tbuckley/cabot-search huggingface dataset:
Real-World single centre experience with Palbociclib as first line treatment in Indian patients with metastatic breast cancer.
Authors: Amit Rauthan, Poonam Patil, SP Somashekhar, Shabber Zaveri
Journal: Journal of Clinical Oncology (2018)

e13030 Background: Palbociclib, a selective CDK 4/6 inhibitor, has been approved in combination with letrozole as a first-line therapy in Estrogen receptor positive(ER+) and HER2 negative metastatic breast cancer(MBC). Palbociclib is available for use in India since Oct 2016. The aim was to analyse safety of Palbociclib in Indian patients. Methods: This is a single-centre, retrospective Indian study, which included female patients diagnosed with ER+, HER2 negative MBC who were receiving Palbociclib between October2016 to Jan2017. The endpoints were adverse events(AE) and objective response. Results: Among 25 metastatic breast cancer patients screened, 16 patients(64%) received Palbociclib with letrozole as first-line therapy, and 9 patients(36%) received Palbociclib in 2nd line and beyond. The 16 first line patients were included in this study. Median age was 58 years (range 36-68years). 7 patients(44%) had bone-only metastases, while 9 patients(56%) had visceral metastases. Palbociclib was started at 125 mg/day, 3 weeks on and 1 week off. Median duration of treatment was 11 months (range 2-15 months) at data cut off. 15 of the 16 patients are currently continuing treatment without progression. Neutropenia was the most commonly reported AE (81.2% all grade): grade 1(23%), grade 2(61.5%) and grade 3(15.4%). No febrile neutropenia was observed. Anemia was seen in 1 patient (6.2%) and thrombocytopenia in 3 patients(18.7%). The AEs led to Palbociclib treatment interruption among 6 patients, with a mean dose delay of 7 days. 2 patients required dose reduction to 100 mg. Serious AE was not reported in any patient. Response was assessed among 12 patients after a mean duration of 4 months. 2 patients(16.6%) achieved complete response, 3 patients(25%) achieved partial response, 6 patients(50%) had stable disease, 1 patient(8.3%) had disease progression. Conclusions: Palbociclib at standard dose of 125mg with letrozole was very well tolerated in our patients. Although haematological AEs were frequent, they were uncomplicated and easily managed by brief dose interruption. Continued use of Palbociclib will help in better assessment of the safety and efficacy in Indian patients.
A prospective, multi-institutional phase II study of induction chemoradiotherapy followed by surgery in patients with non-small cell lung cancer involving the chest wall (CJLSG0801).
Authors: Koji Kawaguchi, Kohei Yokoi, Hiroshi Niwa, Yasuhisa Ohde, Shoichi Mori, Sakae Okumura, Satoshi Shiono, Hiroyuki Ito, Motoki Yano, Kikuo Shigemitsu, Yoshinori Hiramatsu, Jiro Okami, Hideo Saka
Journal: Journal of Clinical Oncology (2016)

8525 Background: The standard therapy for patients with T3N0-1M0 non-small cell lung cancer (NSCLC) involving the chest wall is considered surgical resection and adjuvant chemotherapy. However, the compliance of this treatment is relatively low, and the prognosis for those patients has not been satisfactory. Therefore, we conducted a phase II study of induction chemoradiotherapy followed by surgery with the aim of improving the survival. Methods: This treatment strategy consisted of induction chemotherapy (two cycles of cisplatin: 80 mg/m2 and vinorelbine: 20 mg/m2) concurrent with radiation therapy (40 Gy in 20 fractions) followed by surgery 3-6 weeks after the last administration of chemotherapy. The inclusion criteria were patients with resectable T3N0-1M0 NSCLC involving the chest wall (including superior sulcus tumors, PS: 0-1, 20-70 years old). The primary end point was the 3-year survival rate after the date of registration assuming the expected rate of 67%, adding 20% to the reference rate of 47% based on the previous literatures, and the sample size was calculated to be 48 cases with an α error of 0.05 and a β error of 0.2. Results: From Jan 2009 to Nov 2012, 51 eligible patients (40 stage IIB and 11 stage IIIA tumors) were enrolled in this study. Induction therapy was completed as planned in 49 (96%) patients with no treatment-related death, and 25 (51%) had a partial response. Excluding one patient with progressive disease, 50 patients underwent pulmonary resection combined with chest wall resection. Complete resection was achieved in 46 (92%) patients, and pathologic complete response was seen in 13 (26%) patients. Five patients experienced major postoperative complications, and 1 patient died of postoperative acute exacerbation of interstitial pneumonia. The 3- and 5-year overall survival rates of all registered patients were 77% and 63%, respectively. Conclusions: The final results of this study showed the treatment strategy to be safe and effective with a high rate of pathologic response for patients with lung cancer involving the chest wall in a multi-institutional setting. Clinical trial information: UMIN000001810.
P05.87 Hemoglobin level is a relevant prognostic marker of overall survival in primary central nervous system lymphoma: a retrospective study on 160 PCNSL
Authors: M Le, Y Garcilazo, N Younan, C Houillier, K Hoang-Xuan, A Alentorn
Journal: Neuro-Oncology (2018)

Primary central nervous system lymphomas (PCNSL) are extra-nodal, malignant non-Hodgkin lymphomas of diffuse large B-cell type confined to the CNS or eyes without evidence of systemic spread. PCNSL account for up to 1% of all lymphomas and 3% of primary brain tumors. Despite recent progress in PCNSL treatment, the prognosis remains dismal and there is a medical need to identify novel surrogate markers of the clinical evolution to better tailor their treatment. Recent evidence suggests that routine blood tests like neutrophil-to-lymphocyte ratio (NLR) may be used as an independent prognostic marker in different brain tumors. Therefore, we sought to analyze the impact of different routine blood tests as potential surrogate markers of the clinical evolution of PCNSL. A retrospective cohort of PCNSL treated at Pitié-Salpêtrière Hospital from 2011 to 2018 with available clinical data follow-up and routine blood before high-dose methotrexate based chemotherapy. We have analyzed the impact of NLR, neutrophil-to-platelets and hemoglobin levels to overall survival using univariate and multivariate analysis by Cox proportional hazards ratio regression. We identified 160 PCNSL. The median age was 67 years [Interquartile range, IQR 59–75], median neutrophil was 6595/mm3 [IQR 4790–7275], lymphocyte 1740/mm3 [IQR 1290–2603], platelets 231000/mm3 [IQR 194000–277000] and hemoglobin 13.5g/dL [IQR 12.3–14.4]. Interestingly, in this cohort NLR, NPR and platelets levels were not related with overall survival (OS) p-value > 0.05. However, Hemoglobin level (cut-off median) was strongly associated with OS in univariate (log-rank p-value < 0.001). In addition this result was also confirmed in the multivariate analysis after adjusting by age and Karnofsky Performance Status, (HR 0.46 CI 95% 0.29–0.73, p-value < 0.001). In this retrospective monocentric study, the Hemoglobin level at diagnosis before starting high-dose methotrexate based chemotherapy was strongly associated with OS in PCNSL. We are currently validating these results in two prospective multicentric cohorts of PCNSL to further corroborate this potential easy-to-use clinical marker in PCNSL.
Integrative detection and analysis of structural variation in cancer genomes
Authors: Jesse R. Dixon, Jie Xu, Vishnu Dileep, Ye Zhan, Fan Song, Victoria T. Le, Galip Gürkan Yardımcı, Abhijit Chakraborty, Darrin V. Bann, Yanli Wang, Royden Clark, Lijun Zhang, Hongbo Yang, Tingting Liu, Sriranga Iyyanki, Lin An, Christopher Pool, Takayo Sasaki, Juan Carlos Rivera-Mulia, Hakan Ozadam, Bryan R. Lajoie, Rajinder Kaul, Michael Buckley, Kristen Lee, Morgan Diegel, Dubravka Pezic, Christina Ernst, Suzana Hadjur, Duncan T. Odom, John A. Stamatoyannopoulos, James R. Broach, Ross C. Hardison, Ferhat Ay, William Stafford Noble, Job Dekker, David M. Gilbert, Feng Yue
Journal: Nature Genetics (2018)
Ipilimumab and radiation in patients with unresectable melanoma brain metastases: A multicenter, open label, phase-2, Spanish Melanoma Group (GEM) study (NCT-2013-001132-22).
Authors: Jose A. Lopez-Martin, Ana M. Arance, Luis De La Cruz-Merino, Ana Illescas, Izazkun Valduvieco, Alfonso Berrocal, José López Torrecilla, Ivan Marquez Rodas, Maria Teresa Curiel Garcia, Virtudes Soriano, Ana Alvarez, M.L. Chust Vicente, Delvys Rodriguez-Abreu, M.C. Peñas Sanchez, Eva Muñoz-Couselo, Javier Aristu, Antonio Gomez Caamaño, Salvador Martin-Algarra
Journal: Journal of Clinical Oncology (2018)

9546 Background: Laboratory and clinical experiences suggest that radiotherapy may be synergistic with anti-CTLA-4 strategies. This hypothesis is explored in melanoma patients (pts) with brain metastases (BM) not candidate to surgery/radiosurgery. Methods: Single arm phase-2 trial evaluating Ipilimumab (IPI) and whole brain RT (WBRT), in pts with melanoma and unresectable BM. Endpoints: Primary: 1-year overall survival (OS@1y). Secondaries: progression free survival (PFS), objective response rate (ORR) and safety. Main eligibility criteria: first-BM episode, non-suitable for radical therapy; Barthel Index > 10; RTOG-RPA class-2; measurable disease; Karnofsky > 70%; LDH < 2 xULN; no rapid clinical deterioration; dexamethasone < 16 mg/d. Treatment: IPI 3mg/Kg q3weeks (4 cycles); WBRT 30Gy in 10 fractions (or equivalent). Evaluable pts: Safety > 1 IPI dose. Efficacy: complete WBRT and > 1 IPI dose. Trial required 56 evaluable pts to detect an 35% OS@1y, assuming the historical 20% OS in this population (α:0.05, β:0.8; 1-stage Fleming design). Results: From April/2014 to January/2017, 58 pts were included; 51 completed WBRT and > 1 IPI dose. Demographic characteristics: Age (median/range) 63 (37/85). Male/Female 36/22. Karnofsky (100/90; 80/70) 42. 16. BM (1, > 1, nonspecified) 14; 43; 1. Barthel Index ( > 15; 10-15) 56; 2. Steroids at baseline 31 (53,4%). Prior treatments (1, > 1) 20 (34,5%), 9 (15,5%). Previous BRAF/MEKinhibitors 18 (31%). Liver metastases 16 (27,6%). Treatment intensity: WBRT: completed in 55 pts (3 early termination). IPI 4/3/2/1 doses: 31/10/10/7 pts. Efficacy: OS@1y: 31.8% (95%CI 18.8-44.8%). 15 pts are alive > 1 year. Median PFS: 4.8mo (95%CI 2.2-3.4). Median OS 5.8mo (95%CI 3.6-5.9). Safety: Serious AEs: 40 pts (69%). Treatment-related SAEs: 11 pts (19%). IPI-related: ALT/AST (4), diarrhea (4), intestinal perforation (1), headache (1). RT-related: headache and vomiting (1). Conclusions: Concomitant IPI+WBRT is feasible and there were no unexpected safety issues. Steroids at baseline do not impair the effect of IPI in this population. OS@1y in this trial is higher than the historical results. Clinical trial information: 2013-001132- 22.
Association of multidimensional comorbidities with survival in elderly patients with metastatic colorectal cancer treated with chemotherapy.
Authors: Ki Hyang Kim, Jae Jin Lee, Jongphil Kim, Fabio Renato Morgado Gomes, Marina Sehovic, Martine Extermann
Journal: Journal of Clinical Oncology (2017)

e21530 Background: In geriatric assessments, comorbidity is often assessed with tools such as the Charlson comorbidity index (CCI) and the Cumulative Illness Rating Scale-Geriatrics (CIRS-G). In studies of older patients with colorectal cancer (CRC), comorbidity was mainly measured using the CCI, and inconsistent results about the correlation comorbidity with overall survival (OS) were found. In order to refine our understanding of the impact of comorbidity, we evaluated its correlation with OS using the CIRS-G and heat maps to elicit the subgroups with the highest impact. Methods: We retrospectively reviewed 153 consecutive patients from the Total Cancer Care database, aged ≥65 with stage 4 CRC, who underwent chemotherapy at Moffitt Cancer Center from 2000 to 2015. The association between CIRS-G scores and OS was examined by the Cox proportional hazards regression model. Results: Median age at diagnosis was 71 years. Forty-eight % of patients had an ECOG PS of 0. Median MAX2 score of chemotherapies was 0.119. Median total score of CIRS-G was 8 (1-20) and median severity index was 0.57 (0.07-1.43). The most common comorbidities were vascular, EENT and larynx, and respiratory diseases. Eleven patients had 1 comorbidity and 1 patient had 2 comorbidities at level 4 severity. Median OS of all patients was 25.1 months (95% CI 21.2-27.6). In univariate analysis, the number of CIRS-G level 4 comorbidities was a significant worse prognostic factor for OS (0 vs 1 or 2, HR 2.16, p = 0.017). In multivariate analysis, ECOG PS ≥2, poorly differentiated histology, age at diagnosis and numbers of CIRS-G level 4 comorbidities were significant worse prognostic factors for OS. ECOG PS ≥2 and age at diagnosis were significant worse prognostic factors for unplanned hospitalization. Conclusions: The OS in the elderly metastatic CRC patients was good and similar to the general population with this disease. The number of CIRS-G level 4 comorbidities was associated with worse OS but no specific CIRS-G category was individually associated with OS.
Quantitative MR imaging biomarkers of tumor heterogeneity predict prognosis in metastatic colorectal lesions.
Authors: Dania Daye, Sophia C. Kamran, Azadeh Tabari, Mark Michalski, Jeffrey W. Clark, David P. Ryan, Jill N. Allen, Janet E. Murphy, Theodore S. Hong, Michael S. Gee
Journal: Journal of Clinical Oncology (2017)

e15121 Background: Intra-tumor heterogeneity is an independent determinant of patient survival outcomes in several tumor subtypes. Spatial variations in tumor enhancement on MRI is a macroscopic imaging marker of tumor heterogeneity. The goal of this study is to evaluate the potential role of MRI-based enhancement heterogeneity measures as predictors of survival in patients with metastatic colorectal cancer. Methods: We retrospectively analyzed T1-weighted contrast-enhanced MRI images of metastatic hepatic lesions in 41 patients (mean age 57.2 ±14.2 years) who were diagnosed with stage IV colorectal cancer between 2007 and 2013. Tumor Kras mutation status and patient survival data for up to 95 months was available for all patients. The largest metastatic hepatic lesion was identified by a radiologist and manually segmented. 14 Haralick texture features were extracted from each lesion. Cox proportional hazards regression analysis was used to assess the association between the enhancement heterogeneity measures and patient survival, with adjustment for Kras mutation status as a potential confounder. Backward stepwise feature selection was performed using p &gt; 0.1 (Wald test) to select for statistically significant features. Results:Mean survival time was 39±3.9 months for the study population (51±4.1 months for Kras-wildtype and 37±5.1 for Kras-mutants). 68% of the patients had left-sided colon cancer; 21% had concurrent pulmonary metastases and 0.5% had concurrent brain metastasis. 61%, 27% and 12% of patients were on Flofox, Folfiri or other chemotherapeutic regimen, respectively. Texture matrix homogeneity (HR &gt; 10; p = 0.016), inverse difference moment (HR &lt; 0.1; p = 0.020), entropy (HR &lt; 0.1; p = 0.033) and standard deviation (HR &gt; 10; p = 0.006) exhibited significant independent association with patient survival. With the exception of entropy, these features maintained significant contribution to survival prediction independent of Kras mutation status. Conclusions: MRI-based quantitativeintra-metastasis heterogeneity measures are associated with patient survival and may add information beyond genetic mutation status to optimize prognosis prediction in metastatic colon cancer.
Image guided thermal ablation of prostate cancer metastases to the liver.
Authors: Bruno C. Odisio, Jared Allen Christensen, Sumit Kumar Subudhi, Steven Huang, Sanjay Gupta, Kamran Ahrar, Rahul Sheth, Joe Ensor, Ana Aparicio
Journal: Journal of Clinical Oncology (2016)

e16515 Background: Patients with metastatic castrate resistant prostate cancer (mCRPC) and visceral metastases have a poor prognosis. Thermal ablation of hepatic metastases has become an effective and safe local therapy in other cancers. We hypothesized that ablation of hepatic metastases improves the overall and progression free survival in men with mCRPC. Methods: We performed a retrospective, single institution, IRB-approved evaluation of patients with mCRPC who had biopsy proven metastases amenable to ablation between 2008 and 2015. Patients who had thermal ablation of their hepatic metastases comprised the treatment cohort; patients with lesions technically amenable to ablation (defined as three lesions less than 4 cm) but who did not undergo ablation comprised a control cohort. Time of entry into the study was defined as the date of initial thermal ablation or the date of cross-sectional imaging when the patient was eligible for ablation in the control cohort. Demographic and outcomes data, including original diagnosis, previous treatments, histology, number and sites of metastases, progression on imaging follow-up, time to tumor progression in the liver, overall progression-free survival (PFS) and overall survival (OS) were collected. Results: Twenty-six patients who met inclusion criteria were included, 13 in each cohort. Median follow-up was 12.8 months. There were no significant differences between the cohorts in age, stage, Gleason score, PSA at diagnosis, or previous chemotherapy. Seven of 13 (53.8%) patients in the treatment cohort and 10 of 13 (76.9%) patients in the control cohort are deceased. Median OS was 17.9 months in the treatment cohort and 14.3 months in the control cohort (p = 0.1399). Median PFS was 9.5 months in the treatment cohort and 3.3 months in the control cohort (p = .0068). Conclusions: Thermal ablation of hepatic metastases from mCRPC was associated with a longer median progression free survival and a trend towards a longer median OS. Ongoing studies are exploring molecular determinants of clinical benefit. These data support the conduct of a randomized clinical trial to determine the value of thermal ablation of hepatic metastases in men with mCRPC.
Targeting embryonic transcription factors to affect cancer stem cells and systemic therapy.
Authors: John Milburn Jessup, Robert J. Kinders, Scott M Lawrence, Abid R Mattoo
Journal: Journal of Clinical Oncology (2016)

11573 Background: NANOG is an embryonic transcription factor essential for reprogramming cells. The retrogene NANOGP8 is expressed in human cancers, not in normal tissues. NANOGP8 modulates stemness of human colorectal carcinoma (CRC) cells and can replace NANOG as a cancer stem cell (CSC) driver. Our hypothesis is that NANOGP8 is a therapeutic target to inhibit CSC and enhance systemic therapy. Methods: Ability of single CRC cells to form spheres in serum free medium or to survive exposure to chemotherapy (topotecan – TOPO) or targeted therapy (Afatanib) in a 72 hr in vitro survival assay measured CSC. NANOG was measured in a tissue microarray of 298 primary CRC by quantitative immunofluorescence assay (qIFA). NANOGP8 expression was inhibited by lentivirus or oncolytic chimeric adenovirus Ad5/3 expressing shRNA to NANOGP8 (LVshNP8-1 or AdNP8, respectively). Sub cutis CRC xenografts grown in NOD/SCID mice were injected once intralesionally with LVshNP8-1 or AdNP8. Results: 3-62% of cells within 6 human CRC lines are CSC by spherogenicity. LVshNP8-1not only inhibits spherogenicity but also reduces expression of OCT4 and SOX2, the size of the side population and tumor growth in vivo. Overexpression of NANOGP8 rescues CSC when LV shRNA inhibits expression of NANOGs. qIFA identifies both NANOG proteins since antibody cannot separate the 2 proteins that only differ by 2 of 305 amino acids. NANOG was detected in 65% of primary CRC. NANOG expression is associated with a HR of 2.04 (95% CI 1.18-3.75, P = 0.009) in a Cox PH model where TNM stage and vascular invasion are significant (P < 0.0001) but age, grade, race, gender are not. Exposure to TOPO, but not afatinib, at IC50 increases NANOG gene expression. LVshNP8-1 and AdNP8 increase caspase-dependent cytotoxicity of TOPO and afatanib at their IC50 to > 90%. Single intralesional injection of LVshNP8-1 into 0.7 – 1.0 cm CRC xenografts induces transient inhibition of growth but a single injection of Ad5/3 with shRNA to NANOGP8 causes a sustained 40-50% inhibition of growth in 0.8 – 1.0 CRC xenografts for 30+ days Conclusions: NANOG and NANOGP8 are prognostic factors that drive CSC in CRC. Inhibition of NANOG/NANOGP8 gene expression by gene therapy may augment therapy of cancer and inhibit CSC function.
Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease
Authors: Lauren M. Byrne, Filipe B. Rodrigues, Eileanor B. Johnson, Peter A. Wijeratne, Enrico De Vita, Daniel C. Alexander, Giuseppe Palermo, Christian Czech, Scott Schobel, Rachael I. Scahill, Amanda Heslegrave, Henrik Zetterberg, Edward J. Wild
Journal: Science Translational Medicine (2018)

Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.