tbuckley/cabot-search huggingface dataset:
Inhibiting MUC1 a/b chain interaction mediates cytotoxicity of cells expressing MUC1: The MUC1 dyad oncoprotein as a functional target
Authors: M. Karmely, D. B. Rubinstein, E. Pichinuk, R. Ziv, I. Benhar, N. Feng, D. H. Wreschner
Journal: Journal of Clinical Oncology (2008)

14000 Background: Because of its marked overexpression in a variety of solid tumors including breast, gastrointestinal, and prostate carcinomas as well as on the malignant plasma cells of multiple myeloma MUC1, a heavily glycosylated mucin has generated considerable interest as a target for tumor killing. Full-length MUC1 (MUC1/TM) is proteolytically cleaved generating a and b subunits which specifically bind in a noncovalent interaction. While the b chain remains on the cell surface, the chain binds in an on-and-off interaction. To date, anti-MUC1 antibodies reported recognize epitopes within the highly immunogenic a-chain tandem repeat. Because the a chain MUC-1 is shed into the circulation, anti-a chain Abs are sequestered, fail to reach MUC1-expressing cells, and form antibody-antigen complexes. Methods: We generated antibodies to the MUC1 a/β junction by immunizing with cDNA encoding MUC1/TM and the spliced MUC1/X isoform from which the tandem repeat has been deleted. Results: Pseudomonas toxin PE38 linked to polyclonal anti-MUC1 a/β junction both binds and kills MUC1-positive malignant cells. DMC209, a monoclonal anti-MUC1 a/b antibody binds both the cell-bound MUC1/X isoform and the full MUC1/TM molecule. When injected into SCID mice xenotransplanted with human breast cancer MDA-MB-231, monoclonal DMC209 showed marked in vivo tumor-suppressive activity, confirming that targeting cell-bound MUC1/X a/β junction is biologically tantamount to targeting the complete MUC1 (MUC1/TM) molecule. Conclusions: The fact that the on-and-off binding of MUC1 a and β chains acts as ligand-receptor, the role of that ligand-like interaction in cellular proliferation, and the fact that the molecule is overexpressed by a variety of malignant cell types renders the a/β junction a functional oncogene. Since MUC1-mediated signal transduction in malignant cells depends on unhindered interaction between the oncogene gene products - the intermittently bound a/β subunits - agents disrupting a/β binding are likely to significantly affect cellular proliferation and survival. This in turn suggests that the anti-a/β junction antibodies described here may be effective in target-specific immunotherapy. No significant financial relationships to disclose.
Morphologic and immunohistochemical (IHC) changes in metastatic melanoma (MM) tissue and associations with clinical outcome in patients (pts) on BRAF inhibitors (BRAFi).
Authors: G. V. Long, J. S. Wilmott, J. R. Howle, M. D. Chatfield, V. Tembe, J. F. Thompson, P. Hersey, G. J. Mann, G. A. McArthur, H. Rizos, R. J. Young, L. L. Scurr, R. N. Sharma, R. F. Kefford, R. A. Scolyer
Journal: Journal of Clinical Oncology (2011)

8542 Background: Drugs that target oncogenic mutant BRAF have impressive response rates in MM pts, however resistance usually develops within 12 months. In pts on clinical trials of BRAFi, we investigated mechanisms of action and resistance by analysing MM tissue excised before and after treatment, and on progression. Methods: Pts with V600E or V600K mutant MM enrolled on the Ph 1/2 study of GSK2118436 or the Ph 2 study of RO5185426 had biopsies (bx) ≤7 days prior to (PRE) and 7 days +/-4 after commencing BRAFi (POST), and on progression (PROG). Morphologic and IHC (p27, pAKT, pERK, Ki67, TUNNEL assay) tissue bx features were correlated with clinical outcome data including time to progression (TTP) and overall survival (OS), and measures of response; FDG PET change in SUV max, CT-determined RECIST response and calliper measurement of subcutaneous lesions. Results: 12 pts had paired PRE and POST bx, 7 also had PROG bx. 3 pts had paired PRE and PROG bx only. Of the 15 pts, 2 were treated with RO5185426 and 13 with GSK2118436. Comparing paired PRE and POST bx, there was a marked decrease in Ki67 and mitotic rate in 11/12 pts (p<0.05) regardless of clinical response, and a systematic change in cell type (round to spindle), cell size (decreased), necrosis (increased), intratumoral lymphocytes (ITL) (increased) and apoptosis (increased) on exposure to BRAFi (p<0.05). Peritumoral lymphocytes (PTL) increased (p=0.07). Preliminary data suggest there was no systematic change in p27 or pAKT, however a higher PRE nuclear p27 level maybe associated with a poorer OS (HR 1.5, 95%CI 1.03-2.27, p=0.03) and TTP (HR 1.29, 95%CI 1.06-1.59, p=0.01). Change in calliper measurement of the POST lesion from baseline correlated negatively with changes in necrosis and ITL (p<0.05). For POST to PROG paired bx, apoptosis, ITL and PTL decreased (p<0.05). Conclusions: Specific morphological changes occur in melanoma tissue on exposure to BRAFi, some of which may be associated with clinical outcome. Baseline level of p27 may be prognostic in BRAF mutant pts. Changes in tumoral lymphocytic infiltrates in POST and PROG bx suggest that an immune response may have a role in BRAFi activity.
Successful completion of EGFR/ALK testing in non-squamous non-small cell lung cancer (non-sq NSCLC) with the implementation of reflex testing (RT) by pathologists.
Authors: Ines B. Menjak, Zoe Winterton-Perks, Simon Raphael, Susanna Y. Cheng, Sunil Verma, Ryan Freedman, Nevkeet Toor, Joseph Perera, Matthew Anaka, Charles Victor, Parneet Kaur Cheema
Journal: Journal of Clinical Oncology (2016)

93 Background: EGFR mutation and ALK rearrangement testing is standard in the management of advanced non-sq NSCLC patients (pts). Previously at our centre, EGFR/ALK biomarker testing was requested by medical oncologists (MO). In June 2013 we implemented biomarker RT, defined as pathologists requesting EGFR/ALK at time of diagnosis of non sq-NSCLC irrespective of stage. The objective of this study was to test the hypothesis that if pathologists requested biomarker testing, appropriate tissue would be preserved and selected for testing, which would improve success rates of biomarker testing. Methods: Retrospective review of advanced non-sq NSCLC pts seen by MO at Sunnybrook Odette Cancer Centre from March 2010 to April 2014. Pt and EGFR/ALK test characteristics were compared before and after RT using Chi-square tests of association. Time outcomes were compared using Mann-Whitney U tests. Results: Of the 310 pts included, median age was 68, 44% female, 47% Caucasian, 93% adenocarcinoma, 22% EGFR+, 1% ALK+ and 84% either presented with or developed stage IV. Samples tested for EGFR and ALK were respectively: 53%, 51% core biopsies; 25%, 32% surgical resections; 20%, 16% cytology. The number of biomarker tests across all stages increased with RT (EGFR 70% vs 95%, p &lt; 0.001 / ALK 44% vs 83%, p &lt; 0.001). RT improved the rate of successfully completed tests (EGFR 86% vs 96%, p = 0.04 / ALK 83% vs 97%, p = 0.04). The remainder of tests were unsuccessful due to inconclusive results (EGFR 9% vs 4%, p = 0.25 / ALK 7% vs 2%, p = 0.25), insufficient tissue (EGFR 3% vs 0%, p = 0.33 / ALK 10% vs 0%, p = 0.03) or cancellation due to appropriate tissue not being sent from holding lab to testing lab (EGFR 2% vs 0, p = NS / ALK 0% vs 2%, p = NS). From core biopsies, there was trend to improved success of EGFR testing with RT (82% vs 97%, p = 0.06) and significant improvement of ALK testing (82% vs 100%, p = 0.04), with no impact on success from cytology samples. Rebiopsy rate for biomarker testing was low in both cohorts. Turnaround time for EGFR testing decreased [19 days (IQR 15-25) vs 17 days (IQR 12-21), p = 0.02]; ALK was unchanged. Conclusions: Implementation of RT improved successful completion of EGFR/ALK testing.
Single-institutional analysis of patients with clear-cell papillary renal cell carcinoma.
Authors: Jozefina Casuscelli, Andrew G. Winer, Eduard Reznik, Jianing Xu, Brandon Manley, Jyoti Chouhan, Victor E. Reuter, Satish Tickoo, Paul Russo, Jonathan A. Coleman, James Hsieh, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2016)

512 Background: Recently clear cell papillary renal cell carcinoma (cpRCC) has been recognized as new histologic subtype with immunohistochemical profiles that differentiate it from clear cell (ccRCC) and papillary (pRCC) RCC. Several previous studies highlighted the indolent behaviour of this entity in the reported cases. Our primary objective is to further elucidate the genomic and clinical characteristics of cpRCC. Methods: 44 patients with cpRCC were selected from the MSKCC database with surgery performed between 2007 and 2014. Only tumors with appropriate histological configuration and immunohistochemically confirmed CAIX and CK7 positivity and CD10 negativity were included. Whole exome sequencing (WES) was performed on 5 cpRCC tumor samples and one sample was analyzed by next-generation sequencing (MSK-IMPACT). A further comparison was made to 825 ccRCC and 219 pRCC tumors with initial pT1 diagnosis from our institutional database. Differences in the variables across groups were analyzed with the Chi-Square and the Kruskal–Wallis tests. To visualize and test the survival distribution differences, we used Kaplan–Meier plots and Log-rank tests. Results: Sequencing did not reveal VHL mutations or other known driver mutations commonly seen in ccRCC or pRCC and no recurrent mutations were identified. The median follow up period for cpRCC was 27 months, for ccRCC 59 months and for pRCC 63 months. cpRCC frequently co-occured with ccRCC or other RCC subtypes (17/44 cases). Female patients developed cpRCC significantly more frequently than ccRCC or pRCC (47.7% P&lt;0.001) and Kruskal-Wallis test revealed differences in tumor size between the 3 groups (cpRCC median size 2.5 cm, P&lt;0.001). Recurrence, metastatic development and death from kidney cancer was observed in ccRCC (3.7%, 2.3% and 0.8%) and in pRCC (4.5%, 1.8% and 2%), but not in the cpRCC cohort. Conclusions: cpRCC is genomically distinct from ccRCC and pRCC and lacks driver mutations commonly associated with aggressive disease. The tumors tend to present smaller than other RCC subtypes, commonly co-occur with other RCCs and disproportionately affect women. Extended follow-up of larger cohorts is necessary to confirm the true indolent nature of cpRCC.
Evaluation of the Charlson comorbidity index to predict outcome after esophagectomy in older patients.
Authors: A. Kothari, T. Bretl, T. Weigel
Journal: Journal of Clinical Oncology (2011)

27 Background: Esophagectomy remains a preferred treatment for several neoplastic and non-neoplastic conditions; however it is often avoided in elderly patients with several co-morbid conditions. Several centers endorse the use of the Charlson comorbidity index to predict surgical outcomes in high risk patients. To date, this standard measure of co-morbidity has not been used to predict surgical outcomes following esophagectomy in elderly (age ≥70) patients. Methods: We reviewed data from an IRB-approved, prospectively maintained thoracic surgery database over a three-year period (March, 2006 – March, 2009). We compared incidence of post-operative events, total length of stay, 30-day mortality, rate of readmission, and calculated Charlson comorbidity indices (CCI) for all patients. A validated electronic application was used to calculate CCI based on patient age, BMI, substance use, malignancy, and co-morbid diseases (CV, respiratory, GI, endocrine, inflammatory, psychiatric, neurologic, and immunologic). Results: There were 75 patients below the age of 70 and 41 patients ≥ 70 years old who underwent esophagectomy over the 3-year period studied. Patients over the age of 70 had a significantly higher CCI (5.02) than patients under the age of 70 (3.19, p &lt; 0.05). However, the 30 day mortality in patients ≥ 70 (0.0%) and under 70 (2.3%) was not significantly different between groups (p = 0.33). There was no difference in median length of hospital stay (7 days vs. 7 days, p = 0.95) and rate of readmission (7.5% vs. 9.3%, p = 0.74) when comparing patients ≥ 70 and &lt; 70 years old, respectively. Patients ≥ 70 had a significantly lower incidence of complications than patients under the age of 70 (34.1% vs. 60.0%, p &lt; 0.05). Conclusions: Patients ≥ 70 years old had higher Charlson comorbidity indices than patients &lt; 70 years old, however surgical outcomes in both groups following esophagectomy were similar. In this population, CCI may not be a valid tool for measuring surgical risk perhaps due to the inclusion of age in the index. Future study will focus on the development of a co-morbidity index which can predict outcomes following esophagectomy and is not biased by age. No significant financial relationships to disclose.
Thymidylate synthase expression as a predictive factor for response and progression-free survival in metastatic breast cancer patients.
Authors: Hirohito Seki, Hiromitsu Jinno, Tetsu Hayashida, Maiko Takahashi, Munehisa Kaneda, Keiichi Suzuki, Hidenori Hara, Masayoshi Osaku, Yoshinori Yamada, Humiki Asamuna, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2012)

132 Background: S-1, an oral fluoropyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypryidine, and potassium oxonate in a molar ratio of 1:0.4:1 has been widely used against solid cancers including gastric, colorectal, pancreatic, lung and breast cancer. In a phase II study, the response rate (RR) was 41.7% and the median survival was 872 days among taxane-pretreated patients with metastatic breast cancer (MBC). However, the predictive factor of S-1 in patients with MBC has not been determined yet. The purpose of this study is to investigate the correlation between 5-FU-related enzyme and clinical efficacy of S-1 in patients with MBC. Methods: Forty-eight patients with MBC were treated with S-1 twice daily at a dose of 80 mg/m 2 for 4 weeks, followed by a 2-week rest interval. Laser-captured microdissection was performed from the formalin-fixed, paraffin-embedded tumor sections at surgery and the expression of 5-FU-related enzyme including thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) was evaluated by RT-PCR. Results: The median age was 58 years. ER, PgR, HER2 was positive in 57, 28, and 14% of the entire patients, respectively. The median number of pretreated chemotherapy regimens was 2 (range 0-6). The sites of metastatic disease were the viceral in 25 patients, bone in 9 patients and soft tissue in 17 patients. The overall response rate (RR) was 22.9% (11/48) and clinical benefit rate was 41.7% (20/48). The median time to tumor progresssion (TTP) was 14.3 months (range 6.0 – 22.7). ER, PgR and HER2 status was not significantly correlated with RR. TS expression was significantly associated with clinical efficacy of S-1. Moreover, it is notable that triple negative breast cancer (TNBC) revealed lower TS expression than luminal type (TNBC vs luminal type = 80% (8/10) vs 36.4% (4/11), P= 0.054, OR 0.143, 95% CI 0.020-1.032). According to the correlation between metastatic sites and RR, better RR was noted for soft tissue metastases (soft tissue vs visceral = 25% (5/20) vs 84% (5/6), OR 15.0 (95%CI 1.40–161.05). Conclusions: This study demonstrated that TS is a significant predicitve factor of S-1 in patients with MBC.
Results of a multicenter randomized trial to evaluate a survivorship care plan for breast cancer survivors.
Authors: E. Grunfeld, M. N. Levine, J. A. Julian, G. R. Pond, E. Maunsell, A. Folkes, S. F. Dent, A. A. Joy, L. F. Paszat, K. I. Pritchard, G. A. Porter, D. Rayson, A. Robidoux, S. Smith, J. Sussman, L. Provencher, J. Wiernikowski, J. J. Sisler
Journal: Journal of Clinical Oncology (2011)

9005 Background: Survivorship care plans (SCPs) are recommended for patients who have completed primary treatment and are transitioning to routine follow-up care. SCPs are considered to have face validity but have never been tested in a randomized trial. The objective of this study was to evaluative a SCP for breast cancer survivors transitioning to routine follow-up care with their own family physician (FP). Methods: 408 early -stage breast cancer patients who completed primary treatment at least 3 months previously and without recurrent or new primary cancer were enrolled through tertiary care cancer centers throughout Canada and stratified into 2 groups: <24 months (n=180) and ≥ 24 months (n=228) since diagnosis. All patients were transferred to their own FP for follow-up care. In the intervention group, 200 patients received a SCP consisting of: a treatment summary; a patient-version of follow-up guidelines; brochures and information about local relevant supportive care resources. These were compiled in a binder and reviewed with the patient in a 30-minute educational session with a nurse. FPs of intervention patients received a copy of all documents plus the full guideline and a reminder table of recommended follow-up visits and tests. In the control group, 208 patients received a discharge visit and FPs received a discharge letter, according to usual practice. The primary outcome was psychosocial adjustment (Impact of Events Scale; IES) at 12 months post-intervention. Secondary outcomes were continuity of care, health-related quality of life (SF-36), patient satisfaction, and adherence to guidelines. Results: There were no differences between groups on psychosocial adjustment, or on any of the secondary outcomes studied. There were no differences between groups on any outcomes when the two strata were analyzed separately. Conclusions: This SCP did not have an impact on patient outcomes or adherence to follow-up guidelines. IES Intervention n = 165 Control n = 180 Difference (95% CI) At 12 months* 16.4 (15.7) 17.5 (15.2) -1.2 (-4.4, 2.1) Change from baseline* -2.9 (12.5) -1.4 (12.8) -1.6 (-4.3, 1.1) * Mean (SD)
Inference and forecast of H7N9 influenza in China, 2013 to 2015
Authors: Ruiyun Li, Yuqi Bai, Alex Heaney, Sasikiran Kandula, Jun Cai, Xuyi Zhao, Bing Xu, Jeffrey Shaman
Journal: Eurosurveillance (2017)

The recent emergence of A(H7N9) avian influenza poses a significant challenge to public health in China and around the world; however, understanding of the transmission dynamics and progression of influenza A(H7N9) infection in domestic poultry, as well as spillover transmission to humans, remains limited. Here, we develop a mathematical model-Bayesian inference system which combines a simple epidemic model and data assimilation method, and use it in conjunction with data on observed human influenza A(H7N9) cases from 19 February 2013 to 19 September 2015 to estimate key epidemiological parameters and to forecast infection in both poultry and humans. Our findings indicate a high outbreak attack rate of 33% among poultry but a low rate of chicken-to-human spillover transmission. In addition, we generated accurate forecasts of the peak timing and magnitude of human influenza A(H7N9) cases. This work demonstrates that transmission dynamics within an avian reservoir can be estimated and that real-time forecast of spillover avian influenza in humans is possible.
Outcomes following sequential trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).
Authors: A. Bujold, C. Massey, J. J. Kim, J. D. Brierley, R. Wong, C. Cho, Z. Kassam, R. E. Dinniwell, J. Ringash, B. Cummings, J. J. Knox, M. Sherman, L. A. Dawson
Journal: Journal of Clinical Oncology (2011)

4111 Background: SBRT can precisely deliver ablative doses of radiation while sparing normal tissues. Here are our institution’s outcomes following HCC SBRT. Methods: Two trials of SBRT for patients with active HCC unsuitable for standard local-regional therapies (resection, RFA or TACE) were conducted from 2004-07 (TRIAL 1, phase I/II) and 2007-10 (TRIAL 2, phase II). All had class Child-Pugh A, liver enzymes < 6xULN, platelets ≥ 50x10e9/L, and ≥ 700 ml of uninvolved liver. SBRT dose was 24-54 Gy in 6 fractions. Dose was dependent on a radiation-induced liver toxicity model and proximity of HCC to luminal GI tissues. Primary endpoint was local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST. Fisher’s exact test, Kaplan-Meier, log-rank and Cox model were used for analyses. Results: Total accrual was 102 patients (TRIAL 1: n=51, TRIAL 2: n=51). Underlying liver disease was: hepatitis B, 39%; hepatitis C, 40%; alcohol, 25%; other, 14%; none, 7%. Prior therapies were delivered in 50% of patients (9% surgery, 34% RFA, 22% TACE, 16% other, no sorafenib). Baseline CLIP score was ≥2 in 52% of patients. Median number of lesions was 2 (1 to >10). Median sum of treated liver lesions (STLL) was 10 cm (1.8-43.3 cm). Tumor thrombus (TT) was present in 55%, and extra-hepatic disease in 12%. Median follow-up was 15 months (m). Best RECIST response was: CR11%, PR43%, SD44%. LC1y was 79% (CI 95% 66-87%). STLL was significantly associated with LC (HR=1.09, p=0.02). TRIAL 2 patients had a trend to improved LC (HR=0.45, p=0.09). Toxicity ≥grade 3 was seen in 33%. In 7 patients, death was likely related to treatment (1.1 – 7.8 m post SBRT): 5 liver failures (1 had PD), 1 cholangitis (HCC in bile duct), 1 GI bleed. Median overall survival was 16.8 m (CI 95% 9.6-20.4 m). On multivariate analysis of survival, only TT (21.5 m without TT vs. 10.6 m with TT; HR=2.21, p=0.02) and trial were significant. Median survival of patients treated on TRIAL 2 was 25.1 m vs. 10.6 m in TRIAL 1, HR=0.45, p=0.006. There was a trend for smaller STLL (p=0.09) and use of sorafenib at time of progression (p=0.07) in TRIAL 2 vs. 1. Conclusions: There is strong motivation for studying SBRT for HCC in a randomized trial.
An analysis of low miR-199a expression in renal cell carcinoma (RCC) and and its association with regulation of GSK-3beta.
Authors: M. Tsukigi, V. Bilim, K. Yuuki, S. Naito, A. Ugolkov, T. Sakurai, H. Kawazoe, N. Hosoya, H. Nishida, T. Kato, A. Nagaoka, M. Oya, T. Motoyama, Y. Tomita
Journal: Journal of Clinical Oncology (2011)

e15020 Background: Renal cell carcinoma (RCC) is highly resistant to chemotherapy due to a high apoptotic threshold. Recently, we have shown nuclear accumulation of GSK-3β as a new marker of human RCC and identified that GSK-3 positively regulates RCC cell survival and proliferation. It has been reported that GSK-3β is a miR-199a target. Our objectives were to determine the expression level of miR-199a in human RCC and renal cancer cell lines, and to assess the anticancer effect of reintroduction of pre-miR-199a in renal cancer cells in vitro. Methods: TaqMan MicroRNA assay was applied to examine miR-199a expression in 54 human RCCs and normal kidney counterpart as well as in 8 renal cancer cell lines. Immunohistochemical staining was performed to determine the expression pattern of GSK-3β in RCC tissues. Western blotting, quantitative RT-PCR and MTS cell viability assay were used to study the effect of pre-miR-199a reintroduction into renal cancer cells in vitro. Results: We detected low miR-199a expression in 57% (31 of 54) of RCCs. We found that 87% (27 of 31) of low miR-199a tumors were clear cell carcinomas. Downregulation of miR-199a was correlated with higher stage (Chi square for trend 4.605, p=0.0319) and nuclear accumulation of GSK3β (Fisher’s exact test, p=0.0249) in clear cell RCCs. We found high miR-199a expression in two benign renal hamartomas (angiomyolipoma). Reintroduction of pre-miR-199a into renal cancer cells led to decreased GSK-3β, XIAP, Bcl-2 expression and suppression of RCC cells proliferation and survival. Conclusions: We found that miR-199a is downregulated in most RCCs and this tumor phenotype is strongly associated with nuclear accumulation of GSK-3β and malignant potential of clear cell tumors. Our results identify low miR-199a as a novel diagnostic marker in RCC, and suggest reintroduction of pre-miR-199a as a new treatment strategy in RCC.