tbuckley/cabot-search huggingface dataset:
Abstract 4291: Vitamin B6 biomarkers and colorectal cancer: Modifications by time
Authors: Björn Gylling, Robin Myte, Jörn Schneede, Göran Hallmans, Jenny Häggström, Ingegerd Johansson, Arve Ulvik, Øivind Midttun, Per Magne Ueland, Bethany van Guelpen, Richard Palmqvist
Journal: Cancer Research (2016)

Abstract Background: Pyridoxal 5’-phospate (PLP) is the most commonly used marker of circulating vitamin B6 status. In prospective case-control studies, individuals with higher plasma concentrations of PLP had a 30-50% decreased risk of colorectal cancer (CRC). This may partly be explained by decreased PLP due to inflammatory activity in persons at an increased risk of CRC. We aimed to investigate different markers of vitamin B6 in relation to CRC risk in a population with a very long follow-up time between screening and diagnosis. Methods: This was a prospective case-control study of 613 incident CRC cases and 1190 matched controls nested within the population-based Northern Sweden Health and Disease Study. PLP, pyridoxal (PL), pyridoxic acid (PA), 3-hydoxykynurenine (HK) and xanthurenic acid (XA) were measured in plasma by LC-MS/MS. Besides PLP, we investigated the recently introduced metabolite ratios PAr (PA/(PLP+PL)) and HK:XA as markers of vitamin B6 status in relation to CRC risk. Results: PAr, a marker of vitamin B6 catabolism during inflammation, was linearly associated with CRC risk, with a 50% higher risk in the highest vs. lowest quartile. In the group with a follow up time between screening and diagnosis over 10.5 years no association was observed, while in the groups with a follow up time between 5.8-10.5 years and below 5.8 years risk was approximately twofold in most quartiles vs the lowest quartile. A 50% risk decrease was observed in the in the third vs the lowest quartile of plasma PLP and a similar risk increase was observed in the highest vs the lowest quartile of the functional vitamin B6 marker HK:XA. Conclusions: PAr may influence later stages of tumor development, but possibly not early tumorigenesis. Poor functional vitamin B6 status and inflammatory activity might influence both the risk of CRC and plasma concentrations of PLP. Our results underscore the need to use several biomarkers for vitamin B6 status together with the already well established plasma PLP. This may be generalizable not only to CRC but also other diseases with an inflammatory aspect. Citation Format: Björn Gylling, Robin Myte, Jörn Schneede, Göran Hallmans, Jenny Häggström, Ingegerd Johansson, Arve Ulvik, Øivind Midttun, Per Magne Ueland, Bethany van Guelpen, Richard Palmqvist. Vitamin B6 biomarkers and colorectal cancer: Modifications by time. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4291.
Randomized, controlled trial comparing UFT with S-1 as adjuvant therapy for curatively resected stage III colorectal cancer.
Authors: K. Koda, H. Miyauchi, T. Ochiai, H. Yasuda, T. Kaiho, N. Tanaka, K. Yokoi, S. Kobayashi, H. Matsubara
Journal: Journal of Clinical Oncology (2011)

515 Background: Oral anticancer drug, UFT, has recently been reported to improve both overall survival (OS) and relapse-free survival (RFS) for patients with stage III colorectal cancer in Japan. We conducted a randomized clinical trial to compare S-1 with UFT for adjuvant therapy in patients with stage III colorectal cancer. Methods: Patients with stage III colorectal cancer (PS, 0 to 1; age, 20 to 80 years) were randomized to take either UFT (400mg/m 2 /day, 5days per week) or S-1 (80mg/m 2 /day, 28days per 6weeks) for 1 year started within 6 weeks following curative resection. The primary endpoint was to investigate relations of relapse-free survival (RFS) and tissue mRNA levels of 5-FU metabolism-related enzymes. The secondary endpoint was over all survival (OS) and safety. Results: Between July 2005 and February 2008, a total of 100 patients were registered from 21 centers. There were no clear intergroup differences in background factors. When patients who relapsed within 1 year postoperatively were excluded, the percentages of patients who took expected dosage of medicine were 73% (30/41) and 72% (33/46) in UFT and S-1 groups, respectively. Grade 3 liver dysfunction (4%) or diarrhea (4%) occurred in UFT group, whereas grade3 to 4 myelosuppression (4%), diarrhea (4%), stomatitis (2%) were observed in S-1 group, but all of them were reversible. With a median follow-up period of 1,250 days, OS in patients of UFT and S-1 groups were 86.6% and 95.9%, respectively (p=0.06). The number of patients who relapsed in rectal cancer was significantly higher in UFT group (11/25) than in S-1 group (4/21, p&lt;0.01). In a multivariate analysis, dihydropyrimidine dehydrogenase (DPD) mRNA level was shown as a factor of the recurrences. And S-1 improved RFS in patients with rectum cancer with high orotate phosphoribosil transferase (OPRT) mRNA level. Conclusions: Oral anticancer drug, S-1, was no less effective than UFT as an adjuvant therapy for stage III colorectal cancer. Tissue levels of both DPD and OPRT mRNA were important parameters for postoperative prognosis in patients with stage III colorectal cancer who take oral 5-FU derivatives for adjuvant therapy. No significant financial relationships to disclose.
Abstract 290: NF1 loss modulates cellular fitness in KIT-mutant gastrointestinal stromal tumor (GIST)
Authors: Adrian Marino-Enriquez, Bin Li, Nacef Bahri, Alexandra Lauria, Yuexiang Wang, Jonathan A. Fletcher
Journal: Cancer Research (2016)

Abstract Patients with inoperable GIST obtain substantial clinical benefit from imatinib and other KIT/PDGFRA inhibitors. However, secondary resistance develops in 90% of patients within 18-24 months. Reactivation of oncogenic signaling pathways at time of progression is most often due to secondary mutation in KIT or PDGFRA, but downstream RAS or BRAF mutations are occasionally alternative mechanisms of KIT/PDGFRA-inhibitor resistance. We identified deleterious NF1 mutations in 3 KIT-mutant GIST samples from patients progressing on imatinib. In genomic scale loss-of-function shRNA genomic screens, designed to identify genes involved in imatinib resistance, a shRNA targeting NF1 was the most enriched shRNA in imatinib-treated GIST cells out of 54,000 shRNAs (NF1 gene score 29/11,238). To evaluate the contribution of NF1 loss to KIT-mutant GIST resistance, NF1-deficient GIST models were generated from 2 patient-derived, KIT-mutant GIST cell lines, GIST882 and GIST-T1, by sequential cotransfection with Cas9 and 2 independent NF1-targeting CRISPR-sgRNAs. Complete loss of NF1 protein was observed after 5-10 passages due to on-target heterogeneous genomic deletion at the NF1 locus. Orthogonal validations were obtained using stable shRNA-mediated NF1 knockdown with similar results in the same GIST cell lines. NF1-deleted cells retained expression of mutant KIT but were resistant to imatinib (IC50 196 and 500nM, significantly increased from baseline 34 and 110nM, for GIST-T1 and GIST882, respectively). Notably, after interruption of imatinib treatment, NF1-deficient GIST cells showed reduced proliferation (69% and 77% growth reduction at day 7 off imatinib, for GIST-T1 and GIST882, t test p&amp;lt;0.001) despite continuous expression of activated KIT and downstream signaling effectors. In conclusion, acquired NF1 loss induces TKI resistance in KIT-mutant GIST cells but results in reduced cellular fitness in the absence of KIT-inhibitor treatment. These findings suggest that NF1-deficient GIST subclones that expand on imatinib treatment can be destabilized by intermittently discontinuing KIT-inhibitor therapy. Citation Format: Adrian Marino-Enriquez, Bin Li, Nacef Bahri, Alexandra Lauria, Yuexiang Wang, Jonathan A. Fletcher. NF1 loss modulates cellular fitness in KIT-mutant gastrointestinal stromal tumor (GIST). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 290.
Abstract 3611: SMRT® sequencing of DNA samples extracted from formalin-fixed and paraffin embedded tissues
Authors: Primo Baybayan, Michael Weiand, Kevin Eng, Guillaume Durin, Steve Kujawa
Journal: Cancer Research (2016)

Abstract Recent advances in next generation sequencing have led to the increased use of formalin-fixed and paraffin-embedded (FFPE) tissues for medical samples in disease and scientific research. Single Molecule Real-Time (SMRT®) sequencing offers a unique advantage in that it allows direct analysis of FFPE samples without amplification. However, obtaining ample long read information from FFPE samples has been a challenge due to the quality and quantity of the extracted DNA. DNA samples extracted from FFPE often contain damaged sites, including breaks in the backbone and missing or altered nucleotide bases, which directly impact sequencing and amplification. Additionally, the quality and quantity of the recovered DNA also vary depending on the extraction methods used. We have evaluated the Adaptive Focused Acoustics (AFA™) system by Covaris® as a method for obtaining high molecular weight DNA suitable for SMRTbell template preparation and subsequent single molecule sequencing. Using this method, genomic DNA was extracted from normal kidney FFPE scrolls acquired from Cooperative Human Tissue Network (CHTN), University of Pennsylvania. Damaged sites present in the extracted DNA were repaired using a DNA Damage Repair step, and the treated DNA was constructed into SMRTbell libraries suitable for sequencing on the RSII System. Using the same repaired DNA, we also tested PCR efficiency of target gene regions of up to 5 kb. The resulting amplicons were constructed into SMRTbell templates for full-length sequencing on the RS II System. We found the Adaptive Focused Acoustics (AFA™) system by Covaris® to be effective and efficient. This system is easy and simple to use, and the resulting DNA is compatible with SMRTbell™ library preparation for targeted and whole genome SMRT sequencing. The data presented here demonstrates single molecule sequencing of DNA samples extracted from tissues embedded in FFPE. Citation Format: Primo Baybayan, Michael Weiand, Kevin Eng, Guillaume Durin, Steve Kujawa. SMRT® sequencing of DNA samples extracted from formalin-fixed and paraffin embedded tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3611.
Abstract 4207: microPET/CT imaging of the mobilization of CD11b+ cells
Authors: Qizhen Cao, Qian Huang, Chun Li
Journal: Cancer Research (2016)

Abstract Objectives: Mobilization of immune cells is often associated with prognosis and treatment response for many diseases. The objective of this study was to test whether mobilization of CD11b+ myeloid cells could be noninvasively imaged by PET/CT. Methods: Anti-mouse CD11b antibody was labeled with 64Cu. Immunocompetent mice with 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in the ears, lipopolysaccharide (LPS)-induced inflammation in the lung, mice bearing 3 different syngeneic murine tumors (4T1 mammary carcinoma, CMS4 sarcoma, and CT26 colon carcinoma), and mice bearing ID8 ovarian cancer undergoing photothermal therapy were imaged with [64Cu]-labeled anti-CD11b. microPET-CT imaging and biodistribution were obtained at 24 h after intravenous injection of the radiotracer. Subpopulations of bone marrow cells, cells from spleen, and cells from the disease sites were analyzed by flow cytometry and/or immunohistochemistry (IHC) staining. Results: 64Cu-labeled anti-CD11b bound specifically to CD11b+ myeloid cells. microPET-CT images showed significantly higher uptake of 64Cu-DOTA-anti-CD11b antibody at the inflammatory sites and tumors undergoing photothermal therapy. In addition, microPET-CT images also revealed mobilization of CD11b+ cells from bone marrow to secondary lymphoid organs (spleen and/or lymph nodes). Interestingly, mice bearing 4T1 carcinoma displayed a markedly different imaging/distribution pattern compared to mice bearing CMS4 and CT26 tumors, characterized by a significant increase in blood pool and liver activities with corresponding reduction in the uptake of the radiotracer in the bone marrow and the spleen in different stages of tumor development. These findings were evaluated in the context of flow cytometry and IHC analyses. Conclusions: The differential distribution pattern of 64Cu-labeled anti-CD11b in different disease models could be attributed to mobilization of CD11b+ cells. PET/CT may be used to image systems response of immune cells to disease development and treatments. (Supported in part by the John S. Dunn Foundation) Citation Format: Qizhen Cao, Qian Huang, Chun Li. microPET/CT imaging of the mobilization of CD11b+ cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4207.
Pelvic organ prolapse
Authors: Matthew D Barber
Journal: BMJ (2016)

#### What you need to know

A woman’s lifetime risk of surgery for pelvic organ prolapse (POP) is 12-19% with over 300 000 prolapse surgeries performed annually in the US alone.1 2 3 POP accounts for about 15-18% of hysterectomies, and uterovaginal prolapse is the most common indication for hysterectomy in postmenopausal women.4 About one in 12 women living in the community in the UK report symptoms of pelvic organ prolapse.5

POP is the downward decent of the female pelvic organs (vagina, uterus, bladder, and/or rectum) into or through the vagina. This review provides an evidence based update on the epidemiology, evaluation, and management of this condition.

Loss of vaginal or uterine support is seen in up to 30-76% of women presenting for routine gynaecology care, with 3-6% of those with descent beyond the vaginal opening (that is, level of the hymen).6 7 8 One population based study found that about 3% of 1961 adult women surveyed reported symptomatic vaginal bulging.9

Prolapse of the anterior vaginal wall, or cystocele, is the most common form of POP, detected twice as often as posterior vaginal prolapse (that is, the rectocele), and three times more common than apical prolapse (uterine and/or post-hysterectomy vaginal vault prolapse) (fig 1⇓).10 11 However in most cases of symptomatic POP, prolapse of multiple segments of the vagina are …
Comparison of intratumoral biodistribution of a pegylated and a nonpegylated form of liposomal doxorubicin in orthotopic high-grade glioma xenografts.
Authors: H. Sudour, S. Pinel, M. Lanhers, M. Barberi-Heyob, P. B. Chastagner
Journal: Journal of Clinical Oncology (2010)

e13581 Background: Pharmacokinetic and biodistribution studies showed that liposomal forms of doxorubicin (DXR) reduce DXR concentrations in sensitive organs, but increase it in tumors. Liposomal entrapped DXR (L-DXR) improves penetration through the blood-brain barrier. Using a heterotopic model of human malignant xenografts (U87), we previously demonstrated a synergistic antitumor effect of non-pegylated L-DXR concurrently associated with radiotherapy. We aim to determine the maximal tolerable dose (MTD) of 2 L-DXR forms (pegylated or not) with 2 injection schedules and to evaluate which L-DXR form and schedule allow to obtain the highest and more prolonged tumor concentration in order to design a radiosensitizing treatment. Methods: MTD assessments were performed on a minimum of 7 nude mice free of tumor, treated at each dose level for both schedules. DXR concentrations in normal and tumoral brain hemispheres were assessed by HPLC in an orthotopic model of malignant glioma xenografts (U87). Each L-DXR form was administered at these MTD in 4 or 6 injections over 2 weeks. Results: Four dose levels were necessary to find the MTD which were 30 and 12 mg/kg, respectively for the non- pegylated and the pegylated L-DXR forms, whatever the schedule. Using these equi-toxic doses, average DXR concentrations were always higher in the tumor in comparison with normal cerebral tissue. The best tumoral/normal AUC ratio was 5.9 for the non-pegylated form and 3.6 for the pegylated form. The best AUC observed in the tumoral hemisphere was obtained with the non-pegylated form administered in 4 injections. Conclusions: Multiple injections of non-pegylated and pegylated liposomal DXR forms lead to good and prolonged DXR brain tumor impregnation with a very favorable tumoral/normal brain ratio. These results provide the background for the treatment of high grade gliomas and/or brain metastases using L-DXR forms concurrently with radiotherapy. Experiments evaluating antitumor effect and radiosensitizing effect of these drugs are in process. No significant financial relationships to disclose.
Abstract 5011: Strong FGFR3 staining is a marker for FGFR3 fusions and poor prognosis in diffuse gliomas
Authors: Kirsi J. Granberg, Matti Annala, Birgitta Lehtinen, Juha Kesseli, Joonas Haapasalo, Olli Yli-Harja, Tapio Visakorpi, Hannu Haapasalo, Matti Nykter, Wei Zhang
Journal: Cancer Research (2016)

Abstract Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled coil 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibitors. As high FGFR3 expression has been detected in fusion positive tumors, we sought to determine the clinical significance of FGFR3 protein expression level and its potential to indicate FGFR3 fusions. We thus performed FGFR3 IHC on tissue microarrays containing 676 grade II-IV astrocytoma and 116 grade II-III oligodendroglial tumor specimens. Selected cases were further analyzed using targeted sequencing. Moderate-to-strong FGFR3 staining was detected in all tumor grades, was more common in females, and associated with poor survival. Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 12 strongly stained cases (staining specificity 86%), whereas no fusions were found in 12 negatively-to-moderately stained cases (staining sensitivity 100%). Fusion-positive cases were predominantly female and negative for IDH, TP53, and EGFR/PDGFRA/MET alterations. Importantly, FGFR3 staining revealed intratumoral heterogeneity, with subclonal negative staining in a subpopulation of fusion-positive cases. Taken together, strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a cost-effective predictive marker for FGFR-inhibitor-based treatment regimens. Citation Format: Kirsi J. Granberg, Matti Annala, Birgitta Lehtinen, Juha Kesseli, Joonas Haapasalo, Olli Yli-Harja, Tapio Visakorpi, Hannu Haapasalo, Matti Nykter, Wei Zhang. Strong FGFR3 staining is a marker for FGFR3 fusions and poor prognosis in diffuse gliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5011.
Abstract 4156: Functional analysis of tumor-associated macrophage utilizing virus-guided fluorescent imaging of pancreatic cancer cells in the peritoneal cavity
Authors: Kazuya Kuwada, Shunsuke Kagawa, Megumi Watanabe, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Tetuya Kagawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2016)

Abstract Objectives: Postoperative recurrence occurs in approximately 80% of pancreatic cancer, and the peritoneum is the second most frequent metastatic site next to the liver. Recent evidence suggests that cancer microenvironment plays key roles in metastasis. To investigate mechanism of intraperitoneal metastasis in pancreatic cancer, we tried to detect cancer cell in the peritoneal wash from pancreatic cancer patients and analyze intraperitoneal cancer microenvironment. A genetically engineered adenovirus, TelomeScan, which replicates and expresses GFP only in telomerase-active cancer cells, was employed to detect cancer cells, and it enabled us to distinguish cancer cell from co-existence cells in the abdominal cavity. We explored the role of tumor-associated macrophages (TAMs) by using this virus-guided fluorescent imaging system. Methods: Peritoneal wash was obtained from 20 pancreatic cancer patients during operation. The cells in the wash were infected with TelomeScan for 24 hours. Samples from cases with TelomeScan-expressing GFP-positive cells were further subjected to immunofluorescence assay for analysis of microenvironment. The antibodies against CD45, CD14, and CD204 were used in immunostaining as markers of leukocytes, monocytes and TAMs, respectively. To investigate the effect of TAMs on pancreatic cancer, Panc1 and BxPC-3 cell lines were co-cultured with PMA (phorbol 12-myristate 13-acetate)-treated monocytes and analyzed their changes. Results: The three out of 20 cases were positive in cytology, and GFP positive cells were detected after TelomeScan infection in those cases. In the wash, pancreatic cancer cells existed together with many leukocytes including macrophages. Further analysis demonstrated that those macrophages were TAMs. After Panc1 or BxPC-3 cells were co-cultured with TAMs, E-cadherin was decreased in Panc1, α-SMA and Vimentin was increased in BxPC-3. These results suggested that Epithelial to Mesenchymal Transition (EMT) was induced in pancreatic cancer cells by TAMs. Conclusion: Pancreatic cancer cells and TAMs were detected in the peritoneal wash using TelomeScan and immunostaining. The results suggested that EMT induced by TAMs may promote intraperitoneal metastasis of pancreatic cancer. Citation Format: Kazuya Kuwada, Shunsuke Kagawa, Megumi Watanabe, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Tetuya Kagawa, Toshiyoshi Fujiwara. Functional analysis of tumor-associated macrophage utilizing virus-guided fluorescent imaging of pancreatic cancer cells in the peritoneal cavity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4156.