tbuckley/cabot-search huggingface dataset:
Salvage surgery with abdominoperineal excision of the rectum (APER) following loco-regional failure after chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance 5FU/CisP chemotherapy (CT) in squamous cell carcinoma of the anus (SCCA) and the impact on long-term outcomes: Results of ACT II.
Authors: Robert Glynne-Jones, Helen Margaret Meadows, Andre Lopes, Richard A. Adams, Leslie M. Samuel, James Hill, Andrew Renehan, Maria A Hawkins, David Sebag-Montefiore
Journal: Journal of Clinical Oncology (2016)

3523 Background: Concurrent CRT is standard treatment for patients with SCCA. We explored the results of surgical salvage with APER in ACT II, which compared 5FU/CisP with 5FU/MMC concurrent with a uniform RT dose (50.4Gy, 28 daily fractions of 1.8Gy), and a second randomization to maintenance chemotherapy. Methods: The ACT II trial recruited 940 patients. We examined the overall survival of patients from the time of salvage surgery post CRT according to 4 time periods: Group A - operated ≤ 6 months of CRT (n = 19); Group B - between > 6 and ≤ 12 months (n = 36); Group C - between > 12 and ≤ 24 months (n = 28); Group D - after > 24 months (n = 18) respectively. Results: There were 291 disease failures (31%) overall - males, total radiation dose, and tumor stage were independent predictors of local failure. Of 291 relapses, surgical salvage with APER was attempted in 107 (37%) loco-regional failures of whom 101 were evaluable and 53 subsequently died. The 2-year OS rates after local disease failure from time of salvage APER to death from any cause was 54% (43%-63%). Rates of OS beyond 2 years are unreliable given the small number of patients at risk after 2 years. Death rate after salvage APER was 15/19(79%), 21/36(58%), 12/28(43%) and 5/18(28%) in Groups A, B, C and D. Conclusions: In the management of SCCA, local failure may benefit from early detection and salvage by radical surgery. Results of radical surgery performed in ACT II in 37% compare with 56% in ACT I. These observations suggest close imaging with MRI and clinical surveillance may be helpful in the first 2 years, and imply the need for a trial to test further systemic interventions such as chemotherapy peri-operatively. Clinical trial information: 26715889.Time from salvage surgery until death Group A N = 19 Group B N = 36 Group C N = 28 Group D N = 18 Overall N = 101 Median OS (months), IQR 9.6 (5.8 to 26.3) 21.1 (11.7 to 118.1) 47.7 (15.7 to NR) NR 30.3 (11.7 to 118.1) Hazard Ratio (HR), (95% CI) 1.00 (baseline) 0.53 (0.27 to 1.03) 0.33 (0.15 to 0.70) 0.31 (0.11 to 0.85) HR, (95% CI) p-value - 0.062 0.004 0.024
Food protein–induced enterocolitis syndrome: Increased prevalence of this great unknown—results of the PREVALE study
Authors: Sara Bellón Alonso, Jorge García Ezquiaga, Patricia Torija Berzal, Sara Díaz Tardón, María Muñoz San José, Patricia Alonso López, Teresa Bracamonte Bermejo, Sergio Quevedo Teruel, Luis Ángel Echeverría Zudaire
Journal: Journal of Allergy and Clinical Immunology (2018)
Pilot trial of an Indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor plus a multipeptide melanoma vaccine in patients with advanced melanoma.
Authors: Craig L. Slingluff, Steven Fling, Ileana S Mauldin, Marc S. Ernstoff, Brent Allen Hanks, Keith A. Delman, David H. Lawson, Brian Gastman, Judith C Kaiser, Martin A. Cheever
Journal: Journal of Clinical Oncology (2018)

3033 Background: Melanoma metastases limit infiltration and function of antitumor T cells in part by immunosuppression with IDO1. INCB024360 (epacadostat) is an IDO1 inhibitor that normalizes serum kynurenine/tryptophan (Kyn/Trp) ratios. MELITAC 12.1 multipeptide vaccine induces CD8 T cell responses to melanoma antigens. A clinical trial was designed to test hypotheses that IDO1 inhibition (IDO1i) plus vaccine will be safe, that IDO1i will increase CD8 T cell infiltration into metastases and will enhance immune signatures in tumor, which will be further increased by the vaccine. Methods: Patients (pts) with stage IIIB-IV melanoma were treated with INCB024360 days(d) 1-98 (300 mg po bid), and with MELITAC 12.1 emulsified in incomplete Freund's adjuvant d21, 28, 35, 56, 77, 98. Prior checkpoint blockade therapy was allowed. Tumors were biopsied pretreatment, d21, and d42, when feasible. Safety was assessed by CTCAE v4. The primary immunologic endpoint was tumor infiltration with CD8+ T cells. The biologic effect of INCB024360 on IDO1 function was assessed by serum Kyn/Trp ratio. Clinical outcomes were assessed by RECIST 1.1. Results: Eleven eligible pts were enrolled and treated. There were dose-limiting toxicities (DLTs) in 2 pts: grade 3 transaminase elevation, grade 3 syncope, both of which resolved. Six pts had all evident sites of disease resected in protocol biopsies and 1 had non-measurable disease. Of 4 pts with measurable disease beyond d42, best overall responses were PR (1), SD (3). INCB024360 reduced serum Kyn/Trp ratios 44% (mean) by d21 (normalized in 10/11 pts). In 5 pts with evaluable biopsies d0 and d42, with multispectral immunofluorescence histology, CD8 T cell infiltrates increased significantly to d42. Conclusions: Combination therapy with INCB024360 and multipeptide vaccine was considered safe with transient DLTs in only 2 patients (18%). INCB024360 normalized serum Kyn/Trp ratios in 91% of patients at 300 mg bid. Clinical activity was observed. There is evidence of enhanced CD8 T cell infiltration with the combination. Ongoing studies will assess the impact of INCB024360 on immune signatures and tumor infiltrating T cell function. Clinical trial information: NCT01961115.
The clinical significance of CD70 expression in patients with squamous cell carcinoma of the lung.
Authors: Jin Ho Baek, Young Min Kim, Sungchan Park, Chang Hoon Moon, Won Hyeok Lee, Hee Jeong Cha, Jong-Joon Ahn, Yangjin Jegal, Kwang Won Seo, Seung Won Ra, Taehoon Lee, Byung Ju Kang, Chang Ryul Park, Yong Jik Lee, Woon Jung Kwon, Young Ju Noh, Young Joo Min
Journal: Journal of Clinical Oncology (2016)

e20544 Background: CD70 is a co-stimulatory factor present on B-cells, activated T-cells, and dendritic cells. CD70 overexpression may induce cytotoxic effects in B-cells and T-cells, induce lymphocyte apoptosis, and promote escape from the immune system. In this study, we investigated the clinical significance of CD70 expression in patients with squamous cell carcinoma (SCC) of the lung. Methods: Subjects who were treated with cytotoxic chemotherapy consisting of gemcitabine and platinum as first-line treatment were included in the study. Immunohistochemistry was performed to detect CD70 protein expression. When more than 10% of the tumor cells demonstrated a moderate to strong staining intensity for CD70, the samples were defined as having positive expression. Results: Forty-seven patients were enrolled in this study. Among them, 26 patients (55.3%) showed positive CD70 expression. In the negative expression group, the overall response rate was 38.1%, and the median progression-free survival (PFS) and overall survival (OS) were 5.5 months and 9.5 months, respectively. In the positive expression group, the overall response rate was 30.8%, and the median PFS and OS were 5.3 months and 9.5 months, respectively. The response characteristics were similar, and there were no significant differences in survival between the two groups. Conclusions: Positive expression of CD70 was observed in 55.3% of patients with advanced SCC of the lung. These results suggest that CD70 expression is neither a predictive nor a prognostic marker for advanced SCC of the lung in the era of cytotoxic chemotherapy. Further studies targeting CD70 may reveal the role of CD70 in cancer treatment.
CD205-Shuttle study: A first-in-human trial of MEN1309/OBT076 an ADC targeting CD205 in solid tumor and NHL.
Authors: Elena Garralda, Josep Tabernero, Victor Moreno Garcia, Maria José De Miguel, Elizabeth Ruth Plummer, Guy Heinrich Maria Jerusalem, Michele Spina, Christian Rohlff, Abrahim Fandi, Serena Buontempo, Mariagiuseppa Matera, Mario Cioce, D'Angiolella Paola, Monica Binaschi, Giuseppe Merlino, Paolo Mazzei, Cristina Rossi, Giulia Tonini, Cecilia Simonelli, Andrea Ugo Enrico Pellacani
Journal: Journal of Clinical Oncology (2018)

TPS2606 Background: MEN1309/OBT076 is a DM4-loaded Antibody Drug Conjugate (ADC), directed against CD205/Ly75, a type I transmembrane surface protein belonging to the macrophage mannose receptor family. CD205 is therapeutically relevant, because of its broad expression in multiple cancer types, its emerging role at facilitating metastatic invasion and its effective internalization upon antibody binding. Extensive preclinical evidence demonstrated MEN1309 antitumor activity in vitro, in xenograft and patient-derived xenograft (PDX) models. Methods: The CD205-Shuttle study is a two-step, open-label, multicenter, dose-escalation FIH study. Step 1 involves patients affected by different solid tumors, following an Accelerated Titration Design (ATD) whereby 1 patient per dose cohort is enrolled and the dose doubled at each cohort. If grade ≥2 toxicity is observed the trial design is expected to revert to a 3+3 scheme with a Fibonacci ascending dose scheme. Step 2 is designed to test MEN1309/OBT076 at minus 2 levels of the tolerated doses during Step 1 in patients with Non-Hodgkin-Lymphoma (NHL). Each dose level escalation will be subject to the assessment of the Cohort Review Committee (CRC). CD205-positive patients are selected by IHC staining of archived tumor material. Patient with locally advanced or metastatic solid tumor in progression can be included if failed on ≥2 previous cancer treatments and if no standard therapy is available. The primary endpoint is to identify dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MEN1309/OBT076 administered by i.v. infusion once every 21-days. The secondary endpoints includes assessment of pharmacokinetics (PK), immunogenicity, preliminary clinical efficacy of MEN1309/OBT076 and correlation with CD205 expression. Adverse Events (AE) will be graded according to NCI CTCAE v. 4.03. Responses will be evaluated according to RECIST v1.1 and Cheson criteria (2014). Study variables will be presented by dose-cohort and overall using appropriate descriptive statistics. The enrollment began in October 2017 in European sites; up to date 3 cohort levels have been achieved. NCT03403725. NOTE: First and Second author equally contributed to this work Clinical trial information: NCT03403725.
Risk factors for gastrointestinal stromal tumors (GISTs) with suspicious/obvious tumor spillage.
Authors: Gaku Chiguchi, Haruhiko Cho, Shinsuke Sato, Tsuyoshi Takahashi, Kazuhito Nabeshima, Tsunehiko Maruyama, Mikinori Kataoka, Hirotoshi Kikuchi
Journal: Journal of Clinical Oncology (2016)

e22513 Background: In GIST, tumor rupture is occasionally observed, and this occurrence is associated with a worse prognosis due to probable tumor spillage. The presence of tumor rupture implies a high risk for recurrence even after curative surgery, and the patients with tumor rupture are candidates for treatment with adjuvant imatinib. However, the definition of rupture is unclear and it remains controversial as to whether patients with marginal ruptures should be treated with adjuvant imatinib. Patients and Methods: This retrospective multi-institutional study examined 47 GIST patients who had suspicious/obvious tumor spillage and underwent complete resection (R0/1) between January 2000 and December 2013. The data concerning the timing, degree, diagnostic method, and specific findings of tumor spillage were collected, and the patients who had tumors with microscopic breakage of the tumor capsule or intraoperative minor injury in the tumor capsule were also included in the study as suspicious spillage. A multivariate analysis was performed to identify the risk factors for recurrence-free survival (RFS) using a Cox proportional hazard model. Results: Tumors were classified as gastric (n = 31) or non-gastric (n = 16) tumors depending on location. The median tumor size was 8.0 cm and median mitosis was 15/50 HPF. Adjuvant imatinib therapy was administered to 22 patients. The timing of tumor spillage was 57.4% preoperatively and 42.6% intraoperatively. The two-year RFS of the intraoperative group was higher than that of the preoperative group (74.3% vs 49.1%, respectively). A multivariate analysis identified mitosis (HR = 1.01, p < 0.001), size (HR = 1.10, p = 0.035) and preoperative spillage (HR = 2.76, p = 0.026) as independent predictors of RFS. Conclusions: Among the GIST patients who likely have tumor spillage, the timing, but not degree of tumor spillage, was found to be an independent adverse prognostic factor, in addition to a high mitotic rate and a large tumor size. The indications for adjuvant imatinib should therefore be carefully considered for patients who suffer tumor rupture as a single high risk factor.
A phase 2 study to evaluate the safety and efficacy of Intratumoral (IT) injection of the TLR9 agonist IMO-2125 (IMO) in combination with ipilimumab (ipi) in PD-1 inhibitor refractory melanoma.
Authors: Adi Diab, Shah Rahimian, Cara L. Haymaker, Chantale Bernatchez, Robert Hans Ingemar Andtbacka, Marihella James, Douglas Buckner Johnson, Joseph Markowitz, Ravi Murthy, Igor Puzanov, Montaser F. Shaheen, Suzanne Swann
Journal: Journal of Clinical Oncology (2018)

9515 Background: PD-1/L1 inhibitors have transformed MM treatment, however many patients (pts) remain refractory. Subsequent treatment options including ipi offer modest benefit (~13% respond) (Long, SMR 2016). IT IMO, a Toll-like receptor 9 agonist, may improve response to ipi by activating innate and adaptive immune responses to overcome immune escape. Tumor biopsies obtained from both injected/local and uninjected/distant lesions during earlier studies show maturation of the mDC1 subset (CD1c+CD303-), upregulation of PD-L1 by tumor cells, and an IFNα response gene signature. On treatment( week 8) biopsies of uninjected/distant tumors show expression of CD56+ and Ki67+ effector CD8+T cells in responding pts, indicative of an abscopal effect. Initial clinical experience with IMO + ipi is promising resulting in the selection of 8mg as the RP2D. Here we report an analysis of the first 15 subjects that received 1+ doses of study drugs. Methods: This is a phase 2 study for adults with unresectable or MM refractory to a PD-1 inhibitor pts are eligible if they have an accessible tumor for IT administration of IMO. 8mg IMO is administered to a single tumor during weeks 1,2,3,5,8, and 11 along with ipi per the product label. The primary endpoint is overall response rate (ORR) using a 2-stage design. Results: A total of 24 pts have been treated with IMO + ipi including pts that received injections to deep visceral lesions and lymph nodes. Grade 3 /4 Immune-related AE were observed in 6 subjects [hypophysitis (N = 2), hepatitis (1), Gastritis (1), Guillain-Barre syndrome (1), Colitis (1), Neutropenia (1)]. These responded well to standard measures. Of 24 pts treated at the RP2D of 8mg, 15 were assessed for response with 47% ORR of and 67% disease control rate (1 Complete Response, 6 Partial Response(3 confirmed), 3 Stable disease). Phase 2 accrual is ongoing. Conclusions: IMO + ipi is a robust strategy to revive the immune response in PD-1/L1resistant tumors and the demonstrated substantial clinical benefit including durable responses in this clinically challenging pt population. This data supports the initiation of a phase 3 study compared to ipi alone. Clinical trial information: NCT02644967.
Gout, Xanthine Oxidase Inhibition, and Cardiovascular Outcomes
Authors: William B. White
Journal: Circulation (2018)

Gout, a chronic rheumatologic illness characterized by hyperuricemia, arthritis, tophaceous deposits, and renal calculi, is associated with increased rates of cardiovascular and chronic kidney disease. 1 Prospective observational studies have shown that the risk of cardiovascular mortality is higher in people with gout and coronary heart disease compared with those with coronary disease who do not have gout. 2 Epidemiological associations among hyperuricemia, gout, and risk factors for cardiovascular disease are robust, 3 but whether hyperuricemia and gout are independent risk factors for coronary disease remains controversial.Urate has a complex relationship to oxidative stress, possessing both scavenging properties as well as oxidizing and radical-forming properties. 4,5These data have led to small, interventional studies that have shown that urate-lowering agents such as allopurinol may improve a number of cardiovascular conditions, including heart failure, 6 hypertension, 7 and chronic kidney disease. 8he xanthine oxidase inhibitors are the mainstay of therapy for reducing serum urate levels in patients with gout.The xanthine oxidase inhibitor allopurinol was approved in 1966, and febuxostat, a nonpurine inhibitor of xanthine oxidase, was approved for the management of hyperuricemia in patients with gout in 2009.Allopurinol and its metabolites are structural analogues of both purines and pyrimidine compounds and thus can affect enzymes in both metabolic pathways, whereas febuxostat is a nonpurine inhibitor of only xanthine oxidase. 9In clinical practice, the pharmacological advantages of febuxostat over the commonly used doses of allopurinol have included greater serum urate-lowering efficacy, fewer reported severe hypersensitivity reactions, and no requirement for dose adjustment in patients with moderate renal impairment, a common comorbidity in gout. 1,9uring the development of febuxostat, this drug was compared to placebo and allopurinol in clinical trials involving >5000 patients with gout. 9,10These studies showed a small imbalance in the rates of major cardiovascular events occurring at 0.74 per 100 patient-years with febuxostat versus 0.60 per 100 patient-years with allopurinol.The US Food and Drug Administration approved febuxostat with the contingency that a large cardiovascular safety outcome study be performed to determine its cardiovascular profile compared to allopurinol in patients with gout.This study, the CARES trial (Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities), was conducted between 2010 and 2017 to determine whether febuxostat was noninferior to allopurinol on major cardiovascular events in patients with gout and cardiovascular disease. 11he study population for the CARES trial was limited to patients with gout who had prior evidence of cardiovascular disease, a strategy previously used in the US Food and Drug Administration-mandated cardiovascular safety studies in diabetes
Abstract 12175: Microsurgical Technique in Coronary Surgery Improves Long-term Outcomes
Authors: Andrey Shiryaev, Michael Lepilin, Damir Galyautdinov, Vladislav Vasilyev, Dmitriy Cherkashin, Renat Akchurin
Journal: Circulation (2016)

Introduction: The operating microscope is widely used in surgical practice, but there is no common opinion on the benefits of its use in coronary surgery. Objectives: The aim of this study was to compare the long-term outcomes of coronary artery bypass grafting with microsurgical technique and conventional technique. Methods: We have studied 270 patients operated on for coronary artery disease by the same surgical team in 2004. We included observations of 3-vessel disease in which at least 1 bypassed vessel was type C according to Coronary Artery Surgery Study protocol or had the diameter at the anastomotic site of less than 1.5 mm. Patients were randomly assigned to 2 groups: microsurgical group (n=128); patients were operated on using a microsurgical technique (8-12х magnification, 8-0 polypropylene sutures with a 3/8, 6.5 mm needle for distal anastomoses) and nonmicrosurgical group (n=142); patients were operated on with a magnifying loupes (3.5х magnification, 8-0 polypropylene sutures with a 3/8, 8.0 mm needle). The mean number of distal anastomoses in microsurgical group was 4.1±0.8 vs 3.9±0.9 (p=ns) in nonmicrosurgical group, the number of anastomoses to arteries of less than 1.5 mm - 254 vs 121 (p=&lt;0.001) and patients with endarterectomies - 3 vs 44 (p=&lt;0.001), respectively. In all cases the left internal thoracic artery was anastomosed to the left anterior descending coronary artery. Follow-up was complete in 95% (258 patients). Survival curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Results: Ten-year survival rates in groups of patients operated on with and without the use of microsurgical technique were 82.7% vs 72.0% (p=0.03), incidence of non-fatal myocardial infarction - 9.8% vs 16.1% (p=0.14), recurrence of angina - 14.7% vs 22.7% (p=0.11), repeat interventions - 8.1% vs 17.6% (p=0.02), all cardiac events - 34.4% vs 58.8% (p=0.0001), respectively. Conclusions: The use of the microsurgery compared with the conventional technique yields superior clinical results in coronary surgery during a 10-year follow-up.
New treatment for advanced and hormone refractory prostate cancer (HRPC) with an oral cholesterol derivative (hydroxysterol 24-ethyl-cholestane- 3β,5α,6α-triol).
Authors: Nabil Habib, George Hage, Hamid Elia Daaboul, Abdo Elias Jabbour, Hind Zeitouni, Ryiad Khalife
Journal: Journal of Clinical Oncology (2017)

e16531 Background: Hydroxysterols and oxysterols are oxygenated derivatives of cholesterol. They are involved in the regulation of some aspects of neoplastic cell growth and proliferation, as demonstrated in vitro in a variety of human cancer cells including prostate cancer cells.These effects can be dependent on the activation of the oxysterol-binding liver X receptors (LXRs). LNCaP prostate tumor cells stimulated with synthetic LXR agonists showed G 1 to S-phase cell cycle arrest through the suppression of Skp2.Prostate cancer is the most frequent cancer in men and most patients become resistant to upfront treatments with hormones. At advanced stages most refractory patients are symptomatic and their life expectancy is limited. (24-ethyl-cholestane- 3β,5α,6α-triol) is a new hydroxysterol developed by us. It is the first oxysterol to be tested in the clinic. It is also one of the safest in this class of compounds. Methods: We have treated with this new drug 14 patients suffering from advanced and hormone-refractory prostate cancer (HRPC). Their median age was 73 (60-88). Seven with a Gleason 7, 5 with a Gleason 8 and 2 with a Gleason 9. Eleven had stage IV disease, Eight with bone metastasis, 4 with advanced loco-regional disease and 2 with visceral metastasis. Ten patients were symptomatic. Four patients had received also 1 line of chemotherapy and 2 others received 2 lines of chemo. Four patients were also previously treated with radiotherapy. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided into 3 equal doses, until disease progression. Results: Ten patients experienced either a biological or a radiological partial response (PR), Two patients had a stable disease (NC) and two patients had a disease progression (PD). The median duration of response was 2 years. Patients did not report any side-effect from treatment. Eighty percent of symptomatic patients had a remarkable symptom control. Conclusions: These encouraging results make this new and safe drug a good candidate for further clinical trials either alone or in combination with other drugs in the treatment of HRPC.