tbuckley/cabot-search huggingface dataset:
Long-term survival of patients with therapy-related MDS (tMDS) compared with de novo MDS following allogeneic hematopoietic cell transplantation (alloHCT).
Authors: Anh Tuan Pham, Ibrahim Taha Aldoss, Sierra Min Li, Joycelynne Palmer, Vinod A. Pullarkat, Samer K. Khaled, Monzr Al Malki, Amandeep Salhotra, Haris Ali, Ahmed M. Aribi, Anthony Selwyn Stein, David Snyder, Margaret R. O'Donnell, Stephen J. Forman, Guido Marcucci, Ryotaro Nakamura
Journal: Journal of Clinical Oncology (2016)

7059 Background: tMDS is a well-known complication of prior chemoradiotherapy with poor response to conventional treatments and dismal prognosis. AlloHCT is considered potentially curative, but the potential for long-term survival of these pts remains unknown. Herein, we report prognostics and long-term outcome for tMDS pts who underwent alloHCT at our institution and compared with that of de novo MDS pts. Methods: A retrospective analysis was performed with 264 consecutive pts (64 tMDS, 200 de novo MDS) who received alloHCT from matched related (n = 110) and unrelated donor (n = 154 including 8 from cord blood) from 2000 to 2015. Survival estimates were obtained using Kaplan-Meier method and multivariate analyses were performed to identify independent prognosticators. Results: Median age was 53 yrs for both de novo (range: 15-71) and tMDS (range: 15-70). Relative to de novo MDS, tMDS cohort comprised more women (54% vs. 40%, p = 0.04), more pts with poor-risk karyotype (63% vs. 31%, p < 0.01) and were more likely to receive reduced intensity conditioning (94% vs. 69%, p < 0.01). There was a trend toward higher proportion of Int-2/High IPSS among tMDS pts (61% vs. 45%, p = 0.07). After a median follow-up of 5 yrs (range: 0.5-15.8), the 5-yr overall survival (OS) for the entire cohort was 51.4%. There was no difference in OS between tMDS (49.5%) and de novo MDS (52%, p = 0.6). The 5-yr non-relapse mortality and relapse rate were similar between tMDS and de novoMDS (31.3% vs. 31.2%, p = 0.9, 28.7% vs. 28.7%, p = 0.9, respectively). In multivariate analysis for the entire cohort, tMDS was not associated with poorer OS (p = 0.7). For tMDS, younger age (p < 0.01), and more recent era of alloHCT (p < 0.01) were independently associated with longer OS whereas karyotypes, IPSS, and %blasts before HCT were not. For de novoMDS, patient age (p < 0.01), favorable cytogenetics (p = 0.02) and low/Int-1 IPSS (p = 0.04) were the only independent predictors for longer OS. Conclusions: Our results demonstrate that a large proportion of tMDS pts may achieve long-term survival after alloHCT. The transplant outcomes are similar to that of de novo MDS despite greater frequency of higher-risk karyotypes in tMDS.
Multicenter observational study on re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab.
Authors: Tomomi Kashiwada, Hiroshi Saeki, Yoshikazu Uenosono, Akitaka Makiyama, Masaaki Iwatsuki, Yukiya Narita, Hironaga Satake, Yoshiko Matsuda, Hideto Sonoda, Eiji Oki, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2018)

4038 Background: Addition of trastuzumab to cisplatin and fluoropyrimidine-based doublet chemotherapy is the standard first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or recurrent gastric cancer. However, second-line anti-HER2 therapy did not demonstrate a survival advantage. We assessed the change in HER2 status in cases of HER2-positive gastric cancer refractory to trastuzumab, and analyzed potential biomarkers associated with resistance to trastuzumab. Methods: Key inclusion criteria were as follows; advanced or recurrent gastric adenocarcinoma with HER2-positive status (IHC3+ or IHC2+ with FISH amplification) before trastuzumab treatment; radiologically or clinically diagnosed with progressive disease following trastuzumab treatment; pathologically confirmed adenocarcinoma within 3 months following completion of trastuzumab treatment without receipt of any other anti-tumor agents. We collected biopsy samples from patients who had developed resistance to trastuzumab and evaluated HER2 status before and after. Amplification of EGFR and c-met, as well as PIK3CA mutation were also comparatively analyzed if samples were available. Results: Biopsy samples and clinical data were collected from 33 eligible patients as the full analysis set. HER2 loss was identified in 20 patients (60.6%) with refractory disease. IHC showed that HER2 overexpression was remarkably decreased after treatment (pre-HER2 IHC 3+: 24 [72.7%]; 2+: 9 [27.3%] vs. post-HER2 3+: 13 [39.4%]; 2+: 1 [3.0%]; 1+: 18 [54.5%]; 0: 1 [3.0%]). EGFR amplification, c-met amplification, and PIK3CA gene mutation before and after trastuzumab treatment was observed in 7.7% and 4.2%, 15.8% and 6.7%, and 6.3% and 7.1% of cases, respectively. Conclusions: HER2 loss occurred in a considerable number of patients who were initially diagnosed with HER2-positive gastric cancer, resulting in resistance to trastuzumab. EGFR, c-met and PIK3CA were rarely associated with acquired resistance. Re-evaluation of HER2 status might provide valuable clues with regard to anti-HER2 targeted therapy beyond disease progression.
Trajectories of medical care cost by service type for recurrent and de novo advanced cancer patients.
Authors: Matthew P. Banegas, Michael J. Hassett, Erin Keast, Nikki M Carroll, Maureen Cecelia O'Keeffe-Rosetti, Paul A Fishman, Angel M. Cronin, Hajime Uno, Mark C Hornbrook, Debra P. Ritzwoller
Journal: Journal of Clinical Oncology (2018)

6611 Background: Understanding cost trajectories for advanced cancer patients may identify drivers of high cost transitions and inform cost reduction efforts. Total medical care costs were measured by service type in year prior to and following diagnosis of de novo or recurrent advanced breast (BC), colorectal (CRC), or lung cancer (LC). Methods: Data on patients with de novo or recurrent BC (nstage IV= 352; nrecurrent= 765), CRC (nstage IV = 1072 and nrecurrent= 542) and LC (nstage IV= 4042 and nrecurrent= 339) from 2000-2012 from three integrated health plans were used. Average monthly and total costs of ambulatory, inpatient, medication, and other services were estimated for (1) pre-index: 12 months preceding de novo or recurrent advanced cancer diagnosis (index); and (2) post-index: index month and following 11 months. Separate generalized linear repeated measures regression models estimated costs, controlling for demographic and clinical characteristics, for each cancer. Recurrent patients were stratified based on time from initial diagnosis to recurrence ( < 1 yr versus ≥1 yr). Results: Adjusted total medical care costs increased significantly from pre- to post-index for all services among de novo and recurrence ≥1 yr patients (Table). Among patients with a CRC and LC recurrence < 1 yr, inpatient costs were significantly higher in pre- than post-index. Conclusions: Substantial variations in cost trajectories for advanced cancer patients were observed by cancer site and type of advanced disease. These estimates from a capitated system offer novel insight, as new payment models shift away from fee-for-service to bundled/episode-of-care payments. Cancer Stage IV Recurrent < 1 yr Recurrent ≥1 yr Pre-Index Post-Index Pre-Index Post-Index Pre-Index Post-Index Total Cost, in Thousands [2012$USD] Breast Ambulatory $1.6 $20.9 $16.5 $23.3 $8.1 $18.5 Inpatient $1.8 $19.0 $9.6 $13.4 $3.9 $15.2 Medication $1.5 $27.2 $12.2 $18.1 $6.6 $23.7 Colorectal Ambulatory $2.2 $16.5 $11.3 $15.5 $6.5 $13.9 Inpatient $2.1 $31.5 $34.4 $19.8 $7.2 $14.6 Medication $2.0 $16.8 $6.6 $19.9 $5.1 $17.1 Lung Ambulatory $3.5 $18.2 $18.2 $17.4 $9.2 $18.2 Inpatient $2.8 $19.0 $36.2 $17.3 $9.9 $14.0 Medication $4.1 $12.5 $5.5 $12.3 $6.4 $15.1
OP0187 Fructose-containing beverages is an independent risk factor for gout early-onset in south china
Authors: Q. Li, S.-H. Zeng, X.-Y. Du, Y.-H. Xu, K.-M. Yang, J.-J. Liang, Y.-Q. Mo, L. Dai
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> A trend of earlier onset of gout has been reported even though its incidence increases in a linear fashion with age until 70 years. Dietary factors have been supposed to be contributed to the early onset of gout. <h3>Objectives</h3> To investigate diet characteristics of gout and their impact on the early onset of gout. <h3>Methods</h3> Consecutive gout patients who fulfilled the 2016 ACR/EULAR classification criteria were recruited between Dec 2016 and Dec 2017 A cross-section survey on dietary factors before gout onset was conducted with semi-quantitative diet questionnaire. The questionnaire included alcohol, fructose-containing beverages, soup, animal organs, sea-foods, hotpot, tea and coffee, which impact on serum uric acid (sUA) and aren't major macronutrient provider in Chinese dietary patterns. The patients with gout onset before age 30 years were defined as early-onset group while the others were defined as control group. <h3>Results</h3> Among 180 gout patients recruited, there were 69 (38.3%) patients in early-onset group and 111 (61.7%) in control group. Compared with control group, gout patients in early-onset group presented significantly higher level of sUA, estimated glomerular filtration rate and proportion of obesity, but lower fraction excretion of uric acid and prevalence of hypertension (table 1, p&lt;0.05). The results of diet questionnaire showed that more patients in early-onset group consumed fructose-containing beverages≥3 times/week, but less alcohol, animal organs and tea (all p&lt;0.05, figure 1). There were no significantly difference in the consumption of soup, seafood, hotpot and coffee. Consuming fructose-containing beverages≥3 times/week [OR 8.3 (2.5, 27.1), p&lt;0.001], alcohol ≥1 standard unit/d [OR 0.27 (0.10, 0.80), p=0.017] and tea ≥3 times/week [OR 0.33 (0.12, 0.92), p=0.033] were associated with early-onset gout after adjusted by variables which were significantly different between early-onset group and control group (table 1). <h3>Conclusions</h3> Fructose-containing beverages may be an independent risk factor for gout early-onset in south China. Patient education should emphasise diet management. <h3>Acknowledgements</h3> The present study was supported by Guangdong Natural Science Foundation, China Grant no. 2014A030310086) to Qian-Hua Li. <h3>Disclosure of Interest</h3> None declared
GBR1302: Effect of CD3-HER2, a bispecific T cell engager antibody, in trastuzumab-resistant cancers.
Authors: Jonathan Back, Martin Wermke, Julie Macoin, Amelie Croset, John S. Kauh, Venkateshwar Reddy
Journal: Journal of Clinical Oncology (2018)

12053 Background: Current therapies targeting HER2 overexpressing cancers, such as Herceptin (trastuzumab) and Kadcyla (T-DM1), have proven beneficial but therapeutic benefit is limited by many resistance mechanisms. Checkpoint inhibition therapies demonstrate the potential of mobilizing T cell activities to elicit anti-tumor responses, but these T cell tumor-specific immune responses are highly immune contexture-dependent. Using Glenmark's BEAT platform, we developed GBR 1302, a T cell redirecting antibody targeting CD3 and HER2, as an alternative way of leveraging T cell potency against tumor cells, independently of existing tumor immune response. Methods: In vitro cytotoxic assays. In vivo tumor models. Ex vivo assay recreating native TME, including immune compartment, stroma and vasculature. Results: Preclinical pharmacology studies demonstrated that GBR 1302 can trigger a potent killing of HER2 positive (IHC3+) as well as HER2 equivocal (IHC2+) cancer cells while maintaining an acceptable therapeutic window on cells expressing normal levels of HER2. In vitro assays, as well as in vivo tumor models comparing the potency of GBR 1302 to trastuzumab or T-DM1 demonstrated a superior cytotoxic potential for GBR 1302 against a variety of tumor cells and that GBR1302 is effective in trastuzumab resistant tumors in vitro and in vivo. To further translate these observations into a clinically relevant human context, we studied the effects of GBR1302, as a single agent and combination partner, in a patient derived tumor microenvironment matched ex vivo assay with co-culture of autologous immune system and tumor tissue from 50 subjects with varying levels of HER2 expression ranging from 3+ to 1+. GBR 1302 treatment arm was compared to trastuzumab and to a combination of GBR 1302 + a PD-1 inhibitor on metastatic breast, gastric and gastro-esophageal cancers. GBR 1302 is currently in a phase 1 dose escalation clinical trial in HER2 positive and equivocal cancers. Preliminary data from peripheral blood biomarkers indicate that GBR 1302 triggers relevant T cell activation and cytokine production.
Results of a phase II trial of efficacy and safety of entospletinib (ENTO) in patients with lymphoplasmacytoid lymphoma/Waldenstrom's macroglubulinemia (LPL/WM).
Authors: Sarit E. Assouline, Kathryn S. Kolibaba, Leonard M. Klein, Morton Coleman, Mitchell Reed Smith, Esteban Abella-Dominicis, Wei Ye, Wen Shi, David Jacob Andorsky, Jeff Porter Sharman
Journal: Journal of Clinical Oncology (2017)

7565 Background: ENTO is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk, a mediator of B-cell receptor [BCR] signaling). Targeting the BCR-signaling pathway has been a focus in B-cell related hematological malignancies including LPL/WM. Methods: This reports the LPL cohort in a phase 2 trial that more broadly evaluated efficacy and safety of ENTO (800 mg BID) in patients with relapsed and refractory (R/R) B-cell malignancies. Tumor response was assessed at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 24. Results: 17 LPL patients (median age 72 years [range: 47–89], 65% male, and median of 3 prior regimens [range: 1–8]) were enrolled. Prior therapies included anti-CD20 antibodies (100%), alkylating agents (71%; bendamustine 24%), purine analogues (24%), and vinca alkaloid (41%). No patient had prior ibrutinib. Median treatment duration was 16 weeks (range: 1-84), with 3 patients continuing on treatment. The most common treatment-emergent AEs (any grade/≥grade 3, independent of causality) were fatigue (53%, 6%), constipation (47%, 0%), nausea (47%, 6%), diarrhea (29%, 6%), insomnia (29%, 0%) and lab abnormalities including neutropenia (53%, 12%), increased creatinine (53%, 0%), increased ALT (41%, 6%) and decreased WBC (41%, 6%). One death due to progressive disease (PD) was reported within 30 days from last dose. 12 (71%) patients were evaluable for tumor response. 5 patients (29%) discontinued prior to initial tumor assessment: PD (n = 2), withdrawal consent (n = 2) and AE (n = 1). ORR was 24% (90% CI: 9%, 46%), with 1 (6%) patient achieving PR, 3 with minor response (18%) and 7 (41%) maintaining stable disease. Reductions of IgM from baseline were greatest in the patient with PR. PFS rate at week 24 was 82% (95% CI: 44%, 95%). Median time to treatment failure and median time to response were 3.7m and 1.9 m respectively. Median duration of response has not been reached. Conclusions: ENTO was well tolerated and demonstrated limited activity in patients with R/R LPL. Further development of ENTO in LPL will focus on its role in combination therapies. Clinical trial information: NCT01799889.
Treatment-related side effects as predictors of efficacy of check-point inhibitors (CPIs).
Authors: Rebecca M. Prince, Laura DÃez, Ana Alcaraz-Sanabria, Josee-Lyne Ethier, Alberto Ocana, Bostjan Seruga, Arnoud J. Templeton, Eitan Amir
Journal: Journal of Clinical Oncology (2016)

3062 Background: There is increasing interest in immunotherapy as a treatment for cancer with multiple agents studied in various solid tumors. CPIs activate the host immune system against tumor cells; as a consequence of this mechanism of action, treatment-related adverse events (AEs) can occur. We hypothesized that occurrence of AEs is associated with longer survival. Methods: A systematic review of MEDLINE (from inception until December 2015) identified randomized studies reporting the hazard ratio (HR) for overall survival (OS) as well as data on safety which allowed the calculation of the odds of AEs comparing experimental therapy to control. Safety and tolerability outcomes of interest were treatment discontinuation without progressive disease, grade 3/4 AEs as well as immune-related adverse events (irAEs). If reported, irAEs were extracted from manuscripts. Otherwise, irAEs were assumed to comprise colitis or diarrhea, increased transaminases or endocrinopathy (hypophysitis, thyroiditis, pancreatitis). The association between AEs and OS was explored using metaregression (simple linear regression weighted by sample size). Results: Of 130 articles identified initially, 18 met inclusion criteria. Included trials were all published after 2009 and explored CPIs in melanoma, renal cell carcinoma, prostate cancer, non-small cell and small cell lung cancers. CPIs studied were ipilimumab (n = 12), pembrolizumab (n = 2), and nivolumab (n = 7). There were non-significant positive associations between treatment discontinuation without progressive disease, grade 3/4 AEs, and irAEs, with worse survival (see Table). Conclusions: AEs with CPIs do not predict for improved OS. Positive associations between the odds of AEs and the HR for OS suggest that prolonged exposure to immunotherapeutics may be beneficial. Safety categories R p Treatment discontinuation without progression 0.44 0.18 Any grade 3/4 AEs 0.40 0.22 Reported irAE 0.19 0.81 Presumed irAE 0.40 0.22
<i>PI3K</i> upregulation as a negative predictive factor of survival in <i>HER2</i> amplified gastric cancer treated with Trastuzumab.
Authors: Asunción Díaz-Serrano, Fernando Lopez-Rios, Carolina Dominguez, Paula J. Fonseca, Barbara Angulo, Roberto A. Pazo Cid, Carlos Plaza, Fernando Rivera, Margarita Rodriguez, Ana Leon, Susana Hernandez Prieto, Luis Paz-Ares, Carlos Gomez-Martin
Journal: Journal of Clinical Oncology (2016)

e15567 Background: Use of Trastuzumab accrues significant clinical benefit in the HER2 positive metastatic Gastric Cancer (GC) population. However, many patients do not respond to therapy or develop refractory disease. The identification of potential mechanisms of Trastuzumab resistance may provide a rationale for the development of more effective targeted therapies. Upregulation of the PI3K pathway has been noted as a molecular mechanism of resistance in breast cancer. Our aim was to determine if PI3K activated pathway determined by PTEN loss and/or PI3KCA mutation could be used as a negative predictive factor in a HER2amplified metastatic GC cohort treated with Trastuzumab. Methods: Forty-two formalin-fixed paraffin embedded HER2 amplified GC samples from patients (pts) treated with Trastuzumab-based 1stline chemotherapy were selected. PTEN expression was analyzed with immunohistochemistry and DNA samples were sequenced with the Ion AmpliSeq Cancer Hotspot Panel v2, using the Ion Torrent Personal Genome Machine (PGM) sequencing platform (Life Technologies, Carlsbad, CA, USA). Results: We found PI3K pathway activation in 40.5% (n = 17) of pts: PTEN loss was found in 33.3% (n = 14) and PI3KCA mutation in 11.9% (n = 5). The Kaplan-Meier survival curves displayed a statistically significant difference in overall survival (OS) according to the PI3K pathway status: median OS was 19.5 months in pts without PI3K activation and 14.9 months in pts with PI3K activation (log-rank test, p = 0.042). Cox regression analysis estimated that the PI3K upregulated group had a higher likelihood of death (hazard ratio 2.06, CI 95% 1.01 to 4.20, p = 0.046). After adjustment for RAS and other tyrosine kinase receptors (TKR) alterations, the PI3K status remains as a negative predictive factor only in the non-activated RAS/TKR group (median OS 14.3 vs 19.5 months in patients without PI3K activation, log-rank test, p = 0.047). Conclusions: PI3K pathway activation could be used as a predictive marker for worse outcome in patients with HER2 amplified metastatic gastric cancer treated with trastuzumab. In addition, co-activation of RAS and other TKR in this subgroup may influence the survival benefit of Trastuzumab.
Diagnostic value of <sup>18</sup>F-FDG PET/MRI for the detection of lymph node metastasis in gynecologic cancer.
Authors: Hideaki Tsuyoshi, Tetsuya Tsujikawa, Hidehiko Okazawa, Yoshio Yoshida
Journal: Journal of Clinical Oncology (2017)

e17014 Background: Integrated PET/MRI simultaneously provides the metabolic (PET) and functional (DWI) information. It may provide high diagnostic performance in gynecologic malignancies due to the excellent soft tissue contrast. However, up to the present date, only a few studies have shown the diagnostic value of PET/MRI in gynecologic cancer. The aim of our study was to clarify the diagnostic ability of PET/MRI for the detection of lymph node metastasis which can correlate to the prognosis of gynecologic cancer patients. Methods: Eighteen patients with a primary or a suspected recurrent gynecologic cancer (cervical, endometrial and ovarian cancer) were included. They underwent preoperative PET/MRI and CT scans. The morphological criterion on CT was based on the size of lymph nodes which was larger than 1.0 cm in the long axis. The PET criterion was based on the positivity which was higher 18 F-FDG uptake compared with the surrounding tissue. On DWI, lymph node was defined as positive in the presence of higher signal intensity compared with the surrounding tissue. The presence or absence of lymph node metastasis was confirmed by surgical pathology. McNemar test was used for the comparison of the diagnostic ability of lymph node metastasis among PET, DWI and CT. Results: Lesion-based sensitivity, specificity and diagnostic accuracy were 23.8%, 96.9% and 84.0% for CT, 93.75%, 87.50% and 88.46% for DWI and 90.48%, 92.86% and 92.44% for PET. PET had a significantly higher sensitivity (P &lt; 0.001) and a higher accuracy (P &lt; 0.05) than CT for the detection of lymph node metastasis. PET also tended to have a higher specificity compared with DWI (P = 0.074). The combination of PET with DWI correctly detected 2 additional lesions to PET alone. Conclusions: Our results demonstrate that integrated PET/MRI can offer a high diagnostic value for the detection of lymph node metastasis in gyn ecologic cancer. The combination of PET with DWI may provide a higher diagnostic accuracy than two separate devices.