tbuckley/cabot-search huggingface dataset:
Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer
Authors: Ming Tang, Xiaopeng Lu, Chaohua Zhang, Changzheng Du, Linlin Cao, Tianyun Hou, Zhiming Li, Bo Tu, Ziyang Cao, Yinglu Li, Yongcan Chen, Lu Jiang, Hui Wang, Lina Wang, Baohua Liu, Xingzhi Xu, Jianyuan Luo, Jiadong Wang, Jin Gu, Haiying Wang, Wei-Guo Zhu
Journal: Theranostics (2017)

5-Fluorouracil (5-FU) combined with radiotherapy is a common treatment strategy to treat human cancers, but the underlying mechanisms of this combination treatment remain unclear.Here, we report that NAD + -dependent deacetylase sirtuin-7 (SIRT7) protein levels were decreased due to 5-FU exposure rendering colorectal cancer cells sensitive to radiation.We found that SIRT7 downregulation was mediated via a Tat-binding Protein 1 (TBP1) proteasome-dependent pathway.Specifically, TBP1 was dephosphorylated at tyrosine 381 upon 5-FU treatment, which enhanced its direct interaction with SIRT7 and targeted it for degradation.Depletion of SIRT7 in cultured colorectal cancer cells induced radiosensitivity triggering cell death.Interestingly, decreased levels of SIRT7 mediated by 5-FU correlated well with improved therapeutic effect in patients with rectal cancer and with inhibited tumor growth in immune-compromised mice post-irradiation.Taken together, these data suggest that 5-FU induces radiosensitivity via SIRT7 degradation to favor a cell death pathway in targeted cancer cells.Thus, downregulation of SIRT7 could be a promising pharmacologic strategy to increase the effectiveness of chemoradiation therapy in cancer patients.
Endoscopic resection of large duodenal and papillary lateral spreading lesions is clinically and economically advantageous compared with surgery
Authors: Amir Klein, Golo Ahlenstiel, David Tate, Nicholas Burgess, Arthur Richardson, Tony Pang, Karen Byth, Michael Bourke
Journal: Endoscopy (2017)

Abstract Background and study aims Adenomas of the duodenum and ampulla are uncommon. For lesions ≤ 20 mm in size and confined to the papillary mound, endoscopic resection is well supported by systematic study. However, for large laterally spreading lesions of the duodenum or papilla (LSL-D/P), surgery is often performed despite substantial associated morbidity and mortality. We aimed to compare actual endoscopic outcomes of such lesions and costs with those predicted for surgery using validated prediction tools. Patients and methods Patients who underwent endoscopic resection of LSL-D/P were analyzed. Two surgeons assigned the hypothetical surgical management. The National Surgical Quality Improvement Program (NSQIP), and the Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM) were used to predict morbidity, mortality, and length of hospital stay. Actual endoscopic and hypothetical surgical outcomes and costs were compared. Results A total of 102 lesions were evaluated (mean age of patients 69 years, 52 % male, mean lesion size 40 mm). Complete endoscopic resection was achieved in 93.1 % at the index procedure. Endoscopic adverse events occurred in 18.6 %. Recurrence at first surveillance endoscopy was seen in 17.7 %. For patients with ≥ 2 surveillance endoscopies (n = 55), 90 % were clear of disease and considered cured (median follow-up 27 months). Compared with hypothetical surgical resection, endoscopic resection had less morbidity (18 % vs. 31 %; P = 0.001) and shorter hospital stay (median 1 vs. 4.75 days; P &lt; 0.001), and was less costly than surgery (mean $ 11 093 vs. $ 19 358; P &lt; 0.001). Conclusion In experienced centers, even extensive LSL-D/P can be managed endoscopically with favorable morbidity and mortality profiles, and reduced costs, compared with surgery.
WT1-targeted dendritic cell vaccination as a postremission treatment to prevent or delay relapse in acute myeloid leukemia.
Authors: Zwi N. Berneman, Ann Van de Velde, Sebastien Anguille, Nathalie Cools, Ann Van Driessche, Griet Nijs, Barbara Stein, Inge Vrelust, Alain P. Gadisseur, Wilfried A. Schroyens, Viggo F. Van Tendeloo, Evelien L. Smits
Journal: Journal of Clinical Oncology (2012)

2506 Background: Vaccination with tumor antigen-loaded dendritic cells (DC) holds promise for the adjuvant treatment of cancer. Methods: In a phase I/II trial, we investigated the effect of autologous DC vaccination in 17 patients with acute myeloid leukemia (AML) in remission but at very high risk of full relapse. Wilms’ tumor 1 protein (WT1) was chosen as immunotherapeutic target and introduced into the DC by mRNA electroporation. We are continuing a phase II trial, which is still recruiting. Results: Two out of 3 patients, who were in partial remission with chemotherapy-refractory disease, were brought into complete remission following 4 biweekly intradermal injections of WT1 mRNA-electroporated DC. In those 2 patients as well as in 6 other patients who were in complete remission but who had molecularly demonstrable residual disease, there was a return to normal of the AML-associated WT1 mRNA tumor marker following DC vaccination, compatible with reaching clinical and molecular remission in 8/17 patients. Among the 8 responders, there have been 2 relapses and 2 deaths. Of the 9 non-responders, 8 have relapsed and 7 have died. Of the 2 patients in partial remission who were brought into complete remission by DC vaccination, 1 has died following relapse. Median overall survival was 6 months in non-responders and 52 months in responders (p=0.0007). Median relapse-free survival was 3 months in non-responders as compared to 47 months in responders (p&lt;0.0001). Clinical responses overall were correlated with elevated levels of activated natural killer (NK) cells post-vaccination. Long-term clinical responses, lasting for at least 3 years, were significantly correlated with an increase in polyepitope WT1-specific tetramer+ CD8+ T-cell frequencies. Conclusions: DC-based immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DC emerge as a feasible and effective strategy to control residual disease in AML, in particular as a post-remission treatment to prevent full relapse.
Clinical, pathological, and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma
Authors: J. S. Lam, O. Shvarts, J. W. Said, A. J. Pantuck, D. Seligson, M. E. Aldridge, M. H. Bui, X. Liu, S. Horvath, A. S. Belldegrun
Journal: Journal of Clinical Oncology (2004)

4643 Background: Presence of histologic necrosis in the primary tumor of patients with renal cell carcinoma (RCC) has been demonstrated to be an important predictor of survival. We investigated the relationship of necrosis to other histologic and clinical factors known to be important prognostic indicators for patients with RCC. Methods: The records of 300 patients undergoing treatment for RCC at UCLA were evaluated for basic clinical information including TNM stage, Eastern Cooperative Oncology Group performance status (ECOG-PS), nuclear grade, and survival. Pathologic slides of the primary tumors were reviewed by a single pathologist. Presence and amount of necrosis were correlated with clinical factors, carbonic anhydrase IX (CAIX) expression, and survival. Results: Patents with necrosis presented with higher T stage (p < 0.0001), metastases (p < 0.0001), greater mean tumor size (p < 0.001) and higher grade (p < 0.0001) compared to patients without necrosis. Extent of necrosis in the primary tumor significantly correlated with T stage, nodal status, metastasis, ECOG-PS, grade, tumor size, and UCLA Integrated Staging System (UISS) (p < 0.01). Patients with necrosis demonstrated a significantly lower 5-year disease specific survival compared to patients without necrosis (36% vs. 75%; p < 0.0001). Multivariate analysis demonstrated grade (p = 0.002), T stage (p < 0.0001), and ECOG-PS (p < 0.0001) to be independent predictors of disease specific survival, while necrosis approached significance (p = 0.07). Presence and extent of necrosis were independent predictors of survival in patients with localized (p < 0.05), but not metastatic (p > 0.05) disease. In patients with clear cell histology, necrosis was also an independent predictor of survival for localized (p = 0.04), but not metastatic (p = 0.49) disease. Conclusions: Presence of necrosis in the primary tumor of patients with RCC is associated with large size, high stage, high grade, and poor ECOG-PS, as well as the presence of distant metastases. The presence of this histologic variant is an independent predictor of poor survival in patients with localized, but not metastatic disease. No significant financial relationships to disclose.
The radiosensitivity of brain metastases based upon primary histology utilizing a multigene index of tumor radiosensitivity
Authors: Kamran A. Ahmed, Anders E. Berglund, Eric A. Welsh, Arash O. Naghavi, Youngchul Kim, Michael Yu, Timothy J. Robinson, Steven A. Eschrich, Peter A.S. Johnstone, Javier F. Torres-Roca
Journal: Neuro-Oncology (2017)
Medicine is the ultimate personalised technology
Authors: Rebecca C Fitzgerald, Peter Sasieni
Journal: BMJ (2017)

Modern medicine combines science with the art of communicating and caring for individual patients. Talking with patients to identify the best clinical management has always been central to what clinicians do in all healthcare settings. That medicine is as much a science as an art in the 21st century is thanks to tremendous technological advances. The ability to characterise a tumour at the molecular level …
Predictive factors on the receipt and completion of adjuvant chemotherapy in a mixed sociodemographic cohort of patients.
Authors: Blase N. Polite, David M Smith, Toni Cipriano
Journal: Journal of Clinical Oncology (2012)

6137 Background: African Americans are more likely to die from breast, colon and lung cancer compared to whites. They are also less likely to receive and complete recommended therapy. The reasons for this are unknown. Methods: Breast, colon, and lung cancer patients eligible for adjuvant chemotherapy (stage IB-III breast, stage IIB-III colon, and Stage IB, II lung) and who received surgery at 2 urban medical centers, were approached between 2008 and 2010 and completed a self-administered survey focusing on sociodemographic factors, including social support, anxiety, depression, co-morbidities, trust and God Locus of Control (e.g., Whatever happens to my cancer is God’s will). These variables were related to receipt and completion of chemotherapy. 191 patients were approached, 161 consented and 30 refused (16%); out of the 161, 23 were deemed ineligible because of previous cancers, non-curative stage or receipt of chemotherapy in the neoadjuvant setting. Results: Final sample consisted of 138 pts. Median age: 54; sex:81% F; Race/Ethnicity:47% AA, 38% white, 9% Hispanic, 6% Asian/PI; Cancer Type: 73% Breast, 21% Colon, 6% Lung. Compared to whites, AA were more likely to have incomes&lt;20K (35% vs. 10%, p=.0002), have any comorbidities (80% vs. 57%, p=0.006), and have high levels of God Locus of Control (56% vs 27%, p=0.003). There were no differences by race in chemotherapy receipt (89% vs. 88%) or relative dose intensity (RDI) of chemo&gt;=85% (58% vs. 67%). No factor in our model predicted chemotherapy receipt or RDI at a significant level. Pts with high God Locus of Control were somewhat more likely to start chemotherapy (OR 1.7, p=0.25) but were less likely to complete therapy (OR 0.55, p=0.19). The magnitude of these relationships held after controlling for age, race, comorbidities, cancer type, functional status, and social support. Conclusions: In a mixed sociodemographic cohort of patients, receipt and completion of adjuvant chemotherapy was similar by measured sociodemographic variables. Only high God Locus of Control was suggestive of being less likely to complete chemotherapy. Further attention and research on the role of religious beliefs in the cancer decision making process is warranted.
Toxicity and efficacy of four schedules of intensified neoadjuvant chemoradiotherapy (RCT) with irinotecan and 5-Fu or Capecitabine in patients with locally advanced rectal cancer (LARC)
Authors: G. Klautke, K. Ludwig, E. Klar, M. Freund, R. Fietkau
Journal: Journal of Clinical Oncology (2006)

13550 Background: After neoadjuvant RCT in patients with LARC the rate of complete response (pCR), nearly complete response (nCR)and also the ypN0 category influences survival. So four different schedules of neoadjuvant RCT with irinotecan and 5-Fu or Capecitabine were compared in efficacy (pCR, nCR, ypN0) but also in the main toxicity (diarrea III/IV CTC). Methods: Conventional radiation was given at daily fractions of 1.8Gy to a total dose of 50.4Gy and 5.4Gy boost in all schedules. In our first schedule 5-Fu (250mg/m2, d1–43) and irinotecan (40mg/m 2 , d1,8,15,22,29,36) (group A), in our next schedule capecitabine (1500mg/m 2 , d1–43) and irinotecan (40mg/m 2 , d1,8,15,22,29,36) (group B), and then next capecitabine (1500mg/m 2 , d1–14, 22–35) and irinotecan (50mg/m 2 , d1,8,22,29) (group C) and now capecitabine (1500mg/m 2 , d1–14, 22–35) and irinotecan (60mg/m 2 , d1,8,22,29) (group D) was applicated concurrently. Surgery was performed 4–6 weeks after RCT. Results: Group A-B-C-D: number of patients: 37 - 28 - 20 - up to now 11; clinical state UICC II/III: 6/31 - 2/28 - 5/15 - 1/10; diarrhea (III+IV): 12/37(32%) - 11/28(39%) - 2/20(10%) - 1/11(9%); pCR: 9/37(24%) - 4/26(15%) - 0/20(0%) -3 /9(33%); nCR: 10/37(27%) - 3/26(12%) - 5/20(25%) - 1/9(11%); ypNo: 25/37(68%) - 15/26(58%) - 12/20(60%) - 6/9(67%). Conclusions: Neoadjuvant RCT with 5-Fu or capecitabine in combination with irinotecan is high effective. The splitting of capecitabine with a break in the third week of radiation reduces toxicity but not efficacy. In our trials during RCT a total dose of 240mg/m2 irinotecan in combination with 5-Fu/capecitabine must be applicated to receive a high rate of pCR. No significant financial relationships to disclose.
Toward a Single‐Dose Vaccination Strategy with Self‐Encapsulating PLGA Microspheres
Authors: Brittany A. Bailey, Lukasz J. Ochyl, Steven P. Schwendeman, James J. Moon
Journal: Advanced Healthcare Materials (2017)

Poly(lactic-co-glycolic acid) (PLGA) microspheres have been widely examined for vaccine applications due to their attractive features of biocompatibility, biodegradability, ability to be internalized by antigen-presenting cells, and long-term antigen release. However, one of the major challenges for PLGA particle vaccines is the potential for antigen instability and loss of antigenicity and immunogenicity. To address this challenge, we have developed a new method of "self-healing" encapsulation in PLGA microspheres, where pre-made PLGA microspheres are loaded with protein antigens under aqueous conditions with minimal impact on their antigenicity and immunogenicity. In this report, we show that mice immunized with self-encapsulating PLGA microspheres in a prime-boost regimen generated significantly enhanced antigen-specific CD8α+ T cell and antibody responses, compared with mice immunized with free, soluble protein admixed with calcium phosphate gel, a widely used adjuvant. Furthermore, a single-dose of microspheres designed for >40 day sustained antigen release elicited robust cellular and humoral immune responses as efficiently as the prime-boost vaccinations with calcium phosphate gel. Overall, these results suggest excellent potential of our self-encapsulating PLGA microspheres as a vaccine platform for multiple-dose as well as single-dose vaccinations.
Role of consolidation therapy in adults with high-risk acute myeloid leukemia aged ≤ 60 years: Results of a prospective multicenter trial
Authors: A. Ganser
Journal: Journal of Clinical Oncology (2004)

6615 Background: The impact of the various forms of consolidation therapy has still to be defined in high risk AML. Methods: Patients <61 years with de novo (n=286) or secondary (n=88) AML were treated with risk-adapted therapy. Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all others as high risk (HR). Patients with t(15;17) were excluded. The first chemotherapy cycle consisted of standard dose AraC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21. In patients with bad response, the second cycle was either IVA-II or FlAG/Ida. Early consolidation with intermediate dose AraC was followed by late consolidation: HR patients were allo- [HLA-matched sibling or matched unrelated donor (MUD)] or autotransplanted. Matched sibling allotransplantation was done in all centers whereas MUD transplantation was only done by two centers, while the remaining centers performed PBSCT-autotransplantation. Results: 174 patients were classified as HR, of whom 59% achieved CR (90% in SR patients) and 13% died during induction. After 48 months, overall survival was significantly inferior for HR patients (25%) as compared to SR patients (52%). Regarding the different regimens for late consolidation, the
Smoke and alcohol consumption as a risk factors in the development of second primary neoplasms (SPN) in head &amp; neck cancer (HNC) patients. A case-control study
Authors: T. Macarulla, M. Prado Venegas, X. León, A. López Pousa, M. Quer, C. Orús, R. Guardeño, R. Nadal, B. Ojeda, O. Gallego
Journal: Journal of Clinical Oncology (2004)

5582 Background: HNC patients has an increased risk to develop metachronous epidemiological related SPN. There is a controversy regarding the role who play to maintain toxic factors in the subsequent development of SPN. Methods: We performed a case-control study in oral cavity, oropharynx, hypopharyx and laryngeal carcinoma patients, diagnosed in our Institution from 1985 to 2000. Case-group: 257 patients with metachronous SPN in head and neck, lung or esophagus; control-group: 257 patients SPN free, matched for tumor location, TNM, gender, tobacco and alcohol consumption previous to the primary tumor diagnostic, age, ECOG, type of primary treatment and follow-up period. We analyzed tobacco and alcohol consumption after treatment for primary HNC. Results: 34% in case-group and 14% in control-group patients persisted smoking habits (p=0.001). Odds ratio to develop SPN was 3.2 (95%CI: 1.9–4.7). 14% in case-group and 2% in control-group used alcohol consumption (>80 gr/day) after treatment of primary HNC (p=0.001). Odds ratio to develop metachronous SPN was 10.0 (95%CI: 3.4–28.4). Oropharyngeal tumors was the greatest risk location of SPN. Conclusions: Alcohol and tobacco consumption after treatment for HNC significantly increase the risk for the development of SPN. Primary prevention remains the main objective in the follow-up of this patients. No significant financial relationships to disclose.
Preterm respiratory disease in the modern era: the value of cohort studies
Authors: Gregory S Montgomery, Stephanie D Davis
Journal: Thorax (2017)

Since bronchopulmonary dysplasia (BPD) was first described in 1967, the respiratory phenotype of the preterm infant has evolved.1 Over the past several decades, the management approach to treating these immature lungs, often in the saccular phase of development, has advanced leading to the survival of preterm infants born as early as 23–24 weeks gestational age. In the postsurfactant era, our understanding of the physiologic and structural pathogenesis of the respiratory system of these very low gestational age infants is poorly understood.

In this issue of Thorax , two Australian research teams delineate phenotypic features of the respiratory system in school age children and adolescents born prematurely. Simpson et al 2 present a case-control study evaluating a broad spectrum of lung function and imaging measures in former preterm (≤32 weeks gestation) school age (9–11-year-old) children born between 1997 and 2003. Doyle et al 3 present a prospective cohort study of lung function measures at school age (8 years) and again in late adolescence (18 years) in former premature children (≤28 weeks gestation and/or <1000 g birth weight) born between 1991 and 1992. Both preterm populations consisted of children with and without the diagnosis of BPD.

Prior investigators detail lung function impairment in school age, adolescent and adult individuals born prematurely.4 ,5 Unlike the two reports in this issue of Thorax , few prior studies evaluated participants born in the so-called postsurfactant or ‘new BPD’ era. Other confounding variables in prior studies include inconsistent definitions and application of the BPD diagnosis, as well as lack of uniform lung function reference values that span across all ages.6 Both Australian groups defined BPD based on …
Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease
Authors: Danny W. Bruce, Heather E. Stefanski, Benjamin G. Vincent, Trisha A. Dant, Shannon Reisdorf, Hemamalini Bommiasamy, David A. Serody, Justin E. Wilson, Karen P. McKinnon, Warren D. Shlomchik, Paul M. Armistead, Jenny P.Y. Ting, John T. Woosley, Bruce R. Blazar, Dietmar M.W. Zaiss, Andrew N.J. McKenzie, James M. Coghill, Jonathan S. Serody
Journal: Journal of Clinical Investigation (2017)

Acute graft-versus-host disease (aGVHD) is the most common complication for patients undergoing allogeneic stem cell transplantation. Despite extremely aggressive therapy targeting donor T cells, patients with grade III or greater aGVHD of the lower GI tract, who do not respond to therapy with corticosteroids, have a dismal prognosis. Thus, efforts to improve understanding of the function of local immune and non-immune cells in regulating the inflammatory process in the GI tract during aGVHD are needed. Here, we demonstrate, using murine models of allogeneic BMT, that type 2 innate lymphoid cells (ILC2s) in the lower GI tract are sensitive to conditioning therapy and show very limited ability to repopulate from donor bone marrow. Infusion of donor ILC2s was effective in reducing the lethality of aGVHD and in treating lower GI tract disease. ILC2 infusion was associated with reduced donor proinflammatory Th1 and Th17 cells, accumulation of donor myeloid-derived suppressor cells (MDSCs) mediated by ILC2 production of IL-13, improved GI tract barrier function, and a preserved graft-versus-leukemia (GVL) response. Collectively, these findings suggest that infusion of donor ILC2s to restore gastrointestinal tract homeostasis may improve treatment of severe lower GI tract aGVHD.
Surgeons say they expressed safety concerns to hospital bosses before child’s death
Authors: Clare Dyer
Journal: BMJ (2017)

Surgeons at a leading UK children’s hospital have said that they were worried about the safety of surgery services some time before the death of a child whose urgent operation was repeatedly postponed and that they only decided to speak to the media after management failed to respond to their concerns.

Central Manchester University Hospitals NHS Trust has admitted failings in the case of Kayden Urmston-Bancroft, a 20 month old who died in April 2016 from cardiac failure after waiting several days for a hole in his diaphragm to be repaired at Royal Manchester Children’s Hospital, which is part of the trust.

Surgeons at the hospital told The BMJ that they had repeatedly raised concerns about shortages of staff, emergency operating theatres, and critical care beds at the hospital. Basem Khalil, secretary of …