tbuckley/cabot-search huggingface dataset:
Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.
Authors: Brendan D. Curti, Jon M. Richards, Sigrun Hallmeyer, Mark B. Faries, Robert Hans Ingemar Andtbacka, Gregory A. Daniels, Mark Grose, Darren Shafren
Journal: Journal of Clinical Oncology (2017)

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 10 8 TCID 50 CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.
Post neoadjuvant chemo-radiation positive anterior circumferential resection margin in carcinoma rectum: Extended resection of rectum versus total pelvic exenteration—Results from a single centre retrospective study.
Authors: Kamlesh Verma, Reena Engineer, Vikas S. Ostwal, Suman Kumar, Supreeta Arya, Ashwin DeSouza, Avanish Saklani
Journal: Journal of Clinical Oncology (2017)

e15156 Background: Positive circumferential resection margin has been shown to be powerful predictor of poor prognosis in rectal CA. Radiologically positive anterior CRM (PACRM) after NACT+RT leads to either resection of involved organ alone ie.Extended resection of rectum (ERR) or Total pelvic exenteration (TPE). Purpose of this study is to compare recurrence rate and survival of patients undergoing ERR or TPE for PACRM after NACT+RT. Methods: Retrospective study of patients operated for rectal CA from January 2013 to December 2014. Results: Out of 237 patients with non-metastatic CA rectum, 51 patients (21.5%) had PACRM. After NACT+RT, 22 patients (43.1%) developed systemic metastases, 7 patients (13.8%) were downsized and underwent extra-mesorectal resection (AR/APR), remaining 22 patients (43.1%) had persistent PACRM. 13 patients with PACRM underwent ERR whereas 9 patients underwent TPE. Median duration of hospital stay in TPE group was 13 days (10 - 26) whereas it was 7 days (5 – 21) in ERR group. Negative pathological CRM was achieved in all TPE and 92.3% of ERR patients. After median follow-up of 31.6 months, 5 patients with TPE (55.6%) and 4 patients with ERR (30.7%) developed systemic recurrence. None of the TPE patient, whereas 3 patients with ERR (23.1%) developed local recurrence. Median D.F.S. was 12.3 months in TPE and 18.9 months in ERR whereas mean O.S. was 36.2 and 32.8 respectively. Conclusions: Due to lack of significant difference in O.S./ D.F.S. and low post-operative complication and duration of hospital stay, ERR can be considered acceptable alternative to TPE.
Patient reported outcomes (PRO) results for prophylactic effect of dexamethasone on regorafenib-related fatigue and/or malaise: a randomized, placebo-controlled, double-blind clinical study in patients with unresectable metastatic colorectal cancer: KSCC1402/HGCSG1402.
Authors: Mototsugu Shimokawa, Eiji Oki, Takuhiro Yamaguchi, Hiroaki Tanioka, Yuji Miyamoto, Akihito Tsuji, Masako Asayama, Takeshi Shiraishi, Satoshi Yuki, Masahito Kotaka, Akitaka Makiyama, Takayuki Shimose, Satohiro Masuda, Yoshito Komatsu, Hiroshi Saeki, Yasunori Emi, Hideo Baba, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2018)

10094 Background: KSCC1402/HGCSG1402 is a phase II, randomized, double-blind, placebo (PLC)-controlled study evaluating the prophylactic effects of oral dexamethasone (DEX) on regorafenib-related fatigue and malaise for patient (pts) with metastatic colorectal cancer. The primary endpoint was incidence of fatigue or malaise (CTCAE ver. 4, all grades) during the protocol period. Here we report intervention related PROs. Methods: PROs were assessed at baseline, on every once a week thereafter until 4 weeks, using the Brief Fatigue Inventory (BFI), the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L), Functional Assessment of Cancer Therapy-General (FACT-G) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). QOL scores were compared using a mixed-effects models for repeated measures (MMRM), adjusting for baseline score and the stratified randomization (the presence/absence of fatigue and/or malaise and sex). Results: Between October 2014 and December 2015, 74 pts were enrolled and randomized (DEX group: 37, PLC group: 37). BFI score, EQ-5D-3L score, FACT-G total score and FACT-C total score were improved at each point in DEX group. Least-squares mean difference from PLC group for baseline-to-week 4 changes were -0.68 (95% confidence interval (CI), -1.56 to 0.20; p = 0.1289), 0.02 (95%CI, -0.04 to 0.09; p = 0.4930), 3.9 (95%CI, -0.8 to 8.5; p = 0.0996) and 5.3 (95%CI, -0.6 to 11.2; p = 0.0775), respectively. Conclusions: Among pts who remained on treatment and for whom PROs data were available, dexamethasone had a clinical meaningful improvement at each of the post-baseline timepoints for FACT-G and FACT-C in comparison with those who received PLC, although the relatively small sample size. Clinical trial information: NCT02288078.
Magnesium alterations of graft immune cells (MAGIC).
Authors: Ramy Sedhom, Andrew Zloza, Frederick Joseph Kohlhapp, Daniel Medina, Roger Strair
Journal: Journal of Clinical Oncology (2017)

e18541 Background: Magnesium plays important roles in cellular processes. Allogeneic hematopoietic stem cell transplantation provides potentially curative therapy to patients with a variety of hematologic malignancies. A common abnormality post transplant is hypomagnesaemia. Recent studies identified magnesium transporter 1 deficiency in association with XMEN syndrome. These patients exhibit low intracellular [Mg++] and low T cell and NK cell NKG2D expression. Therefore, we investigated this potential functional link between magnesium deficiency and immune function in patients post transplant. Methods: A pilot study investigated whether detectable changes in T and NK cells were associated with IV magnesium repletion post hematopoietic transplant. Blood was obtained before and after magnesium transfusions. Immunophenotypic analysis of T and NK cell NKG2D levels using commercially available monoclonal antibodies (CD3, CD16, CD56, CD4, CD8, CD314 [NKG2D]) was performed. Samples from patients demonstrating an increase in NKG2D expression were subsequently analyzed for ex vivo NK activity. Here, NK activity and cytotoxicity of Jurkat cells were assayed using standard laboratory techniques and changes &gt; 2 fold were considered significant. A total of 7 patients were enrolled. Results: NKG2D expression on T and NK cell subsets were determined by flow cytometry using commercially available monoclonal antibodies. NK reactivity and killing of K562 were undertaken using standard cytotoxicity assays. Our findings indicate a significant response in five of the seven enrolled patients. NKG2D expression on CD8+ T cells increased by up to 31%. Conclusions: Our results suggest that magnesium infusions post allogeneic transplant are associated with augmented NKG2D expression on immune cells. Additional studies are needed to clarify the mechanisms by which therapeutic magnesium repletion restores the cytotoxicity of NK cells and T lymphocytes. Although the clinical utility of magnesium supplementation remains to be validated, our data indicate that NKG2D is regulated by magnesium post transplant and magnesium may play a key role in immune regulation.
Combination chemotherapy with nintedanib/placebo for patients with advanced or recurrent endometrial cancer: The NSGO ENGOT-EN1/FANDANGO trial.
Authors: Mansoor Raza Mirza, Johanna Unelma Maenpaa, Elena Ioana Braicu, Ignace Vergote, Dominique Berton-Rigaud, Per Rosenberg, Jens Bodo Huober, Hannelore Denys, Florence Joly Lobbedez, Gunnar Kristensen, Toralf Reimer, Frederic Kridelka, Anne Floquet, Anja Knudsen, Bahriye Aktas, Jean-Francois Baurain, Philippe Follana, Trine Juhler-Nøttrup, Christina Jederud, Jalid Sehouli
Journal: Journal of Clinical Oncology (2017)

TPS5611 Background: Endometrial cancer (EC) patients with advanced and recurrent disease relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). With the emerging clinical data on anti-angiogenic agents and with promising results of nintedanib in ovarian cancer, it is apparent to explore its role in EC. Nintedanib is a potent, orally available triple receptor tyrosine kinase inhibitor targeting VEGFR 1-3, PDGFR α/β, and FGFR 1-3. This placebo-controlled, multicenter, two-arm, phase 2 trial compares nintedanib versus placebo as concomitant and maintenance therapy in combination with chemotherapy in patients with advanced or recurrent EC. Methods: The primary objective of this trial is to evaluate efficacy of nintedanib against placebo in combination with chemotherapy, defined by PFS. Key eligibility criteria include: histologically confirmed EC, stage 3C 2 or 4 A &amp; B or relapsed after adjuvant therapy for stage 1-3 disease; prior surgery; adjuvant chemotherapy; radiation therapy; hormonal therapy are permitted; measurable/non-measurable disease. 148 patients will be randomized 1:1 to receive nintedanib 200mg twice daily or placebo days 2-21 during chemotherapy (six cycles of Carboplatin (AUC5) and paclitaxel (175mg/m2) every 21 days) and continuously in maintenance phase. Nintedanib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include PFS in sub-populations, PFS2, disease specific survival, time to first subsequent therapy, time to second subsequent therapy, overall survival, objective response, disease control rate, patient reported outcoms (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24) and safety. Trial is enrolling patients. The following cooperative groups are participating: NSGO (DK, FIN, SWE, NOR), NOGGO (GER), BGOG (BEL), &amp; GINECO (FRA). Clinical trial information: NCT02730416.
TCT-111 Efficacy and safety of glycoprotein IIb/IIIa inhibitors on top of a potent P2Y12 inhibitor in STEMI: A pre-specified sub-analysis of the ATLANTIC trial
Authors: Anne Tavenier, Rik Hermanides, Enrico Fabris, Johanne Silvain, Jens Lassen, Leonardo Bolognese, Warren Cantor, Kurt Huber, Béla Merkely, Uwe Zeymer, Christian Hamm, Gilles Montalescot, Arnoud van 't Hof
Journal: Journal of the American College of Cardiology (2018)
Ending Sexual Harassment in Academic Medicine
Authors: Victor J. Dzau, Paula A. Johnson
Journal: New England Journal of Medicine (2018)

Interview with Dr. Esther Choo on steps that medical institutions can take to support and empower women. (08:14)Download A National Academies report shows that sexual harassment is more likely to occur in environments that are male-dominated and where sexually harassing behaviors are tolerated, hierarchical relationships are enforced, and training environments may be isolating.
Abstract P056: Diabetes Education for Stroke Inpatients is Incomplete and Differs by Stroke Severity, Age, and Substance Abuse History
Authors: Elizabeth Baraban, Lindsey Lucas, Theodore Lowenkopf
Journal: Circulation (2016)

Introduction: Diabetes is a well-established risk factor for stroke and other vascular disease. Consequently, diabetes management is important for prevention of primary and secondary vascular events. Hospitals offer diabetes education, but it is unknown if the appropriate patients are receiving the necessary information. The objective of this study was to determine the factors associated with receiving diabetes management teaching among patients presenting to a hospital with an ischemic stroke (ISC) or Transient Ischemic Attack (TIA) who have a concurrent new diabetes diagnosis. Methods: Data from 20 hospitals in a multi-state healthcare system stroke registry from 2002 to May 2015 were used. ISC or TIA patients with a new, in-hospital diagnosis of diabetes were included. Patients on comfort care, transferred to an outside facility from the emergency department, discharged to hospice or expired were excluded. Associations between receiving diabetes management education and demography, insurance, medical history, BMI, functional status, and stroke severity of the patient were examined using a generalized linear mixed model with a logit link. Results: Data from 336 newly diagnosed diabetes patients were used in the analyses. Of those, 269 (80.1%) received diabetes management education, while 67 (19.9%) did not. Patients with a medical history of drug or alcohol abuse were 79% less likely to receive diabetes management training than those without a history (adjusted odds ratio [AOR] = 0.215, p=.014). Patients who were overweight or obese weight were over three times more likely to receive diabetes management education than patients who were of normal weight or underweight (AOR = 2.92, p=.003). For every one-point increase of the NIH Stroke Scale score, the likelihood of receiving education decreased by 6% (AOR=.913, p=.005), and with each additional five years of age the likelihood of receiving education decreased by 14% (AOR=.861, p=.017). Gender, insurance type, discharge status, and medical histories of atrial fibrillation, CAD/prior MI, previous strokes, previous TIA, hypertension, family history of stroke were not significant predictors. Conclusions: Almost 20% of patients with newly diagnosed diabetes did not receive diabetes management education. While education was appropriately targeted to overweight and obese patients, these results indicate that patients with a history of drug and alcohol abuse, those who are normal or under-weight and those with more severe strokes were underserved. More work needs to be done to ensure that stroke patients are receiving appropriate education to prevent subsequent cerebrovascular events.
miR-125a-induced cellular switch to elicit a response to anti-HER2 targeted therapy in gastric cancer cells.
Authors: Elad Hikri, Lihi Ninio-Many, Salomon M. Stemmer, Ruth Shalgi, Irit Ben-Aharon
Journal: Journal of Clinical Oncology (2016)

4055 Background: HER2 (ERBB2) amplification in gastric cancer ranges from 6-23%, accordingly Trastuzumab has been incorporated into the treatment arsenal of HER2-enriched gastric cancer. We had previously demonstrated the miR-125a-3p induces overexpression of HER2 in basal-like breast cancer cells and sensitizes them to anti-HER2 therapy (AACR-NCI-EORTC 2015). We aimed to study the effect of miR-125a-3p as a potential modulator of the ERBB2/HER2 pathway in HER2-negative gastric adenocarcinoma. Methods: We generated stable KATO-III cells that overexpress miR-125a-3p and control cells that overexpress scrambled miRNA. Relative mRNA level of ERBB2 was measured by qPCR and its protein expression and localisation were examined by western blot and immunofluorescence staining. Moreover, the effect of miR-125a-3p alone or combined with anti-HER2 therapies on cellular proliferation was evaluated using EdU incorporation and XTT assays. Results: miR-125a-3p-overexpressing KATO cells showed a significant increase in the expression level of ERBB2 mRNA and protein as well as a stronger immunofluorescence staining of ERBB2 on cell membrane compared with control cells. Trastuzumab reduced cell growth and proliferation of miR-125a-3p-overexpressing KATO cells. Furthermore, this antiproliferative effect was enhanced following pre-treatment of the miR-125a-3p-overexpressing KATO cells with lapatinib, a dual ErbB1 and ErbB2 receptor tyrosine kinase inhibitor, prior tp trastuzumab administration. Conclusions: Our results indicate that miR-125a-3p is capable of inducing a shift in the expression and function of ERBB2 pathway that may convert the fate of gastric cancer cells to effectively dispose them to anti-HER2 therapies. In an era of personalized medicine, our study proposes a means to enlarge the patient population that may benefit from anti-HER2 therapies.
P01.162 Radiation-induced glioblastoma long survivor: Case report
Authors: R Uriel Lavín, F Ibáñez Plágaro, E González Martínez, R Diana Martín, G Mattos Piaggio, N Ferreras López, A Cuesta Díaz
Journal: Neuro-Oncology (2018)

Gliomas induced by radiation therapy are unusual and present an aggressive behavior and poor prognosis. They can occur as a side-effect of radiation even several decades after the treatment. They are more frequent in young people who suffered acute lymphoblastic leukemia in their childhood and were treated with prophylactic whole brain irradiation. We report the case of a patient diagnosticated of glioblastoma sixteen years after of being treated by radiotherapy for a no-Hodgkin lymphoma. A 21-year-male, presented with clinical onset of intense headache on the right side. Neurological examination revealed nothing abnormal. He had a history of no-Hodgkin lymphoma successfully treated 15 years ago by intrathecal chemotherapy, craniospinal radiotherapy (total dose 14 Gy) and autologous bone marrow transplant. We performed a cranial tomography and magnetic resonance imaging showing a right temporal lesion with perilesional edema and contrast enhancement, suggesting a high-grade glioma. Due to his previous history, we initially performed a stereotactic biopsy. As histopathological study revealed glioblastoma multiforme, 15 days after we performed a pterional craniotomy and the lesion was totally removed. The lesion presented necrosis and high vascularization and we implanted 6 carmustine wafers in the surgical field. Histologic examination confirmed the diagnosis of glioblastoma. Genetic analysis performed years later did not detect any mutation on the IDH1/2 gene. The integrated diagnosis was IDH wild-type glioblastoma. The postoperative period was uneventful, and the patient was discharged on the fifth postoperative day. He was after treated with systemic chemotherapy with temozolomide and cranial radiotherapy. 9 years after the surgery, the patient is alive and asymptomatic. The last cranial magnetic resonance imaging performed shows no evidence of tumor recurrence. Patients with a history of cranial radiotherapy must undergo systematic, long-term surveillance for early detection of intracranial neoplasms. Though rare, gliomas may represent a serious late complication of radiation treatment. As they have previously been treated with radiotherapy, the therapeutic tools are more limited. The treatment should be complete surgical removal of the tumor followed by systemic chemotherapy and cranial radiotherapy only when possible.
Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer
Authors: Weerachai Jaratlerdsiri, Eva K.F. Chan, Tingting Gong, Desiree C. Petersen, Anton M.F. Kalsbeek, Philip A. Venter, Phillip D. Stricker, M.S. Riana Bornman, Vanessa M. Hayes
Journal: Cancer Research (2018)

Abstract African-American men are more likely than any other racial group to die from prostate cancer. The contribution of acquired genomic variation to this racial disparity is largely unknown, as genomic from Africa is lacking. Here, we performed the first tumor-normal paired deep whole-genome sequencing for Africa. A direct study-matched comparison between African- and European-derived, treatment-naïve, high-risk prostate tumors for 15 cases allowed for further comparative analyses of existing data. Excluding a single hypermutated tumor with 55 mutations per megabase, we observed a 1.8-fold increase in small somatic variants in African- versus European-derived tumors (P = 1.02e–04), rising to 4-fold when compared with published tumor-matched data. Furthermore, we observed an increase in oncogenic driver mutations in African tumors (P = 2.92e–03); roughly 30% of impacted genes were novel to prostate cancer, and 79% of recurrent driver mutations appeared early in tumorigenesis. Although complex genomic rearrangements were less frequent in African tumors, we describe a uniquely hyperduplicated tumor affecting 149 transposable elements. Comparable with African Americans, ERG fusions and PIK3CA mutations were absent and PTEN loss less frequent. CCND1 and MYC were frequently gained, with somatic copy-number changes more likely to occur late in tumorigenesis. In addition to traditional prostate cancer gene pathways, genes regulating calcium ion-ATPase signal transduction were disrupted in African tumors. Although preliminary, our results suggest that further validation and investigation into the potential implications for elevated tumor mutational burden and tumor-initiating mutations in clinically unfavorable prostate cancer can improve patient outcomes in Africa. Significance: The first whole-genome sequencing study for high-risk prostate cancer in African men allows a simultaneous comparison of ethnic differences relative to European populations and of the influences of the environment relative to African-American men.
TCT-580 Relationship between adverse plaque characteristics and wall shear stress assessed by computational fluid dynamics
Authors: You Jeong Ki, Jun-Bean Park, Joo Myung Lee, Jung-Kyu Han, Han-Mo Yang, Kyung Woo (KW) Park, Gilwoo Choi, Charles Taylor, Hyo-Soo Kim, Bon-Kwon Koo
Journal: Journal of the American College of Cardiology (2018)