tbuckley/cabot-search huggingface dataset:
A phase I/II study of trifluridine/tipiracil (TAS-102) in combination with nanoliposomal irinotecan (NAL-IRI) in advanced GI cancers.
Authors: Olatunji B. Alese, Walid Labib Shaib, Mehmet Akce, Christina Wu, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2018)

TPS4155 Background: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) is a combination of a nucleoside analogue and a thymidine phosphorylase inhibitor. TAS-102 has shown activity in 5FU-resistant colorectal cancer (CRC). Nano liposomal-Irinotecan (Nal-IRI) achieve higher intra-tumor concentrations than irinotecan (142-fold) and its major metabolite, SN-38 (9-fold), resulting in superior anti-tumor activity compared to free irinotecan in multiple tumor xenografts. Clinical trials have established activity of Nal-IRI combined with 5FU in pancreatic cancer. The combination of Nal-IRI with the more potent nucleoside analogue TAS-102 may result in a more effective systemic therapy regimen in CRC and pancreatic cancer. The aim of this study is to define the recommended phase II dose (RP2D) of the combination and evaluate the activity in pancreatic cancer and CRC. Methods: Eligible patients for the phase I trial include stage IV or locally advanced unresectable gastrointestinal adenocarcinomas, who have failed at least one prior therapy; age ≥18 years, ECOG PS 0-1 and measurable disease per RECIST 1.1. The trial design is standard 3+3. TAS-102 is administered orally in four dose levels of 25, 25, 30, 35mg/m2 BID on days 1-5, with Nal-IRI at corresponding dose levels of 50, 70, 70, 70mg/m2 IV on day 1 , in 14-day cycles. After recommended phase II doses are established, an expansion phase will enroll 20 patients with pancreatic adenocarcinoma (Arm A) and 20 patients with colorectal adenocarcinoma (Arm B). These patients must have either locally advanced unresectable or metastatic disease, and have failed at least one prior therapy that must not have included irinotecan. The primary endpoint of the phase II portion is overall response rate. Simon's two-stage design will be used for each arm of the phase II component. In the first stage, 10 patients will be accrued. If there are fewer than 1 responder, the cohort will be stopped. Otherwise, 10 additional patients will be accrued for a total of 20. Enrollment to the escalation phase I part of the study started in February 2018. Clinical trial information: NCT03368963.
Screening of esophageal varices in children using esophageal capsule endoscopy: a multicenter prospective study
Authors: Jacques Cardey, Catherine Le Gall, Laurent Michaud, Alain Dabadie, Cécile Talbotec, Marc Bellaiche, Thierry Lamireau, Emmanuel Mas, Laure Bridoux-Henno, Jerome Viala, Lioara Restier-Miron, Alain Lachaux
Journal: Endoscopy (2018)

Abstract Background Esophagogastroduodenoscopy (EGD) is the standard method for diagnosis of esophageal and gastric varices in children. In this prospective study we evaluated the use of PillCam esophageal capsule endoscopy (ECE) in pediatric patients. Methods Patients aged 7 to 18 years presenting with portal hypertension and/or cirrhosis underwent ECE (PillCam ESO 2, Given Imaging Ltd.) followed by EGD. Results 102 patients were screened, 81 (52 boys; mean age 13.96 ± 0.25 years) were included and 21 were excluded (16 for “candy test” failure). Esophageal varices were identified by EGD in 62 patients (77 %) and by ECE in 57 patients (70 %) using the de Franchis classification (DFC). The sensitivity of ECE for esophageal varices was 92 % and the specificity was 100 % using DFC. Based upon 57/81 patients with small, medium, and large varices on both ECE and EGD, using DFC, the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were 55 %, 92 %, 89 %, and 63 %, respectively, giving a total overall accuracy of 72 %. To improve sensitivity and specificity in classification of esophageal varices, we propose using a modified score. This score detected esophageal varices with 100 % sensitivity, 93 % specificity, 94 % PPV, and 100 % NPV, giving a total overall accuracy of 97 %. All patients preferred ECE over EGD. No capsule retention was recorded. Conclusions ECE is a well-tolerated and safe procedure in children. Using the modified score, the sensitivity of ECE is currently sufficient to detect esophageal varices and replace EGD in infants with suspicion of esophageal varices or when EGD is refused.
NeuroCog-FX study: A multicenter cohort study on cognitive dysfunction in patients with early breast cancer.
Authors: Oliver Rick, Monika Reuß-Borst, Timm Dauelsberg, Holger Hass, Volker König, Reiner Caspari, Gabriele Götz-Keil, Jürgen Pfitzner, Christa Kerschgens, Klaus Fliessbach, Christian Hoppe
Journal: Journal of Clinical Oncology (2017)

10061 Background: Many breast cancer patients complain about cognitive dysfunction (CD) with mnestic and attentional deficits. These complaints persist even after completion of therapy in approximately one third of the patients and affects both social life and working capacity. The exact nature and genesis of CD in breast cancer patients is still not fully understood and risk factors are not yet described. Methods: To determine CD and risk factors, we used the computer-based neuropsychological test NeuroCog-FX during a three weeks oncological rehabilitation in breast cancer patients. Eight subtests addressed attention, working memory, verbal and figural memory, and language. Test duration was &lt; 30 minutes. A cognitive deficit was diagnosed if at least one subtest was clearly below average (score &lt; M - 1.5 SD) of the normative age group. The data on cognitive function were correlated with the level of depression (PHQ-9 test), QoL (EORTC QLQ-30) and clinical parameters (nodal status, chemo-/radiotherapy and endocrine therapy). Results: From February 2013 to December 2014 a total of 476 patients were recruited in 9 oncological rehabilitation centers in Germany. NeuroCog-FX was used to examine 439 patients. Median age was 50 years (range: 24-62 years); 93% of patients had early tumor stage (T0-T2) and 67% were node-negative. Sixty-one percent of the patients received chemotherapy while 84% of the subjects underwent radiotherapy. CD was found in 59% and a moderate to severe depression in 38% of the patients. The severity of depression was correlated with slower reaction times and reduced verbal memory performance. These two cognitive parameters were also associated with a reduced global health status and a reduced physical function score on the EORTC-QLQ30 questionnaire suggesting an impact of cognitive deficits on quality of life. Cognitive function was not associated with type of treatment or node status. Conclusions: In this large and homogeneous cohort of breast cancer patients, CD has been shown in most of the subjects using a valid test method. CD was associated with depression and reduced quality of life. Neither tumor therapy nor other clinical parameters had a significant impact on development of CD.
Spatial concordance of tumor proliferation and accelerated repopulation from pathologic images to <sup>18</sup>F-FLT PET images.
Authors: Xue Meng, Xiaoli Zhang, Xindong Sun, Jinming Yu
Journal: Journal of Clinical Oncology (2017)

e23100 Background: PET imaging with 18 F-fluorothymidine ( 18 F-FLT) can potentially be used to identify tumor subvolumes for selecting dose escalation in radiation therapy. The aim of this study was to monitor tumor cell proliferation and repopulation during fractionated radiotherapy and investigated the spatial concordance of tumor cell proliferation and repopulation with 18 F-FLT tracer uptake. Methods: Mice bearing A549 xenograft tumors were assigned to 5 different irradiated groups (3f/6d, 6f/12d, 9f/18d, 12f/24d and 18f/36d) with 2 Gy/fractions and non-irradiated group. Serial 18 F-FLT micro PET scans were performed at different time points, the maximum of standard uptake value (SUVmax) were measured to detect the feasible time of tumor repopulation during irradiation. Ex vivo images of the spatial pattern of intratumor 18 F-FLT uptake and Ki-67 labeling index (LI) were obtained from thin tumor tissue sections. A layer-by-layer comparison between SUVmax and Ki-67 LI results, including the thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation, were conducted to evaluate the spatial imaging pathology correlation. Results: The SUVmax were observed decreases in the 3f/6d group (P = 0.000), compared to these for non-irradiated tumors. However, it was significantly increased in the 6f/12d later, and then gradually reduced with treatment time prolonged again after 6f/12d group. Proliferation changes on pathology imaging at 6f/12d were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI of all ROIs in each in vitro tumor of cell proliferation group (Ps &lt; 0.001). Similar results were also found in each tumor of accelerated repopulation group (Ps &lt; 0.001). Furthermore, both of the mean ORRs were more than 50% in all layer of the tumor cell proliferation and accelerated groups. Regions of high-intensity 18 F-FLT uptake in the autoradiographs exhibited prominent staining for Ki-67. Conclusions: 18 F-FLT PET may be a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and might help make adaptive radiation oncology treatment plan.
Low-dose diethylstilbestrol (DES) as frontline treatment for hormone-sensitive metastatic prostate cancer (PC) in a low resource setting.
Authors: Juan Hinojosa, Mauricio Mora Pineda, Fernando Gabilondo, Maria Teresa Bourlon
Journal: Journal of Clinical Oncology (2016)

e16516 Background: Low-dose DES as first-line treatment for metastatic PC is considered equivalent to orchiectomy in time to progression and overall survival. DES no longer enjoys widespread use in developed countries, given its cardiovascular toxicity and the availability of GnRH analogs. However, DES is still prescribed in low-resource settings when patients are not eligible or decline surgical castration, and have no access to GnRH analogs. Methods: A retrospective chart review (01/2005-12/2014) was performed to identify patients with metastatic PC treated at our center. We included those treated with low-dose DES as frontline treatment. Data pertaining to PSA response ( ≥ 50%), progression free survival, and adverse events was analyzed. We estimated the total economic saving of DES compared to GnRH analogs based on the “median time on therapy until progression” and the retail price. Results: We identified 776 patients, a total of 22 were eligible for the study. The median age was 75 yo (range 52-92). Three patients (13.6%) had visceral disease upon diagnosis, the median PSA was 78.4 mg/dl (1.12- 2,790). A PSA response (PSA decrease ≥ 50%) was observed in all 22 patients (100%). The median progression free survival was 25 months (1-114). Toxicity: two patients (9.09%) experienced grade 3/4 cardiovascular events, and four had (18.2%) grade 2 gynecomastia. The estimated expense for the median 25 months on DES treatment with clinical benefit was $13,500 MXN pesos (≈745 USD) per patient. This contrasts with the $26,633 MXN pesos (≈$1470 USD) per patient for GnRH therapy. DES accounts for half the retail cost for medical castration. Conclusions: Our cohort confirms that DES yields high response rates in hormone-sensitive metastatic PC. Time to progression to CRPC and toxicity profile are similar to the reported for GnRH analogs. Its lower cost makes it an option for underserved populations. Our center is a third-care level facility in Mexico City that provides healthcare to insured, and uninsured PC patients with limited access to standard of care treatments in which off-label indications of drugs are often considered.
Impact of age on immune checkpoint blockade tolerability across malignancies: A single institution review.
Authors: Sharon Li, Reetu Mukherji, Sheel A. Patel, Daniel S. Altman, Philip Margiotta, Mario Caldararo, Sean Clark-Garvey, Thomas Holden, Marlana M. Orloff, Ryan Michael Weight, Jennifer Maria Johnson
Journal: Journal of Clinical Oncology (2018)

e15069 Background: Immune checkpoint inhibitors have become an integral part of treatment for a variety of malignancies. Given the favorable side effect profile compared to chemotherapy, there is increased interest in using immunotherapy in senior adults. Unfortunately, there is limited and conflicting data exploring the effect of age on checkpoint blockade efficacy and toxicity. We hypothesize that due to increased immune-senescence, older patients will experience less treatment limiting immune toxicity. Methods: A total of 170 patients were identified as receiving anti CTLA-4 or -1/PDL-1 antibodies between 2012 and 2017 at TJUH. Data was analyzed by age cohorts: age < 65, age 65-74, and age > 75. Chi-square analysis was used to compare the various reasons for therapy discontinuation between age groups. Results: 47% of patients were less than age 65; 37% were between age 65 and 75 and 16% of patients were older than age 75. Baseline characteristics between the groups were similar. Median CCI and RMH score was similar across the groups. Interestingly, the rate of immune toxicity requiring therapy discontinuation was higher among patients > 75 compared to < 65 though not significantly different (p = .098). Conversely, rates of disease progression while on immunotherapy were significantly higher in patients < 65 compared to those > 75 years (p = value here 0.037). Conclusions: Despite evidence for immuno-senescence in the elderly, rates of immune toxicity did not differ significantly by age. Further studies are needed to explore interplay of aging, the immune system and check point inhibitors. Reasons for Discontinuing Checkpoint Blockade, n (%) Age Group (yrs) < 65 65-75 > 75 Number of Patients 80 (47.1) 63 (37.0) 27 (15.9) Number of disease sites; mean (median) 2.91 (3) 2.82 (3) 3.08 (3) Charleston Comorbidity Index at Immunotherapy Initiation; mean (median) 0.76 (1) 0.80 (1) 1.41 (1) Royal Marsden Score at Immunotherapy Initiation; mean (median) 7.22 (8) 8.85 (9) 8.22 (9) Doses of Immunotherapy; mean (median) 7.6 (4) 7.6 (4) 8.7 (4.5) Disease progression Rate 32 (40.0) 33 (52.4) 6 (22.2) Immunotoxicity Rate 10 (12.5) 13 (20.6) 7 (25.9) Death Rate 9 (11.3) 6 (9.5) 4 (18.5) Never discontinued treatment 21 (26.3) 6 (9.5) 5 (18.5)
Abstract 251: Lna- Mediated Mir-92a Inhibition Induces Therapeutic Neovascularization in a Pig Model of Chronic Myocardial Ischemia
Authors: Katharina Klett, Rabea Hinkel, Ariane Fischer, A. Bonauer, A. Zeiher, Stefanie Dimmeler, Christian Kupatt
Journal: Circulation Research (2017)

miRNA are post-transcriptional gene regulators which modulate RNA silencing and gene expression. In chronic myocardial ischemia, miRNA are altered and dysregulated. MiR92a inhibition in a mouse model of LAD occlusion led to improved neovascularisation and reduced infarct sizes. We aimed to investigate this therapeutic effect of miR92a- inhibition in a pig model of chronic myocardial ischemia. Methods: In pigs (n=5/group) reduction stent graft implantation in the circumflex artery led to a gradual occlusion of the vessel within 28 days (d28) after intervention. Using selective pressure-regulated retroinfusion the nucleic acid-modified antisense miR92a (LNA-92a; 5 mg/KG heart weight) was injected 28 days post implantation. The global myocardial function (Ejection Fraction (EF)) and the left end-diastolic pressure (LVEDP) were obtained at day 28 and 56. At day 56 after stent implantation regional myocardial function (subendocardial segmentshortning) as well as post mortem angiographies for collateral growth were analyzed. For the histological quantification the ischemic tissue was stained for PECAM-1 positive cells (capillaries) and for NG2- positive cells (vessel maturation, pericyte coverage). Results: The regionally applied locked nucleic acid-modified anti-sense miR-92a significantly reduced miR-92a expression in the heart and enhanced capillary coverage in the ischemia. Improved collateral growth (3±1 control vs. 6±1 in LNA-92a treated hearts) and distal perfusion of the occluded coronary artery (Rentrop score: 1.3±0.2 control vs. 2.4±0.2 in LNA-92a treated hearts) was seen after miR-92a inhibition. Moreover the increased LVEDP at day 28 (control: 16±1 mmHg vs. LNA-92a 15±1mmHg) was reduced after regional miRNA-92a inhibition (control: 16±1 mmHg vs. LNA-92a 15±1mmHg) and EF clearly increased after LNA-92a application (39±4% vs. 25±2 % in control). Regional myocardial function, obtained in the ischemic area under increased heart rate, was significantly improved after miR-92a inhibition (SES at hear rate 150bpm: 7±3 % of non-ischemic in control vs. 70±11 %% of non-ischemic in LNA-92a treated animals). Conclusion: Even single application of LNA-92a was able to reduce ischemia dependent impaired myocardial function
Prognostic value of the absolute lymphocyte to monocyte (ALC/AMC) ratio on overall survival among patients with mantle cell lymphoma.
Authors: Andre Goy, Tatyana Feldman, Lori Ann Leslie, Alan P. Skarbnik, Tommy Wu, Eric Hansen, Srikesh Arunajadai, Ewelina Protomastro, Marisa Valentinetti, Judy Smith, Kelly Choi
Journal: Journal of Clinical Oncology (2017)

e19030 Background: The peripheral blood absolute lymphocyte-to-monocyte ratio (ALC/AMC) is prognostic of overall survival (OS) in Hodgkin Lymphoma, Diffuse Large B-cell Lymphoma, and several solid tumors. Lymphocyte and monocytes have been suggested to be surrogate biomarkers of immune homeostasis and tumor microenvironment, respectively. We sought to determine if the post-induction therapy ALC/AMC is prognostic in mantle cell lymphoma. Methods: A retrospective review was conducted of 96 consecutive mantle cell lymphoma patients (pts) with available data treated at the John Theurer Cancer Center (n=77) and 4 Regional Cancer Care Associate practices (n=19) by 24 physicians between Aug 2005 and Dec 2015 (90% cases after 2009). Cases were identified via the COTA database which extracts and organizes relevant data from the electronic health records. Peripheral blood counts (to calculate the ALC/AMC) were determined approximately 30 days following completion of initial therapy or immediately prior to stem cell mobilization in those pts undergoing first line transplant. All analyses were performed using the R statistical language. Results: 67 pts had ALC/AMC less than 2 and 29 pts had ALC/AMC greater than or equal to 2. The cohorts (&lt;2 vs &gt;2) had similar median ages (64 vs 68; p=0.18), ethnicities (p=0.38), stage distributions (including 87% vs 79% stage IV disease; p=0.51), elevated beta-2-microglobulin (p=1), elevated LDH (p=1) and MIPI scores (including 19% vs 41% high risk; p=0.13). ALC/AMC was &lt;2 in 10 of 13 (77%) transplanted pts and 57 of 83 (69%) non-transplanted pts (p=0.57). With a median follow-up of 43 months, the median OS has not been reached in either cohort; the 5-year survival rates were higher among pts with ALC/AMC greater than or equal to 2 (90% vs 68%; log-rank p&lt;0.05). Similar ALC/AMC 5-year survival trends were noted when sub-setting to the 25 pts with high risk MIPI scores (72% vs 45%; p=0.07). Conclusions: An elevated ALC/AMC &gt;2, following induction therapy, is associated with improved overall survival in MCL. Novel maintenance programs, including targeting the microenvironment or immune response, might be appropriate among pts with low ratios.
Neoadjuvant chemoradiotherapy to induce the expression of programmed death-ligand 1 of tumor cells and the infiltration of CD8+ lymphocytes in patients with rectal adenocarcinoma.
Authors: Akio Nakagawa, Kimihiro Yamashita, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Yasuo Sumi, Satoshi Suzuki, Yoshihiro Kakeji
Journal: Journal of Clinical Oncology (2017)

e14577 Background: In recent years, immune checkpoint inhibitors have attracted attention and a lot of studies on PD-L1 (Programmed death-ligand 1) have been reported, but their anti-tumor effects are limited to colorectal cancer in which the expression of PD-L1 is infrequent. On the other hand, radiation therapy has been suggested to be closely related to the antitumor effect derived from the immune response. So we report the histological and clinicopathological examination about the relationship between the expression of PD-L1 and CD8 and irradiation in rectal cancer cases in which operation was performed after preoperative chemoradiotherapy (neoadjuvant chemoradiotherapy, NACRT) to clarify the indication for immune checkpoint inhibitors. Methods: Immunohistochemical staining of PD-L1, CD8 as immune related factors was performed on 34 cases in which operation was performed after NACRT(UFT/LV:300mg/m 2 /day and 75mg/body/day, respectively +RT(45Gy)) was done for locally advanced rectal cancer from January 2005 to December 2014, and we evaluated their preoperative biopsy specimens and resected specimens to examine the relationship between their evaluations and clinicopathological factors. Results: The 5-year survival rate and relapse-free survival rate of 34 patients were 84.4% and 65.5%, respectively, and there were 4 pathological CR cases. In 30 patients excluding CR cases, the expression of PD-L1 in tumor cells was enhanced or emerged in 5 cases(16.7%) and the infiltration of CD8 + TIL(tumor infiltrating lymphocyte) was also enhanced in 13 cases(43.7%) after NACRT. Also, patients with PD-L1 expression had significantly poor prognosis (p = 0.0023) than others, and the prognosis tended to be further poor in CD8 + TIL noninvasive cases. Conclusions: NACRT for locally advanced rectal cancer induced PD-L1 expression in tumor cells and also induced the infiltration of CD8 + TIL.
A phase I study of <sup>177</sup>Lu-DKFZ PSMA 617 combined with the radiosensitizer idronoxil in men with metastatic castrate-resistant prostate cancer (mCRPC) (LuPin trial).
Authors: Megan Crumbaker, Anthony M. Joshua, Richard Epstein, Louise Emmett
Journal: Journal of Clinical Oncology (2018)

TPS5088 Background: Despite recent treatment advances, mCRPC remains a challenging disease associated with significant mortality and morbidity. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in most prostate adenocarcinomas. Radiolabelled peptides which bind PSMA receptors induce internalization of the ligand-receptor complex, allowing concentration of PSMA-bound isotopes within targeted prostate cancer cells. 177Lutetium (177Lu) bound to PSMA ligands has a favorable therapeutic-toxic ratio and yields PSA responses in 30-70% of selected patients. However, responses are often partial and acquired resistance common, suggesting a need to augment the clinical benefit of beta-radiation. Idronoxil is an inhibitor of external NADH oxidase type 2, and has a variety of downstream actions including radiosensitization. Given the reassuring safety data of idronoxil as a single agent, we initiated a phase 1 clinical trial of 177Lu-PSMA plus idronoxil. Methods: Sixteen patients will be recruited. Participants will receive up to 6 doses of 177Lu-PSMA at 6-weekly intervals; the first 8 patients will also receive 400mg idronoxil daily for 10 days from day 1 of each cycle, while subsequent patients will receive 800mg daily for 10 days if no major adverse events are noted. Entry criteria include (i) failure of, or (ii) ineligibility to receive both docetaxel and a second-generation androgen pathway inhibitor. Imaging criteria include a PSMA PET that shows significant uptake at all sites of disease with no discordant disease on FDG PET. The primary endpoint is the toxicity (safety, tolerability) of the combination as assessed by CTCAE criteria. Secondary endpoints include PSA response, radiological response, changes in quality of life, radiation dosimetry, overall survival and progression-free survival. Plasma for ctDNA testing will be collected to explore whether DNA repair defects are predictive biomarkers for response and/or mechanisms of resistance. Four of 16 patients have been enrolled, with no significant toxicities or safety concerns as yet.