tbuckley/cabot-search huggingface dataset:
Symptom progression and relation to physical and cognitive activities based on ecologic momentary assessment of patients following concussion
Authors: Douglas J Wiebe, Matthew F Grady, Michael Nance, Eileen Houseknecht, Christina L Master
Journal: British Journal of Sports Medicine (2017)

Objective To use ecologic momentary assessment to measure and compare daily reports of physical/cognitive activity and symptoms among youth for 2 weeks after sustaining a concussion. Design Prospective cohort study, with patients reporting to random prompts on a handheld 3 times daily and wearing an accelerometer. Setting Specialty concussion program within a large regional paediatric healthcare network. Participants 34 patients, ages 11–17 years with the diagnosis of concussion seen in the concussion program. Independent variables Measurements of daily physical activity (step count) and cognitive activity (composite score of texts sent, screen time minutes, reading minutes, school attendance). Outcome measures Daily symptoms on the Post Concussion Symptom Scale (PCSS). Main results Study subjects were enrolled a median of 6 days post-injury (range 5–13 days). Numerous profiles were observed, including being initially highly (PSCC≥20) or less symptomatic (PSCC ≤ 10), initially highly (steps&gt;6000) or less physically active (steps&lt;3000), and initially highly or less cognitively active. Levels of activity also varied greatly over follow-up. Symptoms declined in most subjects regardless of activity levels during follow-up. Regardless of activity levels, most patients were not symptomatic (PCSS ≤ 8) at the end of the follow-up period. Conclusions We found evidence that initial levels of physical and cognitive rest vary greatly in the days immediately following a first visit, and over subsequent weeks, but most patients were asymptomatic after 4 weeks from injury. This protocol can be used in larger studies designed to fully test whether and how physical and cognitive rest and their timing following injury affect recovery. Competing interests None.
Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).
Authors: Priyanka Sharma, William E. Barlow, Andrew K. Godwin, Laura A Knight, Steven M. Walker, Richard D. Kennedy, Sunil S. Badve, Yesim Gokmen-Polar, Harsh B Pathak, Kamilla Isakova, Hannah M. Linden, Debu Tripathy, Gabriel N. Hortobagyi, Daniel F. Hayes
Journal: Journal of Clinical Oncology (2017)

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% &amp; 82% in the lowest &amp; highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.
Abstract 79: Nrf2 Protects From Intermittent Hypoxia-induced Cardiomyopathy via Metallothionein-dependent and Independent Mechanisms
Authors: Shanshan Zhou, Xia Yin, Jingpeng Jin, Ying Xin, Yi Tan, Zhiguo Zhang, Weixia Sun, Taixing Cui, Jun Cai, Yang Zheng, Lu Cai
Journal: Circulation Research (2015)

Background: We recently reported that cardiac expression of the antioxidant metallothionein (MT) was increased by acute expsorue to intermittent hypoxia (IH), and protected from chronic IH-induced cardiomyopathy. However, how IH stimulates MT in the heart remains unclear. Here we tried to define whether nuclear factor erythroid 2-related factor 2 (Nrf2), a critical redox-balance controller in the body, protects from IH-induced cardiomyopathy and its relationship with MT, and whether Nrf2 and MT are indispensable for sulforaphane (SFN) prevention of IH-induced cardiomyopathy. Methods and Results: Mice were exposed to IH for 3 days to 8 weeks. Like MT, cardiac Nrf2 expression was significantly increased in response to 3-day IH, but decreased in response to 4- or 8-week IH. Mice with cardiac overexpression or global deletion of the Nrf2 gene (Nrf2-TG or Nrf2-KO) were completely resistant or susceptible to IH-induced cardiomyopathy. Cardiac protection from IH by endogenous Nrf2 and MT are indispensable each other. Mechanistically 4-week exposure to IH significantly decreased cardiac Nrf2 binding to the promoter of MT, lowing its transcription and translation. MT stimulated Nrf2 function via activation of PI3K/Akt/GSK-3β/Fyn signaling pathway in a feedback manner. Furthermore, Nrf2 inducer SFN prevented IH-induced cardiomyopathy in both WT and MT-KO mice, but not Nrf2-KO mice. Conclusions: These results suggest that a reciprocal regulation between Nrf2 and MT is necessary for an efficiently antioxidant response to and protection from IH. However, the protective effect of SFN on IH-induced cardiomyopathy is Nrf2-dependent, instead of MT.
Type 1 monoclonal cryoglobulinemia: Clinical presentation and outcomes.
Authors: Surbhi Sidana, S. Vincent Rajkumar, Angela Dispenzieri, Martha Lacy, Morie A. Gertz, Francis Buadi, Suzanne R. Hayman, David Dingli, Prashant Kapoor, Wilson I. Gonsalves, Yi Lisa Hwa, Nelson Leung, Amie Fonder, Miriam Hobbs, Steven R. Zeldenrust, Stephen J. Russell, John Anthony Lust, Robert A. Kyle, Shaji Kumar
Journal: Journal of Clinical Oncology (2016)

8062 Background: Type 1 monoclonal cryoglobulinemia (MoC) is a rare disorder with limited data regarding natural history & response to treatment. Methods: Patients (pts) were identified from an institutional registry & EHR was queried to abstract data on presentation & outcomes. Results: 102 pts with Type 1 MoC were identified from 1990-2015. Median age at diagnosis was 58.9 years (30.9-91.1); 53.9% (n- 55) were male. Median follow up was 3.4 years; 74.5% (n-76) were alive at last follow up. 92.2% (n-94) had an underlying plasma cell or lymphoproliferative disorder: myeloma- 20 (n-14 smoldering), MGUS- 39, lymphoplasmacytic lymphoma- 21, lymphoma- 4, CLL/SLL- 5, amyloidosis/other - 5. 87% (n-89) pts were symptomatic. Of these, 72% (n-64) had skin manifestations- purpura n-43, ulcers/gangrene n-35, livedo reticularis n-18; 37% (n-33) had neurological symptoms- peripheral neuropathy n-30, CNS n-3; 28% (n-25) had vasomotor symptoms – Raynaud’s n-22, acrocyanosis n-5; 27% (n-24) had musculoskeletal symptoms & 16% (14) had renal involvement (biopsy (13) glomerulonephritis -12 & thrombotic microangiopathy -1). Atypical symptoms included epistaxis & rhino-sinusitis (n-11), MGUS related xanthomas, worse in cold (n-1), urticarial vasculitis (n-2) & angioedema (n-1). 73 pts received treatment (Table 1) with median duration of 182 days (1-2203); while 16 received no treatment & 13 were lost to follow up. With treatment, 47 pts improved, 16 had stable symptoms, 3 progressed, 5 were asymptomatic at treatment start & outcome was not known in 2. Treatment was stopped due to symptom improvement in 30, stable disease in 11, progression in 16, toxicity/poor performance status in 8, unknown reasons in 4, while 4 were still continuing therapy. Median cryocrit at diagnosis was 7.5 (n-81) and median nadir cryocrit was 0 (n-33). Conclusions: Treatment directed towards the underlying clonal disorder results in resolution or stabilization of symptoms in the vast majority of Type 1 MoC pts & disappearance of cryoglobulin in over half the cases. Treatment. n Steroids 10 Steroids + alkylator 19 Rituximab +/- steroids 11 Rituximab + alkylator +/- steroids 12 Novel myeloma agents 16 Other 3 Plasmapheresis only 2 Overall upfront plasmapheresis 22 Autologous transplant 6
Surveillance imaging with FDG-PET in the follow-up of melanoma patients at high risk of relapse.
Authors: Jeremy Howard Lewin, Alexandra Sanelli, Imogen Walpole, Damien Kee, Michael A. Henderson, David Speakman, John Spillane, David E. Gyorki, Vanessa Estall, Luc Te Marvelde, Kathy Pope, Margaret Chua, Grant A. McArthur, Rodney J Hicks, Mark J. Shackleton
Journal: Journal of Clinical Oncology (2015)

9003 Background: In the modern era of melanoma treatment, approaches to imaging surveillance following surgery require reconsideration. The aim of this study was to evaluate disease sub-stage specific schedules of positron emission tomography (PET) surveillance for resected stage III melanoma. Methods: Between 2009-2013, patients at the Peter MacCallum Cancer Centre with fully resected AJCC stage III melanoma underwent serial whole body PET/CT scans according to schedules based on Bayesian disease sub-stage relapse probabilities. Schedules were stage IIIA: 6, 18 months; IIIB: 6, 12, 18, 24, 36, 48, 60 months; IIIC: 6, 12, 18, 24, 36 months. Descriptive statistics and contingency table analyses were used to evaluate outcomes for each schedule. Results: Eighty-six patients underwent PET surveillance according to schedule (IIIA: 11; IIIB: 50; IIIC: 25). In total, 232 PET scans were performed over a median follow-up of 28 months after surgery. Relapses were identified in 25 (29%) patients (IIIA: 4%; IIIB: 56%; IIIC: 40%), of which 20 (80%) were asymptomatic at the time of scanning. Incidental secondary malignancies were found in 6 (6.5%) patients. Stage IIIA/B relapses were more likely than stage IIIC to be loco-regional (IIIA/B: 42%; IIIC: 10%; p = NS). Nine (36%) relapsed patients underwent potentially curative resection (IIIA: 1; IIIB: 6; IIIC: 2), with 5 (IIIA: 1; IIIB: 4) free of disease after a median 32 months follow-up. The positive and negative predictive values (PPV, NPV) of an individual PET scan for detecting disease relapse at the same time point were: stage IIIB – PPV 69% (CI: 43-87%) and NPV 99% (CI: 95-100%), stage IIIC – PPV 73% (CI: 39-94%) and NPV 97% (CI: 90-100%). The PPV and NPV of each surveillance protocol for detecting any disease relapse were: stage IIIB – PPV 68% (CI: 43-87%) and NPV 97% (CI: 83-99%), stage IIIC – PPV 73% (CI: 39-94%) and NPV 86% (CI: 57-98%). The sensitivity and specificity of the overall approach of sub-stage specific PET/CT surveillance for detecting disease relapse were 88% (CI: 69-97%) and 84% (CI: 72-92%), respectively. Conclusions: FDG-PET is effective in detecting asymptomatic metastases and thus facilitating early treatment in patients who relapse after resection of stage III melanoma.
An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer
Authors: Justin A. Kenkel, William W. Tseng, Matthew G. Davidson, Lorna L. Tolentino, Okmi Choi, Nupur Bhattacharya, E. Scott Seeley, Daniel A. Winer, Nathan E. Reticker-Flynn, Edgar G. Engleman
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Tregs, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DCs use this particular pathway to inhibit CD8 T-cell–mediated tumor immunity. Phenotypically similar DCs accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Tregs and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection. Cancer Res; 77(15); 4158–70. ©2017 AACR.
Engineering challenges for brain tumor immunotherapy
Authors: Johnathan G. Lyon, Nassir Mokarram, Tarun Saxena, Sheridan L. Carroll, Ravi V. Bellamkonda
Journal: Advanced Drug Delivery Reviews (2017)

Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60 years. This is partly because the brain is a critical organ, and poses unique anatomical, physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.
Acute Pancreatitis After Pancreaticoduodenectomy
Authors: Ashley T. Tsang, Scott Belsley
Journal: JAMA Surgery (2017)

A man in his 70s with history of pancreatic adenocarcinoma who had undergone a Whipple procedure 2 years prior to presentation came to the emergency department with a 1-day history of waxing and waning sharp abdominal pain radiating to his back. What is your diagnosis?
Analysis of telomere damage by fluorescence in situ hybridisation on micronuclei in lymphocytes of breast carcinoma patients after radiotherapy
Authors: Birendranath Banerjee, Manoor Prakash Hande
Journal: Clinical Cancer Research (2007)

B23   Radiotherapy has become an indispensable tool in the effective management of most of the cancers. There have been efforts earlier to study the differential radio-sensitivity patterns in patients undergoing radiation treatment to correlate with treatment induced complications such as tissue injury, cell death, and chromosomal aberration frequencies etc. The present study is an attempt to correlate the radiation induced damage in the peripheral blood lymphocytes (PBLs) of breast cancer patients with the frequency of telomere mediated chromosomal damage. Blood samples from 55 patients with (Gr-II and Gr-III) CA-breast were obtained pre- and post-radiotherapy. The patients were treated with external beam radiotherapy of 50.4 Gy over a period of 6weeks. Chromosome damage was measured by analysing micronucleus (MN) frequency in PBLs. The MN-frequency of the irradiated patients increased significantly compared to the patients being self controls. The micronuclei were hybridized with telomere probes to study the extent of telomere damage. The fluorescence signals of the telomere regions in the first generation of the binucleated cells were significantly higher in the post-radiotherapy patients. There was also significant correlation observed in the patients with higher grade tumours. Inter-individual variability was observed in the radiation-induced MN frequency in lymphocytes of patients after six weeks of radiotherapy. There was a significant correlation between functionally intact telomeres and the cellular response to ionising radiation. Our findings suggest that fluorescence in situ hybridisation on micronuclei could be effectively used as routine clinical application to determine the individual sensitivity to ionising radiation with respect to telomere damage  Acknowledgement:  MPH acknowledges the support from National Medical Research Council, Singapore.
Inhibitor of Pancreatic Cancer by RHIL1RA—Letter
Authors: Sinan Lu, Shusen Zheng, Weilin Wang
Journal: Clinical Cancer Research (2017)

We have read the article with interest by Zhuang and colleagues ([1][1]) on the combination of IL1R antagonist and gemcitabine in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC). The article showed that gemcitabine-induced NF-κB and ERK activation in gemcitabine-resistant PDAC cells
Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis
Authors: Yi L. Hwa, Rahma Warsame, Morie A. Gertz, Francis K Buadi, Martha Q. Lacy, Shaji Kumar, David Dingli, Steven R. Zeldenrust, Nelson Leung, Suzanne R. Hayman, Prashant Kapoor, Wilson I. Gonsalves, Taxiarchis Kourelis, Stephen J. Russell, Ronald S. Go, Miriam Hobbs, Amie Fonder, S. Vincent Rajkumar, Angela Dispenzieri
Journal: Blood (2016)
Loop ileostomy-mediated fecal stream diversion is associated with microbial dysbiosis
Authors: Emma L. Beamish, Judith Johnson, Elisabeth J. Shaw, Nigel A. Scott, Arnab Bhowmick, Rachael J. Rigby
Journal: Gut Microbes (2017)

Loop ileostomy is an effective procedure to protect downstream intestinal anastomoses. Ileostomy reversal surgery is often performed within 12 months of formation but is associated with substantial morbidity due to severe post-surgical complications. Distal ileum is deprived of enteral nutrition and rendered inactive, often becoming atrophied and fibrotic. This study aimed to investigate the microbial and morphological changes that occur in the defunctioned ileum following loop ileostomy-mediated fecal stream diversion. Functional and defunctioned ileal resection tissue was obtained at the time of loop-ileostomy closure. Intrapatient comparisons, including histological assessment of morphology and epithelial cell proliferation, were performed on paired samples using the functional limb as control. Mucosal-associated microflora was quantified via determination of 16S rRNA gene copy number using qPCR analysis. DGGE with Sanger sequencing and qPCR methods profiled microflora to genus and phylum level, respectively. Reduced villous height and proliferation confirmed atrophy of the defunctioned ileum. DGGE analysis revealed that the microflora within defunctioned ileum is less diverse and convergence between defunctioned microbiota profiles was observed. Candidate Genera, notably Clostridia and Streptococcus, reduced in relative terms in defunctioned ileum. We conclude that Ileostomy-associated nutrient deprivation results in dysbiosis and impaired intestinal renewal in the defunctioned ileum. Altered host-microbial interactions at the mucosal surface likely contribute to the deterioration in homeostasis and thus may underpin numerous postoperative complications. Strategies to sustain the microflora before reanastomosis should be investigated.
Mouse PDX Trial Suggests Synergy of Concurrent Inhibition of RAF and EGFR in Colorectal Cancer with <i>BRAF</i> or <i>KRAS</i> Mutations
Authors: Yung-mae M. Yao, Gregory P. Donoho, Philip W. Iversen, Youyan Zhang, Robert D. Van Horn, Amelie Forest, Ruslan D. Novosiadly, Yue Wang Webster, Philip Ebert, Steven Bray, Jason C. Ting, Amit Aggarwal, James R. Henry, Ramon V. Tiu, Gregory D. Plowman, Sheng-Bin Peng
Journal: Clinical Cancer Research (2017)

Abstract Purpose: To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models. Experimental Design: Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (n = 1) trial. Results: Consistent with clinical results, cetuximab was efficacious in wild-type KRAS and BRAF PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a P value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition. Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a KRAS or BRAF mutation. Clin Cancer Res; 23(18); 5547–60. ©2017 AACR.