tbuckley/cabot-search huggingface dataset:
Pretreatment serum levels of circulating myeloid-derived suppressor cells (MDSC) as a prognostic indicator in patients with gastrointestinal cancer.
Authors: Masahiko Shibata, Kenji Gonda, Takahiro Nakajima, Yoshiko Matsumoto, Izumi Nakamura, Shinji Ohki, Tohru Ohtake, Kensuke Kumamoto, Tatsuo Shimura, Seiichi Takenoshita, Noriko Abe, Tomoyuki Momma
Journal: Journal of Clinical Oncology (2014)

3059 Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. We have reported that MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, is increased in patients with various types of cancer including gastrointestinal, hepatopancreatic, breast, thyroid and ovarian cancers, and the levels of MDSC were closely related to systemic inflammation, immunosuppression and nutritional impairment. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 123 preoperative patients with gastrointestinal cancer including 18 patients with esophageal, 43 with gastric, 62 with colorectal cancers, and these cells were used for the detection of MDSC (CD11b+CD14-CD33+) by flow cytometry. The circulating levels of MDSC were divided with 1.02% of PBMC which is the median level in healthy volunteer, and the prognosis of these patients was analysed with Kaplan-Meier method. Results: In patients with stage IV disease, the overall survival (OS) was significantly shorter (p<0.05) in patients with high MDSC levels than in those with low MDSC levels. Although in patients with high MDSC levels, both of OS and DFS (disease free survival) of the patients with stage IV diseases were shorter (both p<0.001) than those with stages I, II, and III diseases, there were no significant difference in those with low MDSC levels. Furthermore, in patients with colorectal cancer, the OS was shorter in stage IV patients with high MDSC levels than in stage IV patients with low MDSC levels. However, OS was not significantly different with MDSC levels in patients with Stages I, II, and III diseases. Conclusions: Therefore, the pretreatment levels of MDSC is effective as a good prognostic indicator especially in patients with advanced gastrointestinal cancers.
Immunomodulatory effects of 5-azacytidine in acute myeloid leukemia.
Authors: Anne Letsch, Susanne Doering, Petra Quass, Antonio Pezzutto, Sebastian Ochsenreither
Journal: Journal of Clinical Oncology (2014)

3083 Background: Specific immunotherapeutic approaches in acute myeloid leukemia have recently attracted interest. Several leukemia associated antigens have been identified and early vaccine trials demonstrated promising efficacy. However vaccination strategies might be improved by combination with current standard treatment or other reagents with immunomodulatory activity in order to enhance leukemia directed immune responses. An attractive combination partner is 5-Azacytidine (5-AZA). In preparation of combination studies of specific immunostimulation in concert with 5-AZA, the immunomodulatory effects of 5-AZA on leukemic cells have been analyzed. Methods: The leukemic cell lines ML-2, HL-60, TF-1, Oci-AML5, UT-7, THP-1, NB4, SigM5, and HEL as well as blasts from 3 leukemic patients have been incubated with 2µM 5-AZA for 9 days. Before and during stimulation (day 5, 7 and 9) the following markers have been analyzed by flow cytometry: CD80, CD86, HLA-DR, HLA-ABC, CXCR4, PD-L1, PI-9 and INDO. Mean fluorescence intensity (MFI) of the single markers were compared at different time points. Results: The data obtained on the 9 cell lines and blasts from 3 leukemic patients stimulated by 5-AZA have been heterogenous, but some phenomena were observed in a majority of cell lines and patients. Generally in favour of immune control of leukemic cells are the following mechanism: a) Upregulation of CD86 in 8 of 9 cell lines (8/9) and 0 of 3 patients (0/3), b) downregulation of INDO (7/9 and 1/3), and c) downregulation of PI-9 (3/9 and 2/3). On the other hand we observed mechanisms, which would theoretically enhance immune evasion of leukemic cells: a) downregulation of MHC-class-I molecules (7/9 and 2/3), b) upregulation of PD-L1 (4/9 and 2/3) and c) increase of CXCR4 (8/9 and 2/3) by incubation with 5-AZA. The other markers remained generally unchanged. Conclusions: Results should be confirmed on mRNA-level and by functional analyses. Nevertheless our current data already points to interesting immunomodulatory effects of 5-AZA, being an attractive candidate as adjuvant in combination therapies with other immune interventions in leukemia and other malignancies. Potential leukemic and tumor promoting effects of 5-AZA have to be further evaluated.
Characterization of natural killer (NK) cell activating receptor NKG2D ligands on pediatric solid and hematologic malignancies
Authors: Ping Zhao, Yongjun Jiao, Jin Zhu, Zhengqing Feng, Xiaohong Guan, R. Scot Skinner, Milton Gross, Yanli Su, George Vande Woude, Rick Hay, Brian Cao
Journal: Cancer Research (2005)

4257  NK cells play a significant role in tumor cell recognition and cytotoxicity (Trinchieri et al, Adv Immunol, 1990). Few NK-cell activating ligands have been identified with the exception of those found to interact with the C-type lectin-like receptor NKG2D. Among these ligands are surface glycoproteins, MICA and MICB, which are expressed on many epithelial cell tumors (Bauer et al, Science, 1999). Recently, the UL16-binding proteins (ULBPs) have been identified as NKG2D ligands and have been found on numerous tumor cell lines (Pende et al, Cancer Res, 2002). Enhanced cytotoxicity of allogeneic NK cells against solid tumor cells has been demonstrated in the MHC-C mismatched setting (Igarashi et al, Blood, 2004). In this study, we compared the expression of NKG2D ligands MICA, MICB and ULBPs-1, 2 and 3 in neuroblastoma (NB: NBL, NGP, SH-SY5Y), Burkitt’s lymphoma (Daudi), DLBCL (Pfeiffer), CML (K562), and ALL (REH, RS4:11, SUPB-15). Genomic expression was determined by mRNA isolation, reverse transcription generated cDNA and polymerase chain reaction (PCR) amplified all ligand sequences. Primers included the following: MICA: 5’-GTGCCCCAGTCCTCCAGAGCTCAG3’ and 5’GTGGCATCCCTGTGGTCACTCGTC3’; MICB: 5’GGCGTCAGGATGGGGTATCTTTGA3’ and 5’GGCAGGAGCAGTCGTGAGTTTGCC3’; ULBP1: 5’CTGCAGGCCAG-GATGTCTTGTGAG3’ and 5’TGAGGGTGGTGGCCATGGCCTTGG3’; ULBP2: 5’CTGCAGGCAAGGATGTCTTGTGAG3’ and 5’TGAGGGTGGTGGCTGTGGCCCTGA3’; ULBP3: 5’CTGCAGGTCAGGATGTCTTGTGAG3’ and 5’TGAGGGTGGTGGCTATGGCTTTGG3’; GADPH was used as control. Cell surface expression of the NKG2D ligands was determined by flow cytometry. Increased expression of MIC+/ULBP+ by PCR was seen in all ALL, CML, and B-NHL cell lines, however, MIC-/ULBP+ was expressed in neuroblastoma cell lines (Table). Surface expression of MIC and ULBP ligand receptors was significantly increased in Daudi and K562 vs Pfeiffer and all ALL and NB cell lines (p
Palonosetron (PAL) in combination with 1-day versus 3-days dexamethasone (DEX) to prevent nausea and vomiting in patients receiving paclitaxel and carboplatin (TC).
Authors: Naoto Furukawa, Shozo Yoshida, Seiji Kanayama, Ryuji Kawaguchi, Fuminori Ito, Yasuhito Tanase, Sachiko Morioka, Hiroshi Kobayashi
Journal: Journal of Clinical Oncology (2014)

9608 Background: According to current guidelines the combination of PAL and 3-days DEX is the standard antiemetic treatment in pts receiving TC. However, PAL has prolonged efficacy in preventing delayed nausea and vomiting, and pts receiving DEX reported moderate to severe problems in the week following chemotherapy. The aim of present study was to evaluate the efficacy and toxicity of PAL and DEX on day 1 only in pts with gynecological cancer receiving TC. Methods: This study is a prospective, randomized phase II study. Pts were stratified according to age (over 50 years or under 50 years) and habitual alcohol intake (yes or no). Chemotherapy-naïve pts >20 years old were randomly assigned to receive PAL (0.75mg iv) plus DEX (20mg iv) on day1 before receiving TC (D-1 group), or PAL (0.75mg iv) plus DEX (20mg iv) on day1 before receiving TC and DEX (8mg po) on days 2 and 3 (Std group). Primary endpoint was complete response (CR; defined as no vomiting episodes and no rescue medication) for 24-120 h after the first chemotherapy cycle initiation. Nausea and vomiting were evaluated with the MASCC Antiemesis Tool (MAT). Toxicity assessments were conducted using the NCI-CTC investigator guide (version 4.0). Results: Between April 2012 and December 2013, a total of 88 pts were randomized: 82 pts (D-1 group=43, Std group=39; median age D-1 group=59 years, Std group=62 years; habitual alcohol intake D-1 group=4, Std group=3) were available for the efficacy and toxicity analysis. 69.8% (30/43) and 76.9% (30/39) of pts reported delayed CR in D-1 and Std, respectively (P = 0.465). Acute and overall CR in D-1 and Std were similar (95.4% vs. 94.9%, P =0.920; 67.4% vs. 76.9%, P=0.340). The most common adverse event was grade 1 constipation (18.6% vs. 20.5%, P=0.828) and grade 1 insomina (16.3% vs. 12.8%, P=0.658). In logistic analysis, age under 50 years was associated with a lower incidence of delayed CR (odd ratio 3.79). Conclusions: The antiemetic treatment with DEX on day 1 only seemed as effective as the standard treatment for prevention of nausea and vomiting in pts receiving TC. In addition, in pts < 50 years old other antiemetic drugs may be necessary in addition to DEX and PAL. Clinical trial information: 000007491.
Efficacy, safety, and cost efficiency of rituximab, gemcitabine, dexamethasone, and oxaliplatin (RGDOx) in B-cell NHL: Report of the prospective multicentric trial NCT01019863.
Authors: Marco Lefebvre, Rami Kotb, Jean-Francois Larouche, Mariette Lepine Martin, Anick Champoux, Annie Morin, Eric Turcotte, Jean Dufresne, Hans Knecht, Patrice Beauregard
Journal: Journal of Clinical Oncology (2014)

8581 Background: Cisplatinum-based 2nd line therapy is poorly tolerated. We evaluated the activity and toxicity of an outpatient RGDOx regimen Methods: Patients (pts) with CD20+ NHL, without limitation of age, general condition or prior treatments, were eligible for up to 8 biweekly cycles of rituximab 375 mg/m², gemcitabine 1000 mg/m², oxaliplatin 100 mg/m² on day 1 and dexamethasone 40mg/day orally on day 1- 3. Toxicity was reported according to NCI criteria. Response was assessed at mid and end of treatment. Pts were followed up to 24 months. Costs were collected on per diem canadian interprovincial rates and hospital pharmacy medication costs as of Oct. 2011. Results: The planned 50 pts were included from 2009 to Jan. 2013. Two died before starting therapy and were not included in this analysis; 17 females, 31 males, median age 70 (47 - 86) yrs with relapsed (37) or refractory (11) B-NHL (DLBCL 25, FL 8, MCL 11, Richter 2 and CLL 2). 83% had stage III/IV disease, aaIPI / FLIPI ≥2 (85%), median Charlson co-morbidity score of 4, average 2 (1-8) previous treatment lines, 47 previously treated with rituximab and 9 with cisplatin. A total of 250 cycles were given. This was well tolerated. Common grade I-II AE: Sensory neuropathy 66%, diarrhea 36% asthenia 35%, and bone pain 18%. Grade III/IV: Lymphopenia 12%, neutropenia 3% and thrombocytopenia 4%. Two died after 1 and 3 cycles, before documenting response. The overall response was 57% (n=46, CR 40%, PR 17%, PD: 43%). DLCBL (40%, 8%, 52%), FL (38%, 25%, 38%), MCL (50%, 20%, 30%). The median survival was 18.4 months (n=48) and disease-free median survival among responders was 15.7 months (n=27). Refractoriness to previous treatment or response lasting less than 12 months was associated with poorer outcome. Previous cisplatin therapy tended to predict lower response. Average 6-cycle course was associated with 4.8 days of hospitalization, 0.7 medical visits for iatrogenic side effects and 7.3 visits for additional laboratory tests. Mean cost for 6 cycles of RGDOX was $Can 54,991 with a median cost per life year of $Can 35,863. Conclusions: RGDOx is safe, effective and cost-effective for relapsing/refractory B-Cell NHL. Clinical trial information: NCT01019863.
Genetics of Factor VIII Inhibitor Development in Hemophilia Patients: Novel Statistical Approaches in the PATH Study
Authors: Vincent P. Diego, Marcio A. Almeida, Bernadette W. Luu, Karin Haack, Meera B. Chitlur, Afshin Ameri, Long V. Dinh, Raja Rajalingam, Jerry S. Powell, John Blangero, Laura Almasy, Shelley Cole, Tom E. Howard
Journal: Blood (2018)
Polymorphisms in the apoptosis pathway and prognosis in cutaneous melanoma.
Authors: Cristiane Oliveira, Jose Augusto Rinck, Gustavo Jacob Lourenco, Aparecida Machado Moraes, Carmen Silvia Passos Lima
Journal: Journal of Clinical Oncology (2014)

9084 Background: Cutaneous melanoma (CM) is notorious for its poor prognosis and resistance to conventional chemotherapy. Genes involved in the apoptosis pathway, such as P53, (tumor suppressor gene), MDM2 (p53 inhibitor), BAX (proapoptotic) and BCL2 (anti-apoptotic) are important for survival and tumor growth. The polymorphisms P53 Arg72Pro, MDM2 T309G, BAX G(-248)A and BCL2 C(-938)A alter the expression of the respective encoded proteins. The aim of this study was to evaluate whether these polymorphisms are associated with overall survival (OS) and relapse free survival (RFS) of CM patients. Methods: Our analysis included 185 consecutive CM patients at diagnosis seen at our University Hospital from December 1989 to November 2012. Genomic DNA from peripheral blood of patients was analyzed by polymerase chain reaction followed by enzymatic digestion for discrimination of pertinent genotypes. OS and RFS were calculated using the Kaplan-Meier estimate probabilities, and differences between survival curves were analysed by the log-rank test. OS was calculated from date of first diagnosis until the date of death or last follow-up. RFS was defined as the time to beginning of treatment until the date of the first relapse. Results: The median period of observation of patients in study were 61 months (range: 3-283). We observed at 120 months of segment, that the OS in CM patients with the BAX GA+AA was higher than in those with the GG genotypes (100% versus 79%, P=0.01). The OS were also higher with in patients with BAX GA+AA plus BCL2 CC+CA combined genotype than in those with BAX GG plus BCL2 AA (100% versus 76.7%, P=0.02) and BAX GA+AA plus MDM2 TT+TG than BAX GG plus MDM2 GG (100% versus 58.3%, P=0.006). No difference in RFS was seen in patients with the distinct genotypes of the above referred genes. Conclusions: The data suggest, for the first time, that polymorphism BAX gene may independent or jointly with BCL2 and MDM2 polymorphisms, modulate OS outcome of CM patients. Additional studies will provide some promising guidance for clinical management and tailored or personalized therapeutics in treating for CM.
Genetic alterations of DLC1 in medulloblastoma and primitive neuroectodermal tumor
Authors: Qing Chang, Jesse Chung-Sean Pang, Ho-Keung Ng
Journal: Cancer Research (2004)

91  Medulloblastoma (MB) is the most common malignant embryonic tumor in childhood that arises from the posterior fossa of brain. Tumor with highly similar pathological features as MB but is found in other parts of the brain is referred to as primitive neuroectodermal tumor (PNET). Our group has previously demonstrated a high frequency of allelic loss on the short arm of chromosome 8 in MB and localized two critical regions of deletion that map to 8p21.3-22 and 8p23.1. These deletion regions are also noted as recurrent genetic aberrations in a variety of human tumors. Recently, a novel gene named DLC-1 is identified from 8p22 and its product shares high sequence homology with rat p122-RhoGAP. RhoGAP may function as tumor suppressor by down-regulating Rho activity, which is involved in Ras-mediated oncogenic transformation. Indeed, promotor hypermethylation, homozygous deletion and lack of expression of DLC-1 have been detected in liver, breast, colon, prostate and gastric cancers, indicating that this gene is involved in tumorigenesis. The aim of this study was to investigate whether DLC-1 played a role in the development of MB and PNET. We first evaluated the expression and methylation status in 26 microdissected MB, 4 MB cell lines, 4 microdissected PNET, one PNET cell line as well as 2 normal cerebellum and brain tissues. Reverse transcription-polymerase chain reaction analysis showed that DLC-1 was expressed in majority of tumors, all cell lines and normal tissues. One MB (case MB248) and 1 PNET(case AH312)were found not to express DLC-1. Promoter hypermethylation was detected in the PNET sample not expressing DLC-1, but such aberration was not seen in MB248. Duplex PCR analysis on MB248 revealed no homozygous deletion of the DLC-1 gene. We further screened for somatic mutation of all 14 exons using direct sequencing. One base substitution on exon 5 (800A>G, N267S) of DLC-1 was detected in MB248, which was later confirmed to be genetic polymorphism. Absence of DLC-1 expression in MB248 is probably regulated by other mechanism not examined in the current study. In conclusion, our molecular analyses of DLC-1 suggest that inactivation of this gene by promotor hypermethylation may play an important role in the tumorigenesis of PNET, but this result needs to be confirmed in a larger series.
Clinical Outcomes with Direct Oral Anticoagulants Compared to Low Molecular Weight Heparins in the Treatment of Cancer-Associated Venous Thromboembolism
Authors: Deborah Y. Park, Shyam K. Poudel, Xuefei Jia, Mailey Lynn Wilks, Vicki Pinkava, Meghan O'Brien, Barbara Tripp, Jung-Min Song, Keith R. McCrae, Dana E. Angelini, Alok A. Khorana
Journal: Blood (2018)
Comparison of cisplatin- versus carboplatin-based concurrent chemoradiation for limited-stage small cell lung cancer using SEER-Medicare data.
Authors: Ellen Kim, Tithi Biswas, Siran M. Koroukian, Afshin Dowlati, Neelesh Sharma, Mitchell Machtay
Journal: Journal of Clinical Oncology (2014)

7596 Background: Small cell lung cancer (SCLC) accounts for 14% of lung cancers. Current standard therapy for limited stage (AJCC stages I-III) SCLC is concurrent chemoradiation (CCRT) with cisplatin/etoposide but carboplatin/etoposide is often used for patients with poor tolerance or contraindication to cisplatin. The aim of this retrospective cohort study is to compare survival of cisplatin (cis) and carboplatin (carb) based CCRT in limited stage SCLC. Methods: Cases were selected from the population-based SEER-Medicare lung cancer database if the patient’s first cancer was limited stage SCLC diagnosed at age 66-80 in 1992-2007. CCRT was defined with radiation starting within 60 days of the start of the first cycle of cis/carb. Study endpoints were overall survival (OS, time from diagnosis until death) and cause specific survival (CSS, time from diagnosis until death from lung cancer). SAS v9.3 was used to select cases, and R v3.0.2 was used to calculate Kaplan-Meier survival analysis and log-rank tests for significance. Results: Study sample meeting inclusion criteria included 1603 patients, with median age 72 (66-81) and gender ratio 1.1. Majority were stage III (n=1342, 84%), with some stage I (11%) and II (5%). Cis was used in 617 cases (38%) while carb was used in 986 cases (62%). On average, cis group was younger (p<0.001). Median (OS, CSS) were (1.20, 1.34) and (1.17, 1.33) years for cis and carb groups, respectively. Five-year (OS, CSS) for cis and carb were (13.7%, 24.4%) and (11.1%, 20.5%), respectively. There was no statistically significant difference in OS (p=0.163) or CSS (p=0.683) between the groups. Conclusions: Cis vs carb based CCRT had comparable OS and CSS, even though cis group was younger. This suggests that if carb is better tolerated, it should be preferred for limited stage SCLC, though randomized trials are needed.
Building a regional partnership based on pathway adherence and accountability instead of regulations or finances.
Authors: Timothy Edward Kubal, Richard M. Levine, Keith Weinhold, Kevin Wardell, Charles F. Andrews, Yvette Tremonti, Riti Shimkhada, John W. Peabody, Karen K. Fields
Journal: Journal of Clinical Oncology (2014)

e17689 Background: The era of the Accountable Care Organization has pushed providers to form networks and consolidate referral streams to avoid loss of market share. In 2012, Moffitt launched an initiative focused on quality and improvements in care using an online educational tool, Clinical Performance and Value (CPV) vignettes, to measure adherence to evidence-based clinical pathways. This initiative has been expanded to include 4 Moffitt Oncology Network (MON) partners and targets breast, lung and gastrointestinal (GI) cancer. The objectives of this study are to (1) measure and improve clinical care, (2) increase adherence to pathways and (3) demonstrate value to payers. Methods: Moffitt’s pathways were introduced at all 4 partner sites beginning with breast cancer, with lung and GI cancer to follow. To advance pathway adoption, CPV vignettes were employed to quantify pathway adherence and diagnostic accuracy using virtual patients. Serial assessment every 4 months allowed measurement of pathway comprehension, confidential feedback to clinicians regarding adherence and documentation of improvement in performance. Results: At baseline, CPV scores revealed variation across institutions, with higher history and physical exam scores and lower scores for workup, diagnosis and treatment. The overall range and average scores were consistent regardless of the partnering institution (Table). Based on average wholesale price (breast cancer), Moffitt data suggests that pathway adherence results in conservative savings of between $6,500 to $10,400 per patient due to reduced chemotherapy costs and reduction in unnecessary testing. Conclusions: The MON is based upon the establishment and reinforcement of pathway-based standards of care and other drivers of quality. Value-creation comes from higher quality and lower costs through a culture of self-awareness and continuous quality improvement. Baseline CPV scores, breast cancer. Site 1 Site 2 Site 3 Site 4 Average score 55.4 56.7 53.7 55.8 St. Dev. 12.5 11.3 13.9 13.0 Min 27.9 31.8 27.3 38.0 Max 80.6 81.5 77.8 84.4
Address risk factors to prevent bone stress injuries in male and female athletes
Authors: Elizabeth Anne Joy
Journal: British Journal of Sports Medicine (2019)

Every year in the USA, 8 million athletes participate in high school sports and 460 000 participate in intercollegiate sports.1 Sport participation is an important vehicle for many adolescents and young adults to achieve recommended levels of physical activity. High school and college athletes are more likely to meet nationally recommended levels of physical activity in comparison to non-athlete peers,2 3 and sports participation confers many health benefits not discussed here.

However, sports participation also can be a risk factor for unhealthy behaviours, high training loads and metabolic disturbances in a subset of vulnerable athletes. As the level of competition increases from high school to college, the duration and intensity of an athlete’s training typically increases. For running sports such as cross country and track and field, the transition from high school to collegiate training may result in a substantial increase in weekly running mileage. Along with this increase in training load, college athletes are exposed to changes in their dietary intake (eg, cooking for themselves or eating in a residence hall), sleep patterns (eg, staying up late …
Sixty seconds on . . . missed GP appointments
Authors: Gareth Iacobucci
Journal: BMJ (2019)

NHS England has sparked a fresh debate on this well trodden matter by releasing new figures on “did not attend” (DNA) appointments. It claims that 15 million general practice appointments are being “wasted” each year because patients do not turn up and fail to warn surgeries that they will not be attending.

With lengthy waiting times and practices …