tbuckley/cabot-search huggingface dataset:
Palliative radiotherapy may improve outcomes in metastatic esophageal and gastric (OG) cancer treated with palliative chemotherapy: A single center retrospective experience.
Authors: Mohan Hingorani, Anthony Maraveyas, Sanjay Dixit, Victoria Plested, Rajarshi Roy
Journal: Journal of Clinical Oncology (2014)

e15066 Background: The role of palliative radiotherapy (pRT) in patients with metastatic OG cancer remains poorly defined. We report on the outcomes of patients treated with pRT to primary tumor in the context of stable or responding metastatic disease after initial chemotherapy. Methods: The clinical records of 139 patients with metastatic OG cancer treated with palliative chemotherapy (pCT) between January 2009 and June 2013 were retrospectively reviewed and 104 patients were identified who had responding or stable disease after first 3 months of chemotherapy initiation. Fifty-two patients in the above group received pRT to primary tumor in the presence of well-controlled metastatic disease after initial pCT (pCT-RT) and the remaining 52 patients were treated with pCT alone (pCT). Treatment-related outcomes were assessed in both groups including time to local progression (TTLP) and overall survival (OS). The Kaplan–Meier method was used to analyze OS and corresponding 95% confidence intervals (CI) were calculated using the Cox proportional hazards model. Results: Both groups were well matched in terms of patient demographics, tumor characteristics, and type and intensity of 1st and subsequent 2ndlines of chemotherapy. Following pCT-RT 23% (12/52) patients developed local progression compared to 31% (16/52) in the pCT group. The use of pRT was associated with non-significant increase in median TTLP (17.2 vs 8.32 months) (P=0.054). After combined median FU of 15.8 months 13/52 (25%) patients are still alive after pCT-RT compared to 7/52 (13.5%) after pCT. Patients treated with pCT-RT had significant increase in median OS of 23.3 months (95%CI: 17.7-28.8) compared to 13.8 months (95% CI: 11.5-16.1) after pCT alone (P<0.001). Conclusions: The above study demonstrates one of the highest reported survival rates in metastatic OG cancer. The possibility of pRT influencing systemic disease in advanced OG cancer has not been previously reported. The above results strongly support further investigation of this exciting possibility in randomized trial.
Total en bloc spondylectomy enhancing antitumor immunity for spine tumors.
Authors: Hideki Murakami, Satoru Demura, Satoshi Kato, Katsuhito Yoshioka, Hiroyuki Hayashi, Noriaki Yokogawa, Takayoshi Ishii, Takashi Igarashi, Xiang Fang, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2014)

e13036 Background: Total en bloc spondylectomy (TES) is a surgery designed to achieve complete resection of a malignant spinal tumor such as spinal metastasis. Although this procedure decreases the rate of local recurrence, it is questionable whether local control prolongs patient’s survival. In cryosurgery, antitumor immunity is activated after percutaneous cryoablation of tumors. We applied this tumor-induced cryoimmunity to TES surgery, and developed a “second-generation TES” that brings about TES enhancing antitumor immunity to prolong patient’s survival. Our purposes here are to present novel technique of second-generation TES applied tumor-induced cryoimmunity and assess the immunity-enhancing effect after implementing this surgery. Methods: This is a retrospective review of prospectively collected data. We have performed 65 cases of second-generation TES since May 2010. In second-generation TES, instead of harvesting autograft from the ilium or fibula, the resected lamina and vertebral body from TES are frozen using liquid nitrogen (-196°C) for 20 minutes and used as grafted bone inside a cage for spinal anterior reconstruction. In 60 of 65 cases, interferon gamma (IFN-γ) and interleukin 12 (IL-12) before surgery and at both 1 and 3 months after surgery were measured to assess the immunity-enhancing effect. Results: IFN-γ increased after surgery in 45 of 60 cases (75.0%). The mean IFN-γ relative concentrations at both 1 and 3 months after surgery, as compared to before surgery, were significantly higher (284±596 and 275±354%: P<0.05). IL-12 increased in 44 of 60 cases (73.3%). The mean IL-12 relative concentrations at both 1 and 3 months after surgery, as compared to before surgery, were higher (277±385 and 486±1032%: P>0.05 and P<0.01) significantly at 3 months. Surprisingly, lymph node metastasis diminished in 2 cases with breast cancer, and tumor marker decreased in other 3 cases with thyroid cancer without any other treatments. Conclusions: The second-generation TES affords three benefits: (1) no pain at the bone harvest site; (2) shortening of operation time; and (3) decrease of blood loss. Moreover, our results showed that second-generation TES could provide systemic immunological enhancement.
Social and geographic factors affecting the occurrence of cancer of unknown primary (CUP).
Authors: S. Michael Crawford, Andrew P Jones, Jane Skinner
Journal: Journal of Clinical Oncology (2014)

e17505 Background: Individuals with cancer living far from services and in poorer neighbourhoods may present with more advanced disease, although this has not been well described in large population samples. This study examines the predictors of a diagnosis of CUP. Methods: Records from the Northern and Yorkshire Cancer Registry from 1994-2002 with ICD10 C77-C80 (CUP) and C20 (malignant neoplasm of rectum) were combined with travel time to services and the Index of Multiple Deprivation. C20 patients show little variation in access to services and are unlikely to be classified as CUP. Logistic regression modelled predictors of CUP compared to C20 and, within CUP, the odds of histological diagnosis (HD). Results: 7,654 patients were classified as C80, 9,114 as C77-79, and 10,851 as C20. Compared to C20, fewer males were classified as C80: odds ratio (OR) of 0.56 (95%CI 0.52-0.61) reflecting the sex ratio in C20. Risk increased strongly with age: ORs (1.03, 1.22, 1.84, 2.46) for ages (50-59, 60-69, 70-79, 80+) with reference group of <50, p(trend)<0.001. Risk increased with deprivation, with ORs of (1.53, 1.74, 2.07) for quartiles 2-4 respectively, compared to the least deprived quartile 1, p(trend)<0.001. Travel time to primary care physician (GP) showed a shallower trend: ORs (1.00, 1.09, 1.14) for quartiles 2-4 respectively, compared to the closest quartile 1, p(trend)=0.007. Results for C77-C79 were similar to those for C80, except that time to GP showed no effect: ORs (1.06, 0.99, 1.09), p(trend)=0.241. Considering all CUP alone, there was no effect of sex on the likelihood of HD: OR 0.97 (95% CI 0.91-1.05), but a marked effect of age: ORs (0.52, 0.32, 0.15, 0.06), same age groups, p(trend)<0.001. HD declined with deprivation: ORs (0.75, 0.66, 0.62) for quartiles 2-4, p(trend)<0.001 and with travel time to the nearest hospital: ORs (0.96, 0.88, 0.87) for quartiles 2-4, p(trend)=0.001. Replacing hospital travel time with that to nearest cancer centre, the ORs were (0.91, 0.88, 0.90), p(trend)=0.033. Conclusions: Compared to rectal cancer, risk of CUP diagnosis increases with female sex, age, deprivation and, for C80, travel time to GP. For CUP patients, the chance of HD decreases with age, deprivation and travel time to hospital.
Prognostic significance of PD-L1 expression, angiogenesis, and hypoxia in melanoma brain metastases (MBM): A histopathologic analysis.
Authors: Stergios J. Moschos, Dimitri G. Trembath, Anna C. Snavely, Evan Bradler, Nana Nikolaishvilli-Feinberg, Bentley R. Midkiff, Jonette Werley, Michal Tadeusz Krauze, Ronald L. Hamilton, John M. Kirkwood
Journal: Journal of Clinical Oncology (2014)

9038 Background: We have previously shown that presence of intratumoral hemorrhage and absence of immune infiltrates in craniotomy specimens of MBM are associated with shorter overall survival (OS), defined as time from craniotomy to death (Hamilton Cancer 2013). We hypothesize that immune checkpoint protein(s), angiogenic factors, cytokines, hypoxia, and the density of mature vs. immature blood vessels (MBV, IBV) are important prognostic factors. Methods: Clinicopathologically annotated craniotomy tumor specimens were stained for angiogenic/hypoxic factors (bFGF, VEGF, HIF1α), blood vessel density (CD31), PD-L1, and for vessels (>50 μm2) that are IBV (CD31+SMA—) or MBV (CD31+SMA+). The Aperio imaging system and Definiens Tissue Studio were used to analyze expression of each marker in different compartments within the tumor (tumor, reactive glia, normal brain, mononuclear cell clusters). Results: An average of 44 cases were analyzed for each of the 7 stains. When each variable was treated as continuous using Cox proportional hazards models, no variable was associated with OS. When survival information was used to define the optimal cut-point for each variable between those with long versus short OS, high tumor expression of PD-L1 and bFGF, and low tumor expression of HIF1α were associated with worse OS (unadjusted p<0.05; hazard ratios 1.92, 2.2, 2.1 respectively). PD-L1 expression was significantly higher in tumor compared to normal brain, but insignificantly different between tumor and reactive glia or immune infiltrates. There was a significant inverse association between tumor PD-L1 expression and immune infiltrate. Conclusions: This unique dataset suggests that neither the density nor the quality of blood vessels within MBM is a significant prognostic factor nor correlates with tumor hemorrhage. Tumor response to hypoxia by upregulation of HIF1α may paradoxically be a favorable prognostic factor. More important, high expression of PD-L1 in MBM is an adverse prognostic factor, and could be derived from its immunosuppressive effects in the brain microenviroment. Targeting PD1/PD-L1 pathway in patients with MBM is reasonable on the basis of these findings.
A Phase I/Pilot Study of CPX-351 [Daunorubicin and Cytarabine Liposome for Injection (Vyxeos®)] for Children, Adolescents and Young Adults with Recurrent or Refractory Acute Leukemia
Authors: Michael J. Absalon, Erin H. Breese, Lynn Lee, Maureen M O'Brien, Christine L Phillips, Karen Burns, Benjamin Mizukawa, Qi An, Jennifer Mangino, Joel Kaplan, Robin Norris, John Peter Perentesis
Journal: Blood (2018)
A multimodal (FACILE) classification for optical diagnosis of inflammatory bowel disease associated neoplasia
Authors: Marietta Iacucci, Kenneth McQuaid, X. Gui, Yasushi Iwao, Brendan Lethebe, Mark Lowerison, Takayuki Matsumoto, Uday Shivaji, Samuel Smith, Venkataraman Subramanian, Toshio Uraoka, Silvia Sanduleanu, Subrata Ghosh, Ralf Kiesslich
Journal: Endoscopy (2018)

Abstract Background Characterization of colonic lesions in inflammatory bowel disease (IBD) remains challenging. We developed an endoscopic classification of visual characteristics to identify colitis-associated neoplasia using multimodal advanced endoscopic imaging (Frankfurt Advanced Chromoendoscopic IBD LEsions [FACILE] classification). Methods The study was conducted in three phases: 1) development – an expert panel defined endoscopic signs and predictors of dysplasia in IBD and, using multivariable logistic regression created the FACILE classification; 2) validation – using 60 IBD lesions from an image library, two assessments of diagnostic accuracy for neoplasia were performed and interobserver agreement between experts using FACILE was determined; 3) reproducibility – the reproducibility of the FACILE classification was tested in gastroenterologists, trainees, and junior doctors after completion of a training module. Results The experts initially selected criteria such as morphology, color, surface, vessel architecture, signs of inflammation, and lesion border. Multivariable logistic regression confirmed that nonpolypoid lesion, irregular vessel architecture, irregular surface pattern, and signs of inflammation within the lesion were predictors of dysplasia. Area under the curve of this logistic model using a bootstrapped estimate was 0.76 (0.73 – 0.78). The training module resulted in improved accuracy and kappa agreement in all nonexperts, though in trainees and junior doctors the kappa agreement was still moderate and poor, respectively. Conclusion We developed, validated, and demonstrated reproducibility of a new endoscopic classification (FACILE) for the diagnosis of dysplasia in IBD using all imaging modalities. Flat shape, irregular surface and vascular patterns, and signs of inflammation predicted dysplasia. The diagnostic performance of all nonexpert participants improved after a training module.
CKAP4, a DKK1 Receptor, Is a Biomarker in Exosomes Derived from Pancreatic Cancer and a Molecular Target for Therapy
Authors: Hirokazu Kimura, Hideki Yamamoto, Takeshi Harada, Katsumi Fumoto, Yoshihito Osugi, Ryota Sada, Natsumi Maehara, Hayato Hikita, Soichiro Mori, Hidetoshi Eguchi, Masahito Ikawa, Tetsuo Takehara, Akira Kikuchi
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The survival rate of pancreatic ductal adenocarcinoma (PDAC) is poor; thus, novel molecularly targeted therapy and companion diagnostics are required. We asked whether cytoskeleton-associated protein 4 (CKAP4), a novel Dickkopf1 (DKK1) receptor, is a candidate for PDAC diagnosis and therapy. Experimental Design: Whether CKAP4 can be secreted with small extracellular vesicles (SEV) from PDAC cells was examined. It was also investigated whether CKAP4 can be detected in sera from patients with PDAC by ELISA using newly generated anti-CKAP4 mAbs and whether anti-CKAP4 mAbs can show antitumor activity in vivo. Results: CKAP4 was secreted with SEVs from PDAC cells, and the SEVs exhibited the characteristics of exosomes. The secretion of CKAP4-containing exosomes was mediated by DKK1-dependent endocytosis routes and required exosome biogenesis molecules. Two ELISAs capable of detecting tumor-secreted CKAP4 were developed. The serum CKAP4 levels were higher in patients with PDAC than healthy control individuals. CKAP4 was highly detected in the sera of pancreatic tumor-bearing xenografted mice and patients with PDAC, whereas CKAP4 was barely detectable in sera from normal mice and postoperative patients. Anti-CKAP4 mAbs with different epitopes demonstrated the inhibitory activities for the binding of DKK1 and CKAP4, AKT activity, and proliferation and migration of PDAC cells. Anti-CKAP4 mAbs also suppressed xenograft tumor formation in immunodeficient mice and extended the survival of mice receiving intraperitoneal or orthotopic injection of PDAC cells. Conclusions: CKAP4 secreted in exosomes may represent a biomarker for PDAC. Anti-CKAP4 mAbs can contribute to the development of novel diagnostic methods and therapeutics.
Evaluation of TIM-3+ LSCs Is a Highly Sensitive MRD Monitoring Strategy to Predict AML Relapse after Allogenic Stem Cell Transplantation
Authors: Masayasu Hayashi, Teppei Sakoda, Yoshikane Kikushige, Hidetoshi Irifune, Goichi Yoshimoto, Toshihiro Miyamoto, Koichi Akashi
Journal: Blood (2018)
Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons
Authors: Simon T. Schafer, Apua C. M. Paquola, Shani Stern, David Gosselin, Manching Ku, Monique Pena, Thomas J. M. Kuret, Marvin Liyanage, Abed AlFatah Mansour, Baptiste N. Jaeger, Maria C. Marchetto, Christopher K. Glass, Jerome Mertens, Fred H. Gage
Journal: Nature Neuroscience (2019)
Abstract P168: Animal &amp; Dairy Protein Intakes Associate With Increased Risk of Heart Failure in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study
Authors: Heli E Virtanen, Sari Voutilainen, Timo T Koskinen, Jaakko Mursu, Tomi-Pekka Tuomainen, Jyrki K Virtanen
Journal: Circulation (2017)

Introduction: Different protein sources, such as processed red meat and fish have indicated distinct associations with risk of heart failure. Whether these distinct associations are partly due to the differences in proteins themselves remains unclear. Thus, we examined the associations of proteins from different food sources with risk of heart failure in Finnish male subjects. Hypothesis: We hypothesized that proteins from different dietary sources would have distinct associations with heart failure risk. Methods: The study included 2441 men aged 42-60 y at the baseline examinations in 1984-1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Protein intakes at baseline were assessed with 4-d dietary records. Data on incident heart failure cases were obtained from national registers. The multivariable-adjusted risk of heart failure according to protein intake was estimated by Cox proportional hazard ratios. Multivariable analyses included age, examination year, education, income, family history of ischaemic heart disease, smoking, leisure-time physical activity, and intakes of alcohol, energy, fiber, and saturated, monounsaturated, polyunsaturated and trans fatty acids. Results: During the mean follow-up time of 22.2 y, 334 incident cases of heart failure occurred. Total protein (multivariable-adjusted extreme-quartile HR 1.45, 95% CI: 1.04-2.00, P-trend 0.01), animal protein (HR 1.56, 95% CI: 1.12-2.17, P-trend 0.01) and dairy protein (HR 1.53, 95% CI: 1.11-2.11, P-trend 0.01) intakes were associated with increased risk of heart failure. Especially protein from fermented dairy products associated with higher risk (HR 1.48, 95% CI: 1.08-2.02, P-trend 0.002). Adjustment for the potential effect mediators [body mass index and diseases or medications (coronary heart disease, hypertension, type 2 diabetes, lipid-lowering or heart medications) at baseline and during the follow-up] slightly attenuated the associations, but associations of animal, dairy and fermented dairy protein remained statistically significant. Plant protein intake had no association with heart failure risk (HR 1.00, 95% CI: 0.63-1.59, P-trend 0.82). Conclusions: Our data suggest that high intake of protein, especially from animal and dairy sources, may increase the risk of heart failure.
Volume reduction and metabolic response of primary prostate cancer to enzalutamide (ENZ) : A metabolic evaluation by <sup>18</sup>F-fluorocholine-positron emission tomography/computerized tomography (<sup>18</sup>F-FCH PET/CT) in castration resistant prostate cancer (CRPC) patients (pts).
Authors: Orazio Caffo, Francesca Maines, Davide Donner, Antonello Veccia, Franca Chierichetti, Enzo Galligioni
Journal: Journal of Clinical Oncology (2014)

e16056 Background: ENZ, a novel, second-generation androgen receptor antagonists, is active in CRPC pts in whom it produces a survival gain. We report the ENZ effect on primary prostate tumor, assessed by changes of metabolic tumor activity detected by 18F-FCH PET/CT. Methods: We treated a consecutive series of 31 pre-treated metastatic CRPC pts with ENZ in a named patient programme between November 2012 and March 2013. All pts received ENZ 160 mg daily until disease progression. All pts were evaluated by 18F-FCH PET/CT at the baseline, after the first three months of treatment and every four months thereafter. We identified the most radiotracer-avid lesions which were defined as specific regions of interest (ROIs): for each ROI we defined the maximum standardized uptake value (SUVmax) and the threshold-based Volume Of Interest (VOI) with a cutoff SUV value ≥ 2.5. In the case of pts who did not received a radical treatment for localized disease, prostate was also considered as ROI. The changes of SUVmax and VOI were compared to the baseline values by Wilcoxon matched pairs signed rank sum test. Results: Among the 31 ENZ treated pts, 16 had received a radical treatment for prostate cancer, and 3, with bladder catheter, had prostate ROI not evaluable. The remaining 12 pts were evaluated at the first time-point and were considered as evaluable. The baseline prostate median SUVmax was 7.25 and showed a reduction of 25% (p = 0.012) and 43% (p = 0.009) respectively, after three and seven months of treatment. The baseline median prostate VOI of 12.73 cm3 showed a reduction of 73% (p = 0.002) at three months and of 90% (p = 0.005) at seven months. Conclusions: Beside the metabolic changes of metastatic lesions observed with ENZ in CRPC patients, our data have shown a significant metabolic and volume reduction of the primary tumor, at the 18F-FCH PET/CT evaluation, suggesting a potential benefit of ENZ therapy also in localized prostate cancer.
Predictors and outcomes of venous thromboembolism (VTE) in hospitalized lung cancer patients: A nationwide inpatient sample (NIS) database analysis.
Authors: Conor Ernst Steuer, Madhusmita Behera, Sungjin Kim, Nikita Patel, Zhengjia Chen, Rathi Narayana Pillai, Nabil F. Saba, Dong Moon Shin, Taofeek Kunle Owonikoko, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2014)

e17632 Background: Patients with lung cancer are at high risk of developing VTE, including deep venous thrombosis and pulmonary embolism. We sought to characterize the clinical factors associated with the development of VTE and impact of VTE on outcomes for hospitalized lung cancer patients. Methods: Data captured in the NIS database of the Agency of Healthcare Research and Quality (AHRQ) was used for this analysis. All lung cancer patients hospitalized between 2006 and 2010 with a diagnosis of VTE captured as one of the top three discharge diagnoses were included in the study. This VTE population’s demographics and outcomes were compared to the remainder of inpatient lung cancer patients without a diagnosis of VTE. All analyses were performed using SAS version 9.3. Results: We identified 20,672 lung cancer patient hospitalizations with a clinically relevant diagnosis of VTE out of a total 570,304 lung cancer hospitalizations accounting for 4% of all events. The median age of lung cancer patients with VTE was 68 years, 48% were females, 79% were Caucasians, 57% had metastatic disease, 49% were treated at teaching hospitals and 87% were non-elective admissions. In multivariate analysis, patients with a VTE diagnosis had significantly worse outcomes including higher inpatient mortality rate (RR 1.06, p=.021) and greater disability (RR 1.23, p<.001) (Table). Conclusions: VTE in hospitalized lung cancer patient is associated with longer length of stays, higher inpatient mortality rates, increased cost and greater disability upon discharge compared to other inpatient lung cancer patients. Further studies to identify high-risk patients and prevent this complication are warranted. Outcomes VTE (N=20672) No VTE (N=502153) P-value Inpatient mortality 2072 (10.03) 43624 (8.69) <.001 Moderate to severe disability 11343 (55.14) 242222 (48.61) <.001 Comorbidities 3.32 (± 1.68) 2.94 (± 1.69) <.001 Cost ($10,000) 4.38 (± 5.37) 3.78 (± 4.89) <.001 Length of stay (days) 7.15 (± 6.94) 6.05 (± 6.17) <.001 Data are presented as number of patients (%) or mean (± SD).