tbuckley/cabot-search huggingface dataset:
Genomic Disorders and Neurocognitive Impairment in Pediatric CKD
Authors: Miguel Verbitsky, Amy J. Kogon, Matthew Matheson, Stephen R. Hooper, Craig S. Wong, Bradley A. Warady, Susan L. Furth, Ali G. Gharavi
Journal: Journal of the American Society of Nephrology (2017)

Children with CKD are at increased risk for neurocognitive impairment, but whether neurocognitive dysfunction is solely attributable to impaired renal function is unclear. Data from the CKD in Children Study Chronic Kidney Disease in Children (CKiD) Study indicate that a subset of children with CKD have unsuspected genomic disorders that predispose them to organ malformations and neurocognitive impairment. We therefore tested whether the CKiD Study participants with genomic disorders had impaired neurocognitive performance at enrollment. Compared with noncarriers (n=389), children with genomic disorders (n=31) scored significantly poorer on all measures of intelligence, anxiety/depressive symptoms, and executive function (differences of 0.6-0.7 SD; P=1.2×10-3-2.4×10-4). These differences persisted after controlling for known modifiers, including low birth weight, maternal education, seizure disorder, kidney disease duration, and genetically defined ancestry. The deleterious effect of genomic disorders on neurocognitive function was significantly attenuated in offspring of mothers with higher education, indicating the potential for modification by genetic and/or environmental factors. These data indicate that impaired neurocognitive function in some children with CKD may be attributable to genetic lesions that affect both kidney and neurocognitive development. Early identification of genomic disorders may provide opportunity for early diagnosis and personalized interventions to mitigate the effect on neurocognitive function.
Incidence of venous thromboembolism (VTE) in ambulatory day oncology patients.
Authors: John Patrick Greene, Gina McClelland, Jennifer Lynn Westrup
Journal: Journal of Clinical Oncology (2014)

e20720 Background: Venous thromboembolism (VTE) represents one of the most important causes of morbidity and mortality in cancer patients. VTE commonly includes deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of VTE is increased by the cancer type, histology and the stage of the cancer and by certain types of chemotherapy, hormonal therapy and anti-angiogenic regimens. Current guidelines do not routinely recommend thromboprophylaxis for outpatients with cancer receiving chemotherapy. Methods: We performed a single academic institution retrospective review of the incidence of VTE in all ambulatory oncology outpatients patients with a confirmed cancer diagnosis attending over a twelve month period. Patients did not receive thromboprophylaxis. Results: In total, we reviewed the cases of 314 patients. Of these, 62 patients were investigated for VTE. The overall incidence of VTE was 7%. The incidence of PE was 3.2% and the incidence of DVT was 4.1%. Investigations for PE and DVT with CT pulmonary angiogram(CTPA) and doppler ultrasound were positive in 43% and 35% of cases respectively. VTE was also more likely to be detected in patients with metastatic cancer (57%) compared to patients treated with adjuvant (35%) or neoadjuvant chemotherapy (4%). The highest incidence of VTE occurred in genitourinary cancers (35%) followed by lower colorectal cancers (25%) and gynaecological cancers (17%). There were no deaths directly attributed to VTE in this ambulatory population. Conclusions: In this single academic institution study, our data on the incidence of VTE in ambulatory cancer patients who are not on routine prophylaxis, compares favourably with recently published literature. Current ASCO guidelines do not recommend routine thromboprophylaxis for outpatients with cancer however it may be considered for selected high-risk patients. Novel oral anti-coagulation prophylaxis may decrease the morbidity and mortality of VTE associated with malignancy, however they are not currently recommended for prophylaxis or treatment of VTE in malignancy. Further research will provide more reliable estimates of the thrombotic risk associated with different types of tumours, stages of disease, and antitumour treatments.
Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target
Authors: Heather L. MacGregor, Pamela S. Ohashi
Journal: Clinical Cancer Research (2017)

With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment antitumor responses by targeting other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies. This high expression by tumors in combination with its low or absent protein expression in normal tissues makes B7-H4 an attractive immunotherapeutic target. Preclinical investigation into B7-H4-specific chimeric antigen receptor (CAR) T cells, antibody-mediated blockade of B7-H4, and anti-B7-H4 drug conjugates has shown antitumor efficacy in mouse models. The first clinical trials have been completed to assess the safety and efficacy of a B7-H4 fusion protein in ameliorating rheumatoid arthritis. Clin Cancer Res; 23(12); 2934-41. ©2017 AACR.
Micro-fabricated scaffolds lead to efficient remission of diabetes in mice
Authors: Mijke Buitinga, Frank Assen, Maaike Hanegraaf, Paul Wieringa, Janneke Hilderink, Lorenzo Moroni, Roman Truckenmüller, Clemens van Blitterswijk, Gert-Willem Römer, Françoise Carlotti, Eelco de Koning, Marcel Karperien, Aart van Apeldoorn
Journal: Biomaterials (2017)
Long-term survivors in phase I clinical trials: Who are they and what predicts their survival?
Authors: Begona Jimenez Rodriguez, Caroline Ogilvie Michie, David Lorente, Hasina Hassam, Helen Nicole Toloui, Jimena Lovosgaldeano, Debarati Goswami, Johann Sebastian De Bono, Stan B Kaye, Udai Banerji, L Rhoda Molife
Journal: Journal of Clinical Oncology (2014)

9590 Background: Phase I trials (PhIT) participants are those who have exhausted standard treatment (tx) or for whom no standard tx exists; most patients (pts) are unlikely to benefit from new drugs. Response rate and median overall survival (OS) are ~ 5-10% and 10 months (m), respectively; however, we observe pts with improved outcomes. This study aims to characterize who these long-term survivors are and define factors predicting for this prolonged OS. Methods: Retrospective analysis of patients treated at the Drug Development Unit, RMH-ICR, UK, between 01/05-12/12 and who survived ≥12m within ≥1consecutive PhIT. Kaplan-Meier method was used to estimate OS. Cox-regression-model was applied for HR estimation and for MVA of prognostic (px) factors for OS. Results: Of 1424 pts, 86 pts (6%, 44M/42F) survived ≥12m. Median (range): age 56 (23-85), PS 0 (0-1) and no. of prior Tx 2 (0-7). Most common tumor types: 34% gynaecological (79% ovarian) & 24% genitourinary (GU) (86% prostate). RMHscore (0-1/2-3) 76/10. Visceral disease (Y/N %) 46/54 (14% only bone metastases). 20% pts BRCAmut. 37 pts (43%) were treated in >1PhIT. % pts and drugs administered: 39.5% DNA repair-chromatin remodeling; 16.3% hormone synthesis; 46.5% growth-factor-receptor-pathways; 28.8% cytotoxic+new drug and 34.9% others. 42% pts had CR+PR v SD in 58% pts. Median OS was 46.5 m, with improved median OS for those who achieved CR+PR v SD (59.7m v 41.8m, p=0.02). Survival rate at 18,24 &36m was 95,90 & 68%. Cox-regression univariate analysis showed px significance of: GU-tumors [HR 0.43 (0.22-0.85),p=0.016), no-visceral –disease [HR 0.42 (0.25-0.72),p=0.002], only-bone-metastases [HR 0.28 (0.1-0.78),p=0.015], RMH<2 [HR 0.45 (0.21-0.96); p=0.034] clinical benefit with last anticancer tx[HR 0.56 (0.32-0.96), p=0.034] and response to PhIT [HR 0.55 (0.32-0.94), P=0.028]. MVA showed only the presence of visceral disease to be an independent px factor for OS. Conclusions: Despite an overall poor prognosis, a proportion of pts treated on PhIT demonstrate a clinically meaningful OS; moreover, in those who respond this outcome is significantly better. This is primarily dictated by low burden of disease, and may support the earlier referral of appropriate pts.
Phase I study of LJM716, BYL719, and trastuzumab in patients (pts) with HER2-amplified (HER2+) metastatic breast cancer (MBC).
Authors: Payal Deepak Shah, Sarat Chandarlapaty, Maura N. Dickler, Gary Ulaner, Stephen James Zamora, Valentina Sterlin, Alexia Iasonos, Christina Marie Coughlin, Alex Morozov, Joy Ero, Neal Rosen, Teresa Gilewski, Monica Nancy Fornier, Nancy T. Sklarin, Michael F. Berger, Mary Ellen Moynahan, Clifford A. Hudis, Jose Baselga, Shanu Modi
Journal: Journal of Clinical Oncology (2015)

590 Background: HER2+ breast cancer is driven by HER2/HER3/PI3K signaling. Single agent targeted therapy (tx) is limited by redundant mechanisms of pathway activation and feedback loops; preclinical models support combinatorial tx. This phase I trial examined HER2, HER3 and PI3K inhibition in pts with HER2+ MBC (NCT02167854). Methods: Pts received weekly intravenous (IV) trastuzumab (T) at 2 mg/kg, LJM716 (L, HER3 inhibitor) at 20 mg/kg, and escalating dose cohorts of daily oral BYL719 (B, PI3Kα inhibitor) starting at 250 mg. Eligible pts had HER2+ MBC with a PIK3CA mutation and prior ado-trastuzumab emtansine and pertuzumab. Endpoints were: to define MTD (toxicity based on CTCAE 4.0) using the Continual Reassessment Method, to assess efficacy (RECIST v1.1), to evaluate genomics and proteomics of pre- and on-tx tumor biopsies, and to quantify cell-free DNA and PIK3CA mutant allele fraction (MAF). Results: 8 pts have been treated with a median (M) age 56y (range (R): 46-68), M ECOG of 1 (R: 0-1), and M of 6 (R: 3-10) prior tx. M duration on study was 10 weeks (R: 2-21.9). 7 pts were treated with B 250 mg. 1 pt was treated at 300 mg and had a DLT of supraventricular tachycardia in the setting of hypokalemia. A second pt had a DLT of G3 transaminitis at B 250 mg. Significant toxicities (and worst grades) included diarrhea (G3: 5 pts; G1/2: 2 pts); hyperglycemia (G3: 2 pts; G1/2: 6 pts); hypokalemia (G3: 2 pts; G1: 4 pts); mucositis: (G3: 1 patient; G1/2: 4 pts); and transaminitis: (G3: 2 pts), with no G4 toxicity. Despite prophylactic antidiarrheals, diarrhea led to dose reduction in 1 (13%) and tx interruptions in 5 (63%) pts. Overall, toxicities limited drug delivery, with only 72%/83% of total planned B/L doses given. In addition, B was dose-reduced in 2 (25%) and L in 4 (50%) of pts. Best response was SD in 5 of 6 evaluable pts. Pre-tx genomics and PIK3CA MAF will be correlated with response. Conclusions: The combination of T, L, and B has antitumor activity in these pre-treated HER2+ pts with MBC with PIK3CA mutations. Clinically significant gastrointestinal and metabolic toxicities limit drug delivery and dose escalation of B/L. Based on preclinical modeling, exploration of intermittent dosing schedules is warranted. Clinical trial information: NCT02167854.
Phase II study of postperative radiotherapy (RT), cisplatin (Ci), and cetuximab (Ce) in resected bad prognostic head and neck squamous cell carcinoma (HNSCC): Toxicity analysis.
Authors: Karen Benezery, Christian Righini, Emmanuel Chamorey, Benjamin Lallemant, Herve le Caer, Franck Darloy, Bruno Guelfucci, Charlotte Dupuis, Olivier Dassonville, Frederic Peyrade
Journal: Journal of Clinical Oncology (2012)

e16051 Background: Despite toxic multimodal about 60% of resected HNSCC relapse. The addition of both Ce or Ci to RT improved overall survival of patients with HNSCC. Consequently, we designed a prospective phase II study, to evaluate the feasibility and efficacy of concomitant RT-Ci and Ce in bad prognostic resected HNSCC. Methods: Patients have resected HNSCC of the oral cavity , oropharynx, larynx or hypopharynx, and at least one of the following adverse prognostic factors: microscopically incomplete resection, &gt;2 metastatic lymph nodes and/or &gt;1 lymph node with extracapsular spread, vascular and/or lymphatic emboli, &gt;2 perineural invasion, positive margins and pT4. All patients received: RT 70-72Gy in 7 weeks concurrent with Ce 250mg/m² weekly (6-7 weeks), after a loading dose of 400mg/m², and Ci 75mg/m² every 3 weeks x3 cycles. The primary endpoint is the 2 years disease-free survival. Results: 45 patients (35 Male) were enrolled, and 44 were evaluable for toxicity. Median age was 56 years (27-70). The tumor site was oral cavity (21), oropharynx (17), hypopharynx (3) and larynx (4). 39% of the patients had stage T2, 14% stage T3 and 27% stage T4. The nodal status was 0-2b in 80% of cases. The main adverse prognostic factors were the nodal involvement and microscopical positive resection (80% of patients). The RT-Ce-Ci regimen was discontinued in 11 cases including 7 due to toxicity. Among the 352 cycles (ie Ce+/-Ci) initially planned, 301 were delivered. Cutaneous and mucosal toxicity were the most common grade 3/4 side effects, accounting for 35% and 33%, respectively, and remained manageable. Grade 3 lymphopenia has been noted in 25% of cases. No treatment-related death was recorded. Conclusions: The triple association of RT-Ce-Ci appears to be safe and feasible in patients with bad prognostic resected HNSCC. The toxicity profile is comparable to that reported for RT-Ci or RT-Ce alone. Longer follow-up is required to evaluate the impact of addition of Ce to RT-Ci on survival.
Ponatinib (PON) in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation: Longer-term follow up of the PACE trial.
Authors: Hagop M. Kantarjian, Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D. Le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane Apperley, Hanna Jean Khoury, Moshe Talpaz, John F DiPersio, Michele Baccarani, Stephanie Lustgarten, Frank G. Haluska, Francois Guilhot, Michael W.N. Deininger, Andreas Hochhaus, Timothy P. Hughes, Neil P. Shah, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2014)

7081 Background: PON is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the resistant T315I mutant. The efficacy and safety of PON (45 mg QD) were evaluated in the phase 2 PACE trial. Methods: 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation were enrolled. Data are as of 3 Sept 2013; median follow-up 24 (0.1-35) mo. NCT01207440. Results: Pts were heavily pretreated: 58% received ≥3 TKIs. 42% remained on study (55% CP-CML). The most common reasons for discontinuation: PD (21%) and AEs (14%, most common was thrombocytopenia, 4%). Table shows response rates at any time. In CP-CML, 89% pts maintained MCyR for at least 2 yr; progression-free survival (PFS) and overall survival (OS) at 2 yr were 67% and 86%. For AP-CML, BP-CML, and Ph+ ALL, OS at 2 yr was 72%, 18%, and 21%, respectively. Most common treatment-emergent AEs (≥30%) were thrombocytopenia (43%), rash (40%), abdominal pain (40%), headache (36%), constipation (36%), dry skin (36%). Pancreatitis and pneumonia were the most common serious AEs (SAEs; both 6%). Vascular occlusive AEs [SAEs] were reported as follows: overall 20% [14%], including cardiovascular 9% [6%], cerebrovascular 6% [4%], peripheral vascular 6% [4%] (collectively arterial thrombotic events, ATEs), venous thromboembolic 5% [3%]. Higher dose intensity, older age, and CV risk factors were associated with a higher likelihood of an ATE; pts with and without CV risk factors experienced these events. OS at 2 years was not reduced in pts with an ATE (73%) vs those without (69%); MCyR in CP-CML pts with vs without ATE was 70% vs 51%. Conclusions: PON has substantial clinical activity in heavily pretreated pts with Ph+ leukemias. PON is an important treatment option for pts in whom the need and benefit outweigh the risk. Clinical trial information: NCT01207440. R/I, n (%) T315I, n (%) Total, n (%) CP-CML N=203 N=64 N=267 MCyR 113 (56) 46 (72) 159 (60) CCyR 98 (48) 45 (70) 143 (54) MMR 63 (31) 37 (58) 100 (38) AP-CML N=65 N=18 N=83 MaHR 40 (62) 11 (61) 51 (61) BP-CML N=38 N=24 N=62 MaHR 12 (32) 7 (29) 19 (31) Ph+ ALL N=10 N=22 N=32 MaHR 5 (50) 8 (36) 13 (41)
Treatment-free remission (TFR) following nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom, ENESTop, ENESTgoal, and ENESTpath.
Authors: Francois-Xaxier Mahon, Michele Baccarani, Michael J. Mauro, Timothy P. Hughes, Giuseppe Saglio, Michael Savona, Tomasz K. Szczudlo, Hans D. Menssen, Christopher Hunt Keir, Claudia Walasek, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2014)

TPS7124 Background: Approximately 40% of pts who achieve deep, sustained molecular response (MR) on imatinib (IM) are able to successfully maintain TFR (Mahon FX, et al. Lancet Oncol. 2010;11:1029-1035). NIL results in higher rates of deep, sustained MR vs IM and may enable more pts to achieve successful TFR. Four ongoing studies will evaluate the key factors for achieving and sustaining TFR following NIL in pts with CML-CP (Table). Methods: Each study includes a NIL consolidation phase, during which pts undergo frequent molecular monitoring, followed by a TFR phase. In ENESTfreedom and ENESTop, pts with MR4.5 (BCR-ABL ≤ 0.0032% on the international scale [BCR-ABLIS]) on NIL directly enter the 1-y consolidation phase upon enrollment. In ENESTgoal and ENESTpath, pts without deep MR on IM are switched to NIL upon enrollment; after switching to NIL, pts in ENESTgoal who achieve MR4.5 and pts in ENESTpath who complete 2 y of NIL therapy and achieve MR4 (BCR-ABLIS ≤ 0.01%) will be randomized to a 1- or 2-y consolidation phase. Each study protocol defines a required MR level that pts must maintain during the consolidation phase to be eligible for the TFR phase. During the TFR phase of each study, pts must re-initiate therapy if their MR rises above a defined threshold (ie, molecular relapse). The rate and duration of successful TFR on NIL will be evaluated in each study. Clinical trial information: NCT01784068. ENESTfreedom NCT01784068 ENESTop NCT01698905 ENESTgoal NCT01744665 ENESTpath NCT01743989 Planned N 175 117 300 1,058 Treatment prior to enrollment (duration) Frontline NIL (≥ 2 y) Second-line NIL (≥ 3 y total; ≥ 2 y NIL) IM (≥ 1 y) IM (≥ 2 y) Response at enrollment MR4.5 MR4.5 MMR but not MR4.5 Complete cytogenetic response but not MR4 NIL consolidation phase duration 1 y 1 y 1 y or 2 y 1 y or 2 y MR required during NIL consolidation phase to be eligible for TFR phase MR4.5 MR4.5 MR4.5 MR4 Trigger to re-initiate therapy Loss of MMR Loss of MMR or confirmed loss of MR4 Confirmed loss of MR4 Loss of MMR or confirmed loss of MR4 Abbreviations: MMR, major molecular response (BCR-ABLIS ≤ 0.1%).
Clinical outcomes in borderline resectable pancreatic cancer: A cohort study.
Authors: Davendra Sohal, Mohammad Altujjar, Katherine Tullio, Mohamed Abazeed, Robert James Pelley, Michael J. McNamara, Bassam N. Estfan, Marc A. Shapiro, Alok A. Khorana
Journal: Journal of Clinical Oncology (2017)

494 Background: The management of borderline resectable pancreatic cancer (BRPC) remains unsettled and the predictors of outcome are uncertain. We evaluated the role of neoadjuvant therapy (nRx) and outcomes in patients with BRPC. Methods: We conducted a retrospective cohort study of consecutive patients with BRPC who received nRx and were followed at the Cleveland Clinic. A histopathologic diagnosis of pancreatic carcinoma was required. Tumor anatomy was assessed by contrast-enhanced cross-sectional imaging (CT or MRI), and BRPC was defined as a tumor-vessel wall interface involving one or more of: celiac artery, superior mesenteric artery, common hepatic artery, main portal vein, superior mesenteric vein; making margin-negative resection unlikely. Baseline laparoscopy was performed to rule out occult metastatic disease. Chemotherapy (CT), radiation (RT), surgery details, and pathologic and survival outcomes were evaluated. Hazard ratios (HR) with 95% confidence intervals (CI) and 2-sided p-values are presented. Results: The study population comprised 79 patients from 2009 to 2014. Median age was 64 years; 52% were male; 85% were Caucasian. Pancreatic head/neck were the primary site in 81%; body/tail in 19%. Vascular involvement included arterial in 32 (41%), and venous in 65 (82%) patients. nRx included RT in all patients; 77 (97%) received CT; gemcitabine (n = 50, 63%) was the most common agent. After CT/RT, 36 (46%) patients had unresectable/inoperable disease: 29 (37%) for anatomic reasons, 4 (5%) for physiologic reasons, and 3 (4%) for both. Surgical resection was performed in 43 (54%) patients; 38 (88%) had negative margins; 30 (70%) had negative nodes; 32 (74%) received adjuvant CT. There were no statistically significant predictors of resection. After median follow-up of 27 mths, there have been 45 deaths (57%); median overall survival (mOS) is 23.5 mths (95% CI: 16-28 mths). Only cancer resection was associated with survival (mOS, resected: not reached; mOS, not resected: 12.8 mths; HR: 0.30, 95% CI: 0.16-0.56, p = 0.0002). Conclusions: Surgical resection, if feasible, of BRPC is associated with improved OS. Strategies to improve the odds of resection should be evaluated in prospective studies.
Visceral thromboses (VT) in pancreas adenocarcinoma (PDAC): A systematic review.
Authors: Angel Mier Hicks, Antonio Derosa, Micheal Raj, Richard Kinh Gian Do, Kenneth H. Yu, Maeve Aine Lowery, Anna M. Varghese, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

268 Background: Within the spectrum of gastrointestinal malignancies, primary liver (HCC) and pancreatic ductal adenocarcinoma (PDAC) are frequently associated with visceral thromboses (VT). Thrombus formation in the portal (PVT), mesenteric (MVT), or splenic vein (SVT) system leads to portal hypertension and intestinal ischemia. VT in PDAC may convey a risk of increased distal thrombosis and poses therapeutic uncertainty regarding the role of anticoagulation. An increasing number of reports describe VT associated with PDAC. It is possible that early diagnosis of these events may help reduce morbidity speculatively improve oncologic outcomes. Methods: Perform a systematic review to study occurrences of visceral thromboses (portal, mesenteric and splenic vein thromboses) associated with PDAC and provide a clinical review on this area. Main databased were searched; PubMed, EMBASE, Web of Science, Scopus, and the Cochrane library. Two blinded independent observers extracted and assessed the studies for diagnosis of PVT, MVT, and SVT in PDAC. Studies were restricted to English literature published after 2007 to 2016. Results: Eleven articles were identified. Five case reports and 7 retrospective studies were found with a total of N=127 patients meeting the inclusion criteria. The mean age at diagnosis was 64 years. PVT was found in 35% (N= 46), SVT in 52% (N= 65), MVT in 13 %( N= 15). Mean follow up time was 26 months. Only 3 of the selected articles studied the impact of anticoagulation in visceral thrombosis. All patients with non-visceral thrombosis (e.g. DVT, PE) were therapeutically treated, in contrast, to only rare occurrences with VT received treatment. Conclusions: Visceral thrombosis in PDAC can be a frequent finding at diagnosis or during disease progression. This literature analysis has shown VT to be a poor prognostic indicator for short term survival. Evidence to guide treatment choices are inadequate and current management is based on inferred experience from other non-oncologic populations. Anticoagulation appeared to be a safe modality in visceral thrombosis with most of the large studies recommending a careful assessment for patients with high risk of bleeding.