tbuckley/cabot-search huggingface dataset:
Inter and intra-tumor heterogeneity of PD-L1 and MET expression in metastatic renal cell carcinoma (mRCC).
Authors: Lisa Derosa, Gwenael Le Teuff, Manal Khordahi, Brice Chanez, Emanuelle Zalcman, Gwenaelle Gravis, Sylvie Negrier, Camelia Radulescu, Laurence Albiges, Zahira Merabet, Bernard J. Escudier
Journal: Journal of Clinical Oncology (2017)

4569 Background: Although inhibition of PD-1/PD-L1 and MET receptors have clinical efficacy in mRCC, their expression is not a predictive biomarker. Heterogeneity between the sites of disease might be one explanation. The aim of our study was to evaluate PD-L1 and MET expression in primary and metastases (brain (BM)/pancreas (PM)) RCC lesions and their correlation with clinicopathologic characteristics. Methods: RCC specimen from different institutions were collected. Clinicopathologic characteristics were assessed by revision of samples. PD-L1 and MET expression in tumor cells (TC) and immune cells (IC) ( &gt; 1%) were assessed by immunohistochemistry. Results: 180resected RCC specimen were successful collected (42 primary tumors and 138 metastases (87 BM/51 PM)). Overall, 22%, 51% and 23% of patients had at least one specimen expressing PD-L1 TC, IC and MET, respectively. In primary tumours, the proportion was 12%, 50% and 0%, respectively. In metastasis, the proportion of PD-L1 TC was 22% (23% in BM vs 19% in PM, p = 0.631), PD-L1 IC was 48% (47% in BM vs 49% in PM, p = 0.821) and MET was 24% (35% in BM vs 2% in PM, p &lt; 0.001). Comparing paired samples (primary tumour and metastasis) there was discordances of PD-L1 in TC or IC and of MET expression in 30%, 27% and 24% of samples, respectively. These two first disagreements seem varied over time. The discordance in PD-L1 TC or IC and MET between primary tumor and PM (BM) was 15% (40%), 33% (22%) and 0% (67%), respectively. Some correlations were observed between MET and PD-L1 and clinicopathologic characteristics. Conclusions: In this largest analysis, evaluating heterogeneity between primary tumor and metastases (brain/pancreatic lesions) in mRCC, PD-L1 and MET expression suggests that the assessment as predictive biomarkers may require analysis of metastatic lesions. [Table: see text]
Long-term outcomes in women with low-risk hormone-sensitive early-stage breast cancer.
Authors: Jinani Jayasekera, Clyde Schechter, Joseph A. Sparano, Suzanne C. O'Neill, Jeanne S. Mandelblatt
Journal: Journal of Clinical Oncology (2018)

e12583 Background: Oncotype DX test is useful in the identification of women who have a low risk of recurrence and can safely avoid chemotherapy. However, there are persistent gaps in knowledge on the use of Oncotype testing in treatment decisions to minimize harms and maximize benefits of chemotherapy among women with favorable prognosis breast cancer. We evaluated long-term outcomes in women diagnosed with early-stage, node negative, hormone receptor positive breast cancer with Oncotype scores of 0-10, using an established Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer model. Methods: A Monte Carlo microsimulation was conducted to project long-term (up to 15+ years) outcomes for any first event, recurrence, distant recurrence, and all-cause mortality among women diagnosed with HER2 negative, ER positive, node–negative breast cancer tumors of 1.1-5.0 cm with Oncotype scores of 0-10. The input parameters were derived from the Oxford Overview and published NSABP trial data. We assessed model validity by comparing Kaplan-Meier survival estimates for each trial endpoint up to 5-years with Trial Assigning IndividuaLized Options for Treatment (TAILORx) published results. Results: Women with favorable gene-expression profiles had high recurrence-free interval rates for any recurrence (92%) and distant recurrence (97%) at 15-years of follow-up with omission of adjuvant chemotherapy. However, rates of invasive disease-free survival (74%) and overall survival (88%) at 15-years were comparatively low. The results for the preliminary model showed excellent concordance with the initial published results from TAILORx for all trial outcomes in the first five years for patients with 0-10 Oncotype scores. Conclusions: Although more recurrences are expected with longer follow-up, our model projections show that long-term recurrence rates remain low among women with Oncotype scores of 0-10. Competing risks are the major drivers of morbidity and mortality among women at low risk for recurrence. Modeling and simulation are useful in extending clinical trial data by synthesizing information from historical trials.
Management problems associated with the length of hospital stays in medical oncology departments in Italy: The experience of the Reggio Emilia Clinical Cancer Center.
Authors: Mario Larocca, Ermanno Rondini, Alicia Garcia Arias, Angela Damato, Massimiliano Marino, Carmine Pinto
Journal: Journal of Clinical Oncology (2018)

e18842 Background: After specific treatments, patients may be transferred to other non-acute wards, discharged to home or entrust to local care facilities. This process is frequently hampered by social problems. The aim of this study is to highlight the non-clinical factors that reduce the ability of oncology wards. Methods: We examined 479 hospital records in the Oncology Unit. For each access, we assessed age ,family situation ,diagnosis,causes of hospital admission ,length of hospital stay and reasons for discharge delay, if any. Results: From 10/16 to 09/17, we have performed 479 hospitalizations, for a total of 4378 days(d) of stay and an average of 8d. Of these admissions, 319 (67%) were useful for starting or continuing oncological treatment, 66 (14%) for treating deterioration of condition, 47 (10%) for performing diagnostic tests and 46 (10%) for managing toxicity during chemotherapy. In 34 cases (7%) we observed a discharge delay resulting in an average increase in time of stay of 17d. In these cases, corresponding to 847d (19%) of total hospitalization, the average duration of hospital stay was well above other types of stays, with an average of 25d. 25 cases (74%) occurred within the first six months of the period in question and 9 (26%) within the second six months.This resulted in a median prolongation of 0.6d for all hospital stays, corresponding to a total of 260d (6%) of non-clinical needs.The delays were due to waiting time for entrust to local care facilities (27%), inadequate support by caregivers (23%), waiting time for home medical devices (26%)and transfer to other departments (24%). Conclusions: This study shows the complexity of managing patients with social problems with an increase in costs for health care. Although our data isn't statistically significant, the reduction in the number of cases of delayed discharge in the second semester can be attributed to an improved ability to identify fragile social situations earlier. Although the sample must be enlarged, this data suggests that prognostic and assistance scoring at intake could identify patients earlier that have complex management and assistance problems, even outside the hospital.
Molecular characterization of TP53 mutations and copy number change in colorectal cancers.
Authors: Maliha Nusrat, Ganiraju C. Manyam, Jonathan M. Loree, Michael Lam, Michael J. Overman, Dipen M. Maru, Mark Routbort, Jeffrey Morris, Scott Kopetz
Journal: Journal of Clinical Oncology (2017)

e15143 Background: TP53 mutations (mut) are prevalent in colorectal cancer (CRC) patients (pts) and can result in oncogenic gain of function effect as well as loss of tumor suppressor function depending on the mut. Methods: The Cancer Genome Atlas (TCGA) data of 220 CRC pts with tumors sequenced and gene copy numbers (CN) annotated was obtained. Pts with CMS subtype data also available were included (n = 167). Chi square test was used to compare frequency of TP53 mut and CN change among CMS subtypes. TP53 mRNA and protein levels were compared by TP53 mut and CN change using independent sample t test. Results: 86 (51.5%) pts were TP53 mutant, with 35.3% missense and 16.2% loss of function (LOF) mut. LOF mut included 14 non-sense and 13 frameshift mut, and occurred mostly in codons 213 and 306. Missense mut mostly affected codons 175, 248 and 273 in 10, 9 and 8 pts respectively. TP53 mut were most frequent in CMS2 and CMS4 subtypes (62.7 and 62.5% respectively). TP53 mut in CMS2 were mostly missense and CMS 4 pts mostly had LOF mut. TP53 CN loss was seen in 74.7% CMS 2, 68.8% CMS 4, 43.5% CMS 3 and 6.9% CMS1 pts. 84.9% pts with TP53 mut had CN loss vs 28.4% of wild type pts (p &lt; 0.001). Frequency of TP53 CN loss did not vary significantly by type of TP53 mut. Pts with TP53 missense mut had higher p53 mRNA and protein levels than those with LOF mut. Pts with TP53 CN loss had lower mRNA levels but no change in protein levels than those with normal CN. Conclusions: The higher TP53 mRNA and protein levels with missense mut suggest possible gain of function. Research on interactions of TP53 change with wnt, myc, and TGF beta pathway genes may reveal synthetic lethal treatment combinations. [Table: see text]
Lorlatinib in patients (Pts) with previously treated ALK<sup>+</sup> advanced non-small cell lung cancer (NSCLC): Updated efficacy and safety.
Authors: Benjamin Besse, Benjamin J. Solomon, Enriqueta Felip, Todd Michael Bauer, Sai-Hong Ignatius Ou, Ross A. Soo, D Ross Camidge, Rita Chiari, Shirish M. Gadgeel, Gregory J. Riely, Eng Huat Tan, Hidetoshi Hayashi, Julien Mazieres, Holger C. Thurm, Jean-Francois Martini, Antonello Abbattista, Gerson Peltz, Jill S. Clancy, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2018)

9032 Background: Despite advancement of 2nd generation (gen) ALK tyrosine kinase inhibitors (TKIs), ALK+ NSCLC pts continue to develop resistance and CNS metastases (mets) become more difficult to manage. Lorlatinib, a potent brain-penetrant 3rd gen ALK/ROS1 TKI, has shown robust clinical activity in ALK+ or ROS1+ NSCLC pts, most of whom had CNS mets and failed ≥1 ALK TKI. Methods: This ongoing ph 2 study (NCT01970865) enrolled 275 pts with ALK+ or ROS1+ advanced NSCLC ± CNS mets in cohorts (ALK: EXP 1–5; ROS1: EXP 6) based on prior treatment; starting dose was lorlatinib 100 mg QD. Antitumor activity (by independent central review per RECIST 1.1), safety and biomarkers were evaluated. Results: In 198 ALK+ pts assessed for antitumor activity (ITT population) in pooled subgroups (EXP 2–3A [only prior crizotinib ± chemotherapy (CT)], EXP 3B [only 1 prior 2nd gen ALK TKI ± CT], and EXP 4–5 [2 or 3 prior ALK TKIs ± CT]), lorlatinib led to rapid (median time to response 1.4 mo) deep and durable systemic and intracranial (IC) responses (Table). Of a total 139 pts in EXP 3B + EXP 4–5, 62, 47 and 8 received alectinib, ceritinib and brigatinib, respectively, as last ALK TKI prior to lorlatinib. Additional efficacy, including PFS, in all cohorts will be presented. The most common treatment-related AEs (TRAEs) and grade 3/4 TRAEs across all cohorts (N = 275) were hypercholesterolemia (84%/16%) and hypertriglyceridemia (66%/16%); 32% and 24% of pts had TRAEs that led to dose delays and reductions, respectively. No treatment-related deaths occurred; TRAEs led to permanent discontinuation in 8 pts. Antitumor activity was seen across a range of ALK resistance mutations, eg G1202R and G1202del. Clinical trial information: NCT01970865. Conclusions: Lorlatinib showed clinically meaningful benefit in ALK+ NSCLC pts with ≥1 prior ALK TKI and was generally tolerable with AEs managed by dose modification or supportive therapy. ORR Median DOR, mo (95% CI) IC ORR Median IC DOR, mo (95% CI) IC ORR Target Lesion Onlya N n (%) N n (%) N n (%) EXP 2–3A 59 43 (73) NR (10, NR) 37 25 (68) 19 (19, NR) 23 20 (87) EXP 3B 28 11 (39) 7 (4, NR) 13 6 (46) NR (4, NR) 9 6 (67) EXP 4–5 111 43 (39) 7 (6, 13) 81 38 (47) 15 (8, 20) 48 24 (50) a≥1 measurable brain lesion at baselineDOR, duration of response; NR, not reached
Exploratory investigation of PSCA-protein expression in primary breast cancer and its clinical relevance.
Authors: Pauline Wimberger, Theresa Link, Armin Ehninger, Jan Dominik Kuhlmann, Andreas Werner, Axel Gatzweiler, Barbara Richter, Michael Kramer, Friederike Kuithan, Katrin Friedrich
Journal: Journal of Clinical Oncology (2016)

e23267 Background: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein, which can be up-regulated in various human malignancies such as prostate, bladder or pancreatic cancer. Its over-expression was primarily described in prostate cancer and it has been suggested as prognostic biomarker and potential therapeutic target. Up to now, however, only little is known about PSCA expression and its clinical relevance in breast cancer. Therefore, we analyzed PSCA protein expression in a comprehensive cohort of primary breast cancer patients and assessed its clinical significance. Methods: PSCA protein expression was studied by immunohistochemistry on tissue microarrays/TMAs with FFPE tissues (antibody MB1) from 405 breast cancer patients. The main histological subtype was “invasive carcinoma of no special type (NST)” (84.4%). PSCA protein expression was analyzed by Chi-square-test for clinicopathological features and correlated with patient’s survival, using Kaplan-Meier analysis. Results: PSCA expression in at least 10% of the tumor cells was observed in a subgroup of 94/405 patients (23%), thereof a weak PSCA expression was detected in 66/407 patients (16%) and a moderate or strong expression in 28/405 patients (7%). Interestingly, PSCA expression was significantly associated with tumor grading (p = 0.038) and Ki67 proliferation index (p = 0.015). Furthermore, we could verify a very strong correlation between PSCA protein expression and Her2/neu status (p = 0.00003). First survival analysis indicated a shorter overall survival for patients with PSCA positive breast cancers (p = 0.038). Conclusions: To the best of our knowledge,this is the first comprehensive analysis of PSCA expression in different histological types of breast cancer. We were able to show a correlation of PSCA expression with unfavorable prognostic markers. Therefore, PSCA might be an attractive target for novel targeted treatment strategies alone or in combination with Her2/neu directed therapies.
TCT-127 Platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and red cell distribution width as predictors of contrast-induced acute kidney injury following coronary angiography
Authors: Jayakumar Sreenivasan, Muhammad Khan, Heyi Li, Yuchen Wang, Setri Fugar, Min Zhuo, Neha Yadav
Journal: Journal of the American College of Cardiology (2018)
Prognostication of outcome in men with bone metastatic castration-resistant-prostate-cancer with early rising PSA after initiation of abiraterone acetate.
Authors: Martin Boegemann, Phillip Grossmann, Julie Steinestel, Katrin Schlack, Laura Maria Krabbe, Benedikt Brücher
Journal: Journal of Clinical Oncology (2017)

e16514 Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC in the pre- and post chemotherapy setting and is mainly used in asymptomatic men. In the first 12 weeks an early rise of prostate specific antigen (PSA) may occur followed by either delayed decline (PSA-flare) or true progression. Bouncing of alkaline phosphatase (ALP-Bouncing) was shown to be a promising marker for outcome and response during very early AA therapy. This retrospective study was conducted to analyze the capability of ALP-Bouncing to predict overall survival (OS) in men with bone mCRPC (bmCRPC) with rising PSA after initiation of AA therapy. Methods: Men with bmCRPC and rising PSA during early AA therapy were includeded and analyzed. PSA response rate (RR) was monitored according to PCWG2 criteria and assessed 12 weeks after start of AA treatment. PSA-flare vs. no flare and ALP-Bouncing vs. no Bouncing were analyzed using Kaplan-Meyer estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bouncing was defined as increase of ALP after the beginning of AA with a subsequent significant decline below baseline during the first 8 weeks of therapy. Results: Forty men were evaluable for analysis: 20 men were chemotherapy naïve, 20 pretreated with docetaxel. The PSA RR was 30%. The median survival for ALP-Bouncing was 20 months (95% confidence interval (95%CI): 4.7-13.3) vs. 9 months (95%CI not distinguishable) for no ALP-bouncing (p = 0.04) and 13 months (95%CI: 8.8-17.2) for PSA-flare vs. 9 months (95%CI 4.4-13-6) for no PSA-flare (p = 0.62). In UV no ALP-bouncing was significantly associated with worse OS (Hazard Ratio (HR): 2.65 (95%CI: 1.0-7.0); p = 0.05). After adjustment for PSA-flare no AP-bouncing remained an independent prognosticator of worse OS (HR: 2.78 (95%CI: 1.0-7.71); p = 0.05). Conclusions: ALP-Bouncing, occurring earlier than delayed PSA-decline, may be a helpful marker to identify patients with subsequent favorable outcome in men with bmCRPC and rising PSA after initiation of AA therapy. These results have to be validated in a prospective trial.
Methodologic challenges of defining oncology provider networks from administrative claims data.
Authors: Karyn Beth Stitzenberg, Saray Shai, William H Weir, Peter Mucha, Tzy-Mey Kuo, Anne-Marie Meyer, Justin G Trogdon
Journal: Journal of Clinical Oncology (2018)

6523 Background: Provider characteristics measured from administrative claims data are increasingly used to study health care organization/delivery and to measure quality of care. Most studies use claims from a single large payer to calculate provider statistics and examine networks. This study compares and contrasts findings generated from claims of different but overlapping payer populations. Methods: Outpatient claims data from 2003-13 Medicare and a large private payer were used to construct colorectal cancer provider networks where edges between providers correspond to the number of shared patients. Payer-specific network and provider statistics were compared. Network metrics on the private network were compared to distributions of subsampled Medicare networks to identify statistical differences controlling for patient numbers. The study was IRB approved. Results: 1735 surgeons and medical oncologists were identified from Medicare and 1321 from private claims with 1163 appearing in both. Across networks, there were 33164 pairs of providers connected by at least one patient. 4835 (14.6%) pairs appeared only in the private network, while 18218 (54.9%) appeared only in Medicare. Average volume for surgeons and medical oncologists was similar between networks (R^2 = .85), but 24.5% of providers’ volume rank differed by at least one quintile group between payers. Likewise, average clustering coefficients were similar in magnitude across payers (.51 vs .53), but many providers had vastly different values in the two networks. Most of the same clusters/communities of providers were detected in both networks. However, there were two cases in which the combined network detected distinct communities of providers that Medicare alone missed. Conclusions: Provider networks constructed from Medicare claims alone differ from networks constructed from other large payers. Researchers should be cautious extrapolating findings from networks constructed from a single payer to other contexts. For example, this study brings into question whether Medicare data alone can be used to accurately quantify patient volume of any individual provider.
A phase I trial of T4 CAR T-cell immunotherapy in head and neck squamous cancer (HNSCC).
Authors: Sophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, May van Schalkwyk, Ana Parente Pereira, Leticia Bosshard-Carter, Lynsey Whilding, Sjoukie van der Stegen, David Davies, Farzin Farzaneh, Teresa Guerrero Urbano, Jean-Pierre Jeannon, James F. Spicer, John Maher
Journal: Journal of Clinical Oncology (2018)

3046 Background: Recent FDA approvals make CAR T-cell therapy a clinical reality for hematologic malignancy. Toxicity and antigen loss-mediated resistance remain problematic. Solid tumors impose additional challenges, foremost the paucity of safe targets. Moreover, CAR T-cells need to home to, penetrate and persist in an active state within a profoundly immunosuppressive tumor microenvironment. To address these issues, we developed T4-immunotherapy: T-cells that co-express: (i) T1E28ζ, a CAR containing a promiscuous ErbB ligand coupled to a CD28+CD3ζ endodomain; and (ii) 4αβ, an IL-4-responsive chimeric cytokine receptor. T1E28ζ engages 8/9 ErbB homo/heterodimers, providing broad anti-tumor scope while minimizing risk of antigen escape. 4αβ enables IL-4-driven selective CAR T-cell enrichment/expansion during manufacture. Pre-clinical data demonstrate potent anti-tumor activity of T4-immunotherapy. However, risk of on-target off-tumor toxicity is significant, due to normal tissues low-level ErbB expression. Methods: We undertook a Phase I dose-escalation trial of T4-immunotherapy in HNSCC. T4-immunotherapy was manufactured using a blood draw (40-130mL) in a two-week closed process, employing IL-4 as the sole cytokine stimulus post transduction. CAR T-cell dose was escalated through 5 cohorts from 1x107 -1x109 T4+ T-cells administered as a single treatment, by multifocal intra-tumoral injection without lymphodepletion. Results: Despite a lymphopenia rate of 62%, T4 manufacture was successful in 13/13 cases, yielding 2.5-7.5Bn T-cells (69+/-13% transduced). Treatment-related AEs were ≤ grade 2, with no dose-limiting toxicities (CTCAE v4.0). Frequent AEs were steroid-responsive tumor swelling, pain, pyrexias, chills and fatigue. Circulating T4+ T-cells were undetectable in all patients at all times. At 6-weeks, stable disease (SD) was seen in patients treated with ≥10x107 T4+ T-cells. Overall disease control rate was 69% (RECIST 1.1), despite rapidly progressing tumors on trial entry. Subsequent PD1 + oncolytic virus therapy in one patient achieved a rapid complete clinical response. Conclusions: These data demonstrate the safe intra-tumoral administration of T4 in patients with advanced HNSCC. Clinical trial information: NCT01818323.
Abstract 19525: Role of Nitric Oxide in Sonoreperfusion Therapy for Microvascular Obstruction
Authors: Francois T Yu, Xucai Chen, Flordeliza S Villanueva, John J Pacella
Journal: Circulation (2016)

Introduction: Microembolization during PCI for acute myocardial infarction causes microvascular[FY1] obstruction (MVO). We have shown that ultrasound (US) and microbubble (MB) therapy restores perf...