [LV tip] to right ventricular coil [RVC], LV2 to RVC &amp; LV1 to LV2) were utilized in 56% of SUB. LV1 was not used in the final vector in 46% of SUB. The LV1 to RVC was utilized in 19%, LV1 to LV2 in 18% &amp; the short bipole (LV2 to LV3) in 12%. Conclusions: This large multicenter study demonstrated that implantation of the Model 4298 LV quadripolar lead is associated with a low complication rate and no unanticipated complications. PNS can be readily resolved with reprogramming &amp; that PCT values are low &amp; stable over time. Moreover, At least 1 back-up LV pacing vector was available in the vast majority of SUB. Non-standard vectors, including the short bipole (LV2-LV3) were used in 56% of subjects.