tbuckley/cabot-search huggingface dataset:
Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment.
Authors: Andrew J. Armstrong, Rhonda Lynn Bitting, Gabor Kemeny, Daniel J. George
Journal: Journal of Clinical Oncology (2014)

178 Background: Serum alkaline phosphatase (AP) changes in men with metastatic prostate cancer have been described since the Nobel Prize winning discovery of the hormonal dependence of PC. High serum AP is independently associated with mortality in men with castration-resistant prostate cancer (CRPC) and reductions in AP with treatment are favorably prognostic. Transient rises in AP may occur during treatment initiation and reflect bone remodeling/healing. The source of serum AP in men with metastatic prostate cancer, however, remains unclear. We hypothesize that cancer cell osteomimicry and epithelial plasticity may contribute to serum AP elevations in these men. Methods: We examined the expression of AP in the circulating tumor cells (CTCs) of men with metastice CRPC on abiraterone acetate who had elevated serum AP to determine if one possible source of serum AP may be tumor-derived rather than host/bone derived. CTCs were isolated using the CellSearch method and EpCAM ferromagnetic capture, and only CD45 negative cells were considered CTCs. AP was evaluated using immunofluorescence and real time positive and negative controls. Liver function was evaluated to ensure lack of confounding with liver-derived AP. Results: We identified AP to be commonly expressed in the CTCs of men with CRPC who had high serum AP, with no expression in patient leukocytes. One patient had a transient rise in serum AP with no change in other liver enzymes during a dramatic response to abiraterone acetate while his prostate-specific antigen and CTC declined. AP expression was evident and common in his CTCs during this serum AP flare. A second patient was found to have common CTC AP expression in both CK+ and CK- CTCs. This patient had evidence of AR amplification, PTEN loss, and TMPRSS2-ERG fusion in his CK- and CK+ CTCs, accompanied by a high number of OB-cadherin + CTCs, indicating likely osteomimicry and plasticity of these clonal epithelial tumor cells. Conclusions: We provide clinical evidence that PC CTCs express AP, supporting the hypothesis that AP expression is associated with osteomimicry as part of the biology of epithelial plasticity in prostate cancer. These findings support the existence of multiple CTC phenotypes, the clinical significance of which is unknown.
Glucose Levels and Risk of Dementia
Journal: New England Journal of Medicine (2013)

BackgroundDiabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes. MethodsWe used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension. ResultsDuring a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes,...
Optimal Post-Dose Levels of Cyclosporine A at a Higher Peak Concentration Are Correlated with the Area Under the Concentration-Time Curve of Twice-Daily Infusion and Oral Administration in Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yasuyuki Inoue, Tasuku Saito, Kohei Ogawa, Yuji Nishio, Seiju Kosugi, Yoshinori Suzuki, Yasushi Shibuya, Masayuki Kato, Masatomo Takahashi, Ikuo Miura
Journal: Blood (2009)
Impact of objective response and overall survival in patients with inoperable or metastatic gastric and esophagogastric junction (EGJ) cancer: Landmark analysis of 10-year data from first-line clinical trials.
Authors: Toki Anna Bolt, Claudia Pauligk, Dominique Werner, Ralf Dieter Hofheinz, Frank Mayer, Kim Barbara Luley, Nils Homann, Harald Schmalenberg, Matthias Egger, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2014)

57 Background: The aim of the study is to determine whether the achievement of an objective response to 1 st line chemotherapy is prognostic of patient’s outcome in gastric/EGJ adenocarcinoma. Methods: Individual patient (pts) data from prospective 1 st line trials conducted by a single study group were used. Response data, pts’ characteristics, type of chemotherapy and overall survival (OS) data were analyzed. Responses were evaluated according to WHO criteria in all trials and landmark analysis conducted. Results: Response rates were complete (CR) in 3.1%, partial (PR) in 37.7%, stable disease (SD) in 33.8% and progressive disease (PD) in 15.4% pts (9.9% were not evaluable). Overall response rate (OR= CR + PR) was 40.8%. Median OS in pts with CR vs. PR vs. SD vs. PD were 28.9 vs. 14.8 vs. 10.8 vs. 5.2 months, respectively; p= 2.6 x 10 -42 . OR also strongly predicted OS (16.7 vs. 8.6 months in pts with vs. no OR; p= 9.0 x 10 -14 ). Landmark studies were established with landmarks set on 2 and 4 months. Median OS at landmark point 2 months in pts with CR vs. PR vs. SD vs. PD were 17.3 vs. 14.5 vs. 11.1 vs. 5.4 months, respectively; p= 3,7 x 10 -12 . Pts with OR vs. no OR had a median OS of 14.7 vs. 10.9 months, p= 0.0001. Median OS at landmark point 4 months in pts with CR vs. PR vs. SD vs. PD were 23.9 vs. 14.8 vs. 11.8 vs. 7.7 months, respectively; p= 1.2 x 10 -10 . Pts with OR vs. no OR had a median OS of 16.1 vs. 11.1 months, p= 7.0 x 10 -6 . OR remained the strongest predictor of OS in the multivariate analysis (p= 6.3 x 10 -7 ) followed by the presence of non-regional LN as the only site of metastasis (p= 8.2 x 10 -5 ) and ECOG (p= 0.002). Conclusions: The achievement of an objective response is the strongest predictor of survival in pts with gastric and EGJ cancer and could serve as surrogate marker if validated.
Phase I trial of sequential decitabine plus high-dose interleukin-2 (HD IL-2) in patients with advanced melanoma
Authors: J. Gollob, M. Thoreson, T. Richmond, C. Sciambi, T. Bael
Journal: Journal of Clinical Oncology (2005)

7527 Background: The response rate of melanoma to HD IL-2 is 15%. Resistance to apoptosis in melanoma has been linked to the downregulation of Apaf-1 via DNA methylation. Reversal of this epigenetic change with the demethylating agent decitabine restores Apaf-1 expression and the sensitivity of melanoma to apoptosis. We initiated this study to determine whether the combination of decitabine with HD IL-2 was a feasible strategy for modulating the response of melanoma to IL-2. Methods: On this phase I trial, decitabine was administered SC qd x 5d on weeks 1 and 2 of a 12-week course of therapy at 5 dose levels: 0.10, 0.15, 0.2, 0.25, and 0.3 mg/kg/dose. The standard IV bolus HD IL-2 regimen, consisting of two cycles of IL-2 600,000 IU/kg IV q8hrs x 14 doses separated by a 1 week break, was administered starting on week 3, and tumor response was assessed on weeks 8 and 12. Responding patients could receive up to 3 courses of therapy. Results: 14 patients (median age 45, PS 0/1:7/7, M/F:10/4) were enrolled from August 2003-October 2004, including 7 cutaneous melanoma, 2 ocular melanoma, and 5 renal cell cancer (RCC). Transient grade 4 neutropenia during HD IL-2 was seen in 1 of 10 patients treated on the first 3 dose levels. However, grade 4 neutropenia lasting >7 days (defined as a dose-limiting toxicity) occurred during and after HD IL-2 in 2 of 3 evaluable patients at 0.25 mg/kg, establishing 0.2 mg/kg as the MTD. Among 8 melanoma patients evaluable for response, there were 2 PRs and 2 MRs (including ocular melanoma). Responses were seen in lung, lymph nodes, and soft tissue. Responders received 2–3 courses of therapy. Three evaluable RCC patients had SD. Conclusions: The combination of decitabine and HD IL-2 can be administered safely and has activity in cutaneous and ocular melanoma. Additional melanoma patients are now being treated at the MTD to better assess the response rate and biologic effects of this regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron Chiron
Reply to P.B. Singh et al
Authors: Laurence Klotz, Andrew Loblaw
Journal: Journal of Clinical Oncology (2010)

Drs Singh, Ahmed, and Emberton have expressed quite clearly the conundrum at the heart of conservative management. Accurate characterization of disease aggressivity is the key to safe and successful management of favorable-risk prostate cancer patients, most of whom are not destined to have clinical progression during their lifetime. We agree that more precise tools to identify the “bad actors” will enhance the appeal of surveillance and improve the results. For example, recent evidence suggests that many patients who harbor higher-grade cancer missed on the original peripheral zone biopsy have sizable anterior lesions. The question now is not whether to do surveillance but how to do it better. We differ with the authors who describe the current attributes of active surveillance as “not particularly attractive.” Multiparametric magnetic resonance imaging, transperineal mapping/saturation biopsies, and genomic/proteomic correlative studies need to be evaluated as strategies to improve patient selection for surveillance. However, we believe that the reported results of current surveillance series, enhanced by strategies including repeat biopsy directed at the anterior prostate and antero-lateral horn at 1 year and periodically thereafter, make surveillance both attractive and compelling to patients who understand the natural history of favorable-risk disease.
Quality improvement opportunities in prostatectomy care in a regional hospital-based urologic quality collaborative.
Authors: John L. Gore, Michael P Porter, John M. Corman, Douglas Edward Sutherland, Zeila Schmidt, David R Flum
Journal: Journal of Clinical Oncology (2014)

234 Background: Prostate cancer care is susceptible to regional variation in treatment and outcomes. Recent national recommendations have highlighted the harms of prostate cancer treatment including urinary incontinence and impotence. We prospectively evaluated radical prostatectomy (RP) outcomes at participating Washington-state hospitals to identify quality improvement opportunities in RP care. Methods: A local clinician advisory group developed a chart abstraction tool that captures potential quality concerns in RP care. The abstraction tool was implemented at nine regional hospitals with data consolidated for review quarterly. The research team and clinician advisory group were blinded to hospital identities in feedback reports. Data were analyzed as aggregate rates and hospital-specific rates without risk adjustment using descriptive statistics. Results: We identified 461 patients undergoing RP at nine area hospitals from 2011 to 2013. The majority (74%) were robot-assisted minimally invasive RPs, Participating hospitals report as many as 97% or as few as 12% robot-assisted procedures. 26.3% of cases were pathologic non-organ-confined prostate cancer (pT3 or higher); pathologic stage was not further classified beyond "T2" or "T3" in 31% of RPs. Surgical margins were positive in 18% of cases overall; hospital-specific positive margin rates ranged from 12 to 25% among organ-confined cases and 0 to 75% among stage pT3 or higher prostate cancer. Length of stay exceeded three days post-prostatectomy in more than 10% of cases at 4 hospitals including one hospital where 36% of cases had prolonged lengths of stay. Conclusions: We identified several quality improvement opportunities that may improve health outcomes among men undergoing RP for prostate cancer. Positive margin rates were excessive at some hospitals and may represent uncertainty in the surgical approach to higher risk cases. Variation in lengths of stay may represent provider variability in post-prostatectomy clinical care algorithms. Survey of provider practices may inform development of quality improvement initiatives such as clinical pathways that may address the variations in RP care identified.
Environmental organochlorine pesticide pollutants in patients with benign and malignant breast disease.
Authors: K. S. Sodhi, I. D. Sharma, A. Chaturvedi
Journal: Journal of Clinical Oncology (2011)

1545 Background: The estrogenic property of the organochlorine insecticides have focused attention on the possible role of these chemicals in breast cancer etiology. Though many countries have banned the use of these insecticides, in India they are still widely being used. Methods: We conducted a case control study in thirty women and studied levels of organochlorines (DDT and HCH) in the samples obtained from the diseased breast tissue, adipose tissue of the breast and blood. Results: The levels of organochlorine pesticides in the diseased tissue, blood and adipose tissue were significantly raised in the breast cancer patients as compared to the women with benign breast disease It was noticed in our study that the relative risk of developing breast cancer was significantly higher in the women with highest terciles of total DDT and total HCH in their adipose tissue and diseased breast tissue samples (OR 21, 95%, CI 2,983 ‘p’ 0.0052). Conclusions: Organochlorine pesticides may have a role in the causation of breast cancer. A larger population based study needs to carried forward to further strengthen our findings. If this association can be further defined it may be an important evidence to support legislation and control of use of pesticides containing these agents, in our country.
Patterns of recurrence and nodal staging in rectal cancer (Rca) patients undergoing sentinel lymph node mapping (SLNM) compared to conventional (conv.) surgery
Authors: M. Ghanem, S. Saha, E. Walsh, D. Iddings, H. Gayar, J. Nettleton, D. Wiese, S. Kaushal, M. L. Arora, T. Singh
Journal: Journal of Clinical Oncology (2008)

15004 Background: Nodal status remains one of the most important prognostic factors in RCa.SLNM has been found to upstage more patients (pts) with nodal disease compared to conv. surgery (surg). Hence, a comparative study was undertaken in R Ca pts for nodal staging and pattern of recurrence in SLNM vs. conv. surg. Methods: Group A (gpA) pts (n=75) underwent SLNM with 1% lymphazurin followed by standard oncologic resection including total mesorectal excision. Group B (gpB) pts (n=100) underwent conv. surg without SLNM. Pts with distant metastases were excluded. Data for median age, T stage, neoadjuvant (NeoAdj) treatment (Rx), nodal status, and recurrence were compared. Recurrence rate and patterns of recurrence were calculated for pts with minimum follow up of 12 months. Results: A total of 175 consecutive R Ca with a median age of 66.2 yrs were included. For 75 gpA pts, SLNM was successful in 92% of cases with 2.2 SLNs/pt. All 6 pts with SLNM failure had undergone NeoAdj Rx. Number of lymph nodes (LN) for gpA was 11.5 vs. 8.1 in gpB (p=0.01). NeoAdj Rx was received by 80% of gpA vs. 39% of gpB pts. In spite of downstaging by NeoAdj Rx, overall nodal metastases were similar in both groups (28.2% and 29.4% respectively; p=0.88). Overall recurrence rates between 60 gpA pts vs 61 gpB pts were 10% vs. 28% respectively (p=0.02; Table 1), including statistically significant differences in the number of total and distal recurrences (10% vs. 39% p<0.001; 7% vs. 28% p<0.005 respectively; Table 1). Among distant metastasis, there were less liver and lung mets in gpA vs. gpB (17% vs. 47% and 17% vs. 24% respectively). In addition, the recurrence in node -ve pts was lower for gpA compared to gpB (6.3% and 20% respectively). Conclusions: In our study, SLNM technique identifies significantly more LNs than conv. surg despite the higher use of NeoAdj Rx and its downstaging effect on SLNM pts. Both overall recurrence rates and distant recurrences were significantly lower in SLNM pts compared to conv. surg. Table 1: Recurrence rate and pattern of recurrence for Gp A (n=60) vs. Gp B (n=61) [10% and 28% respectively] Group A (SLNM) n=60 Group B (Conv) n=61 p value Pts with recurrences 6/60 (10%) 17/61 (28%) 0.02 Number of recurrences 6/60 (10%) 24/61 (39%) <0.001 Local 1/60 (2%) 4/61 (7%) NS Regional 1/60 (2%) 3/61 (5%) NS Distant 4/60 (7%) 17/61 (28%) <0.005 *Minimum follow up of 12 months for both groups, with mean follow up of 52.1 months for gp A and 43 for group B. No significant financial relationships to disclose.
NCCTG N047D: Relationship between phase II endpoints of 12 month overall survival and 6 month progression-free survival for glioblastoma multiforme (GBM) phase II trials
Authors: K. V. Ballman, K. A. Jaeckle, P. D. Brown, P. J. Flynn, J. C. Buckner
Journal: Journal of Clinical Oncology (2005)

1508 Background: Common endpoints for GBM Phase II trials are 6 mo progression-free survival (PFS6) & 12 mo OS (OS12). OS12 can be accurately measured, but may be confounded with subsequent therapies upon progression whereas the converse is true for PFS6. Our goal was to assess the relationship between these endpoints separately for Phase II trials in newly diagnosed & recurrent GBM pts. Methods: Data were pooled from 12 NCCTG trials for newly diagnosed GBM pts (n = 1359). All pts received RT and pharmaceutical therapy (pre-, during, or post-RT). Data were pooled from 16 recurrent GBM trials (n = 345) that used various pharmaceuticals. All trials were negative by design criteria. Overall per-pt concordance was estimated with a Kappa statistic. The relationship between OS12 and PFS6 across study arms was assessed by linear regression and Pearson’s correlation. Results: 97% (95%) of the newly diagnosed (recurrent) GBM pts, respectively, are dead. The OS12/PFS6 for newly diagnosed (recurrent) pts was 0.40/0.45 (0.14/0.12). There was only moderate concordance between the endpoints both per-pt and across study arms. We established Phase II efficacy criteria for each endpoint based on the pooled estimates of OS12 (PFS6). We simulated 1000 trials using the pooled data: 89% & 73% of the simulated newly diagnosed GBM trials were negative using the OS12 & PFS6 endpoints, respectively, and 80% & 57% of the recurrent GBM trials were negative using the OS12 & PFS6 endpoints, respectively. Conclusions: For newly diagnosed and recurrent GBM Phase II trials, there was only moderate concordance between PFS6 and OS12 on a per-pt and study arm basis. Furthermore, simulation showed OS12 predicts a negative result (truth) more often than PFS6. Assuming minimal survival impact of additional therapies, these results suggest OS12 is a better endpoint for GBM Phase II clinical trials in both newly diagnosed and recurrent GBM. No significant financial relationships to disclose.
Abstract 286: Long Noncoding RNAs Are Differentially Expressed in Heart Failure
Authors: Emma L Robinson, Syed Haider, Hillary Hei, Richard T Lee, Roger S Foo
Journal: Circulation Research (2012)

Heart failure comprises of clinically distinct inciting causes but a consistent pattern of change in myocardial gene expression supports the hypothesis that unifying biochemical mechanisms underlie disease progression. The recent RNA-seq revolution has enabled whole transcriptome profiling, using deep-sequencing technologies. Up to 70% of the genome is now known to be transcribed into RNA, a significant proportion of which is long non-coding RNAs (lncRNAs), defined as polyribonucleotides of ≥200 nucleotides. This project aims to discover whether the myocardium expression of lncRNAs changes in the failing heart. Paired end RNA-seq from a 300-400bp library of ‘stretched’ mouse myocyte total RNA was carried out to generate 76-mer sequence reads. Mechanically stretching myocytes with equibiaxial stretch apparatus mimics pathological hypertrophy in the heart. Transcripts were assembled and aligned to reference genome mm9 (UCSC), abundance determined and differential expression of novel transcripts and alternative splice variants were compared with that of control (non-stretched) mouse myocytes. Five novel transcripts have been identified in our RNA-seq that are differentially expressed in stretched myocytes compared with non-stretched. These are regions of the genome that are currently unannotated and potentially are transcribed into non-coding RNAs. Roles of known lncRNAs include control of gene expression, either by direct interaction with complementary regions of the genome or association with chromatin remodelling complexes which act on the epigenome.Changes in expression of genes which contribute to the deterioration of the failing heart could be due to the actions of these novel lncRNAs, immediately suggesting a target for new pharmaceuticals. Changes in the expression of these novel transcripts will be validated in a larger sample size of stretched myocytes vs non-stretched myocytes as well as in the hearts of transverse aortic constriction (TAC) mice vs Sham (surgical procedure without the aortic banding). In vivo investigations will then be carried out, using siLNA antisense technology to silence novel lncRNAs in mice.
Capecitabin (Cap) compared with flurorouracil (5FU)-leucovorin (LV) as concurrent chemotherapy for preoperative chemoradiation (preop CRT) in rectal cancers: A retrospective study.
Authors: B. Schipman, T. Nguyen, M. Mercier, C. Borg, J. Miny, J. Bosset
Journal: Journal of Clinical Oncology (2011)

606 Background: The aim was to compare acute toxicities, compliance to treatment and tumor response after preoperative chemoradiation between two different regimen of concurrent chemotherapy, Cap or 5FU-LV, for the treatment of locally advanced rectal cancers. Methods: Patients with a resectable rectal cancer (T3-4, N0-2) treated from 1993 to 2006 were included. We compared two groups of patients. One treated with preop CRT including 5FU-LV (5FU 350 mg/m 2 short IV infusion daily for 5 days - week 1 and 5. LV IV push 20mg/m 2 with 5FU. RT 45 Gy 1.8 Gy/F over 5 weeks). The second group received the same RT scheme. 5FU-LV were substitute for Cap 850 mg/m 2 twice daily along the RT except week-end. Results: 101 patients received 5 FU-LV and 51 patients Cap. Patients and tumour characteristics were similar. Grade 3-4 acute toxicities rates (especially leucopenia and diarrheas) after chemoradiation were 4 and 9.8% for 5 FU-LV and Cap respectively (p=0.16). Chemotherapy was modified for toxicities (dose reduction or interruption) in 5.9 and 17.6% of patients receiving 5 FU-LV and Cap respectively (p=0.04). Radiotherapy was stopped in 7.9 and 3.9% of patients treated by 5 FU-LV and Cap respectively (p=0.50). Complete histological response rates were 10.3 and 6% (p=0.54), tumour regression (downstaging) rates were 44.3 and 41.2% (p=0.73) for patients treated by 5 FU-LV and Cap respectively. Conclusions: In this retrospective analysis CRT with Cap obtained a similar tumor effect to the 5 FU-LV scheme. However the Cap scheme induced more grade 3-4 toxicities had no impact on the RT compliance but conducted to modify more frequently the chemotherapy scheme. No significant financial relationships to disclose.