tbuckley/cabot-search huggingface dataset:
Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial.
Authors: Andrew J. Armstrong, Michael Haggman, Walter Michael Stadler, Jeffrey R. Gingrich, Vasily J. Assikis, Jonathan Polikoff, Samuel R. Denmeade, Daniel J. George, Cal Andreou, William R. Clark, Paul Sieber, Richy Agajanian, Laurence Belkoff, Jan-Erik Damber, Orjan Nordle, Goran Forsberg, Michael Anthony Carducci, Roberto Pili
Journal: Journal of Clinical Oncology (2012)

4550 Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative that binds S100A9 protein and has preclinical anti-angiogenic and anti-tumor activity. Between 12/07-6/09, 201 (134 T, 67 Placebo (P)) men with metastatic CRPC were randomized and received treatment once-daily at an initial dose of 0.25 mg/day escalated to 1.0 mg/day over 4 weeks. Placebo patients could cross over to T after 6 months or at disease progression. The primary endpoint of improved PCWG2 criteria-defined progression at 6 months was met (69 vs. 37% of patients (T/P) were progression free) with PFS of 7.6 vs. 3.3 months for pts on T vs. P 1 with acceptable toxicity. This abstract provides the first analysis on symptomatic progression, overall survival (OS) as well as a multivariate analysis for PFS and OS. Methods: Survival data were collected between June 2011 and January 2012 with a median time to censoring of 32 months. Survival data was also evaluated in an exploratory multivariate model of known prognostic factors in CRPC. Results: An imbalance of several baseline prognostic criteria favored placebo (e.g. baseline PSA of 29 vs. 19 (T/P)) (JCO 2011;20:4022). Time to symptomatic progression was longer in T treated patients (p=0.039, HR=0.42). Record of death (97 events) or survival &gt;13 months was documented in 182 patients. Median time to death was 34.2 vs. 30.2 months (T/P). Median time to death in the PCWG2 bone-metastatic subgroup (N=92/44) was 34.2 vs. 25.6 months. A multivariate analysis of known prognostic factors including PSA, LDH, PSA kinetics, and hemoglobin demonstrated an adjusted HR for PFS of 0.54 (95% CI 0.37,0.81) and OS of 0.72 (95% CI 0.46,1.12) in the total population and 0.63 (95% CI 0.37,1.07, n=136) in the bone-metastatic group. Conclusions: OS observed after tasquinimod treatment is longer than previously reported in this patient population. The current exploratory data indicates that the prolongation in PFS observed with tasquinimod treatment may lead to a survival advantage in men with metastatic CRPC. A phase III placebo-controlled study (NCT01234311) is ongoing in men with bone-metastatic CRPC powered to detect an OS improvement.
Fire, in the Kingdom of Animals
Authors: Ian Wicks
Journal: JAMA (2017)

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Clinical and sociodemographic data of cancer patients seeking out-patient based psycho-oncological psychotherapy.
Authors: Jens Peter Panse, Evangelia Athanatou, Clarissa Kayser, Marike Anna Simon, Susanne Singer, Tim H. Brummendorf, Andrea Petermann-Meyer
Journal: Journal of Clinical Oncology (2012)

e19610 Background: Although there is a defined need for out-patient psychosocial care for cancer patients, data about out-patient psycho-oncological health care services and patients’ usage of ambulatory infrastructure outside certified cancer centres are scarce. Methods: We retrospectively analyzed charts and treatment protocols from 1,369 patients treated between 1998 and 2009 in a psycho-oncology (PO) practice retrieving socio-demographic and cancer-specific data plus data regarding PO intervention. Results: Of 1,180 patients analysed so far, 808 were documented cancer patients and 372 were relatives or friends of cancer patients. Median age of cancer patients was 50 (range 21-81) years, the majority being female (91%). Although PO interventions are not generally covered by most health care insurances in Germany, 87.7% of patients had public health insurance and only 12.7% had private insurance. 62,5% of patients (n=505) were diagnosed with breast cancer, followed by colorectal cancer (n=46), ovarian cancer (n=42), leukemia/lymphoma (n=38) and lung cancer (n=34), although all types of malignancies were represented. 60.1% received curative and 20.3% palliative treatment, while 19.6% could not specify their treatment intention. 503/663 (n=186 not specified) patients had at least one child with 39.5% being less than 18 years of age. 75.9% (176/232) had received high school education, and 37.1% (151/407) were actively working, while 40.3% (164/407) were incapable of work or on retirement pay (22.6%, 92/407). Half of the patients (50.2%) were Aachen residents, while the other half resided within a 50 km radius. Median number of therapy sessions was 12 (range 1-97). Other treatment specific aspects are still being analysed and will be presented at the meeting. Conclusions: Despite the clear demand for all cancer patients, the majority of cancer patients actively seeking out-patient psycho-oncological support are women with breast cancer, while men and other cancer subtypes are clearly underrepresented. Better information, optimized resources, allocation strategies and comprehensive coverage of PO services are needed in order to address more cancer patients with psycho-social distress.
Comparison of microfilter-based capture to CellSearch in detection of circulating tumor cells (CTCs) in patients with metastatic castration-resistant prostate cancer (mCRPCa).
Authors: Christos Kyriakopoulos, Paul Elson, Ernest C. Borden, Anthony Williams, Zheng Ao, Siddarth Rawal, Ram H Datar, Richard J. Cote, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2014)

e22018 Background: CTCs can be detected in the blood of men with prostate cancer and have been used as a biomarker. The only FDA-approved technology (CellSearch) utilizes epithelial cell adhesion molecule (EpCAM) expression for CTC detection. Methods: We aimed to detect CTCs in the blood of patients with mCRPCa using both CellSearch and a novel microfilter-based device. Detection by CellSearch was performed according to standard protocol. For the microfilter-based capture peripheral blood from mCRPCa patients was diluted 1:1 with PBS and 1% formalin. Cells were captured with microfilters and subsequently stained with pancytokeratin (CK) and CD45. CTCs were identified as large CK+/CD45- events with morphologic criteria consistent with a tumor cell. Data were analyzed using non-parametric methods: Spearman rank correlations, Mann-Whitney test, and the Jonckheere-Terpstra test. Results: Forty-one patients with mCRPCa were tested for CTCs using both methods. The median age was 65 years (range, 42-87). The majority of patients had high Gleason Score (56% with >7 vs. 31% with 7 vs. 14% with <7), low performance status (42% KPS <90 vs. 30% KPS of 90 vs. 28% KPS of 100) and bone metastasis (80% bone metastasis vs. 22% visceral metastasis or both). The median PSA at the time of the blood drawn was 31.36 (range, 0.04-1667) with a median PSA doubling time of 3.79 months (range, 0.57-68.95 months). CTC detection by the two methods was concordant in 74% of patients. Detection by CellSearch was positively associated with PSA (p=0.007) and alkaline phosphatase (p=0.0005) and negatively associated with PSA doubling time (p=0.04) and KPS (p=0.004). Similar associations were not seen with the microfilter-based technology; however microfileter-based detection was positively correlated with lymph node metastasis (p=0.04) and there was some suggestion of an association with both bone and visceral metastasis (p=0.07). Conclusions: Microfliter-based technology is an effective method for the detection of CTCs in mCRPCa. More studies are needed to evaluate the association of CTC detection by this method with disease parameters and clinical outcome.
Abstract 17509: The Influence of Chronic Total Occlusion Recanalization on Fractional Flow Reserve Value of Collateral Donor Artery
Authors: Akinori Sumiyoshi, Kenichi Fujii, Masahiko Shibuya, Takahiro Imanaka, Kenji Kawai, Hiroto Tamaru, Tetsuo Horimatsu, Ten Saita, Machiko Nishimura, Tohru Masuyama, Masaharu Ishihara
Journal: Circulation (2015)

Background: Although recent guidelines recommend the use of fractional flow reserve (FFR) measurements to make decisions for patients with multi-vessel disease and borderline lesions, the presence of a concomitant chronic total coronary occlusion (CTO) may alter the FFR of the interrogated vessel due to collateral circulation. The purpose of this study was to investigate the change in donor artery FFR associated with PCI of a concomitant CTO. Methods: Nineteen consecutive patients who underwent PCI for CTO lesions were prospectively enrolled. All patients underwent myocardial stress perfusion scintigraphy before PCI. An intracoronary pressure/temperature sensor-tipped wire was advanced through a guiding catheter to a point 7cm distal from the ostium of both non-target arteries. At steady-state hyperemia, hemodynamics including FFR and the hyperemic mean transit time (Tmn), which are inversely proportional to coronary flow velocity, were calculated before and immediately after PCI. Coronary blood flow (CBF) was calculated as 1/Tmn х π х (diameter/2) 2 . Coronary wedge pressure was also measured after 30 s of balloon occlusion within the stented segment of the target arteries after PCI. Results: The average FFR values of the donor artery before PCI were 0.89±0.09. None of patients had signs of ischemia in the territory of the donor arteries, even though five patients had an FFR value of &lt;0.80 in the donor arteries. After the successful recanalization of the target arteries, FFR values in the donor artery increased to 0.95±0.06 (mean difference, 0.06 [0.04 to 0.09]: p &lt;0.001). On the other hand, CBF in the donor artery significantly decreased from 35.5±15.7 to 25.7±13.8 (p=0.02). No linear correlation was identified between the change of FFR in the donor artery and coronary wedge pressure in the occluded artery (r= -0.05, p= 0.78). Conclusions: Revascularization of a CTO lesion provides moderate increase in the FFR value of the collateral donor artery as a result of the reduction of coronary blood flow. Therefore, the hemodynamic significance of intermediate stenosis in the donor artery by FFR should be carefully evaluated in the presence of CTO.
Engineering Resistance to Antigen-Specific Immunotherapy in Normal Hematopoietic Stem Cells By Gene Editing to Enable Targeting of Acute Myeloid Leukemia
Authors: Miriam Y Kim, Saad S Kenderian, Daniel Schreeder, Michael Klichinsky, Miroslaw Kozlowski, Olga Shestova, Marco Ruella, Saar I Gill
Journal: Blood (2016)
Effect of adjuvant trastuzumab (Tadj) therapy (Tx) for early-stage breast cancer (ESBC) on demographics, survival and likelihood of durable complete response (DCR) of HER2+ metastatic breast cancer (HMBC): A 15-year study.
Authors: Alessandra Zacchia, Giuseppe Gullo, Imelda Parker, Annamaria De Giorgi, David William Fennelly, Daniele Zanoni, Janice Maria Walshe, Anne Marie Defrein, Nuno Silva, Norma O'Donovan, Josephine Ballot, Enda McDermott, John P Crown
Journal: Journal of Clinical Oncology (2015)

e11604 Background: We hypothesize that in addition to its powerful effect on the outcome of patients (pts) with HESBC, Tadj has also altered the epidemiology and prognosis of pts with HMBC. Methods: We constructed a database of 742 pts treated with Tadj (224 HMBC since 2000, 518 HESBC [trials 2001-2004, routinely since 2005]). We conducted a cohort analysis of all HMBC treated between January 2000 and December 2014. We compared incidence of de novo (DN) versus relapsed (R) HMBC, and overall survival (OS) between DN versus R and across cohorts. Results: Cohort 1 (Jan 2000 – Dec 2004: 67 pts), Cohort 2 (Jan 2005 – Dec 2009: 85 pts), Cohort 3 (Jan 2010 – Dec 2014: 72 pts). The proportion of pts with R HMBC decreased (I-84% vs. II-64% vs. III-57%) whereas the proportion with DN increased (I-16% vs. II-36% vs. III-43%, p < 0.01). DN pts had significantly improved median OS (58m, [95%CI: 26-90]) compared to R (29m [21-37]), p < 0.001 log rank. Median OS improved from Cohort 1 to Cohort 3. Best Objective Response (OR) to antiHER2 Tx was evaluable on 214 pts and defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD) according to RECIST 1.1. In the 3 Cohorts combined OR was a strong predictor of (median) OS [95%CI]: CR 163 [92-234], PR/SD 41 [36-46], PD 16 [11-21] mos [p < 0.001]. CR was obtained in 31 pts (14%), 21 never relapsed. The likelihood of CR was significantly correlated with DN and single site of metastasis (excl bone-only). Median OS of CR pts treated before 2005 is 128mos [95%CI: 46-210] but median OS has been not yet reached for pts treated after 2005, though likely to be superior. Conclusions: (1) Tadj has changed the demographics of HMBC, with a significant increase in the proportion with DN. (2) DN pts have significantly better OS compared to R. (3) DCR is significantly more likely in DN versus R. (4) OS of pts with HMBC has significantly improved with time (across cohorts) despite equal access to HTx, likely due to improved post relapse HTx and by increasing %DN. (5) Changing HMBC characteristics complicate interpretation of trials that accrued in pre-Tadj era.
Biomarker and in vitro chemoresistance profiles of undifferentiated ovarian cancers
Authors: J. K. Chan, D. S. Kapp, E. Mechetner, I. Yu
Journal: Journal of Clinical Oncology (2007)

2532 Background: To determine the biomarker expression and drug resistance patterns of undifferentiated ovarian cancers. Methods: Biomarker expression was determined by immunohistochemistry. In vitro drug resistance profiles were analyzed by assays exposing tumors to suprapharmacologic doses of chemotherapy. Results: Of 177 ovarian cancer specimens, 63 were classified as undifferentiated tumors and 114 well-differentiated cancers were used for comparison. Of the undifferentiated tumors, 46.7% were primary cancers and the remainder were recurrent cancers. Most of the well-differentiated tumors were obtained from primary (82%) vs. recurrent disease specimens. The average DNA index and S-phase fraction were significantly higher in the undifferentiated vs. well-differentiated tumors (1.42 vs. 1.23, p=0.025 for DNA index; 1.69 vs. 3.06, p&lt;0.0001 for S phase fraction). In addition, the percent of tumors with p53 mutations was also higher in the undifferentiated compared to the well-differentiated tumors (47.8% vs. 17.8%; p=0.005). The mean percent cell inhibition was significantly lower in the undifferentiated tumors compared to well-differentiated cancers after exposure to etoposide (54%±21 vs. 80%±18; p=0.0002), doxorubicin (59%±28 vs. 80.0%±21; p=0.07), and topotecan (61.7%±20 vs. 71%±21; p=0.015). Compared to well-differentiated tumors, undifferentiated tumors tended to be more resistant to etoposide (40% vs. 11%), doxorubicin (22% vs. 9%), and topotecan (19% vs. 16%). However, the drug resistance patterns after exposure to taxanes (paclitaxel and taxotere) and platinums (carboplatin and cisplatin) were similar. Conclusions: Undifferentiated tumors of the ovary have a significantly different biomarker expression and drug resistance profiles compared to well-differentiated tumors. Given that undifferentiated cancers provide a treatment challenge for the clinician, this data can provide additional prognostic and therapeutic information, and warrants further investigation. No significant financial relationships to disclose.
Is fluid overload a target to treat sleep disordered breathing in patients with end-stage renal disease, and what are the underlying mechanisms?
Authors: Michael Arzt, Danny J. Eckert
Journal: European Respiratory Journal (2017)

Sleep problems are more common in patients with renal failure compared to populations without overt severe comorbidities. Both central and obstructive forms of sleep disordered breathing (SDB) are present in patients with renal failure [1, 2]. Other sleep problems, including restless leg syndrome, periodic limb movement syndrome and insomnia, also occur at high rates in this population. As the severity of renal impairment increases so too does the prevalence and severity of sleep disorders [3, 4]. Indeed, in end-stage renal disease, significant SDB (apnoea–hypopnoea index ≥15 per hour sleep) can occur in up to 70% of cases, regardless of whether such patients are on haemodialysis or peritoneal dialysis [5, 6]. In patients with end-stage renal disease fluid overload contributes to the development of sleep disordered breathing <http://ow.ly/dEve309KM6s>
Frequency of Hsa-miR9 aberrant methylation in metastatic breast cancers.
Authors: Paola Parrella, Anca Florescu, Massimiliano Copetti, Roberto Murgo, Vanna Maria Valori, Marina Castelvetere, Tiziana Pia Latiano, Carmela D'Addetta, Vito Michele Fazio, Evaristo Maiello
Journal: Journal of Clinical Oncology (2012)

e21092 Background: MicroRNAs (miRNAs) are a recently discovered class of very small non-coding RNAs involved in the regulation of gene expression by interfereing with mRNA translation. It has been shown that human miR-9 expression levels are reduced in breast cancer samples due to the aberrant methylation of its promoter region . Methods: We analyzed74breast cancer cases treated by surgery at the IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. Pathological assessment included evaluation of histological type, grade and stage. Estrogen receptor (ER), progesterone receptor (PgR), Ki-67 labeling index and Her2 amplification were also evaluated. Six of the 74 patients showed metastases at the diagnosis, and 8 patients developed metastases during the follow up. The median follow up time for the patients cohort was 44 months (range 28-57+). All metastatic patients (n=14) died from the disease. Genomic DNA extracted from 6 normal breast tissues obtained by reductive mammoplasty, and tumour samples was subjected to bisulphite treatment and the converted DNA was used as a template for MSP using primers specific for the methylated hsa-miR9 sequence. Results: Methylation at the hsa-miR9 promoter region was detected in 33 of 74 (44%) breast tumours and none of the 6 normal breast tissues (p=0.02). Interestingly, hsa-miR9 methylation was significantly more frequent in patients with syncronous or metachronous distant metastases (8 of 14, 57%) as compared with patients free from metastases (11 of 33, 32%) (p=0.02 χ 2 Test). In particular, methylation was detected in all 5 tumours showing only bone metastases (100%), whereas methylation was less frequent (33%) in the group characterized by the the presence of visceral metastases (P=0.03 χ 2 Test). Conclusions: Our results suggest that hsa-miR9 methylation in breast cancer is associated with tumour metastatic behaviour and might represent a novel biomarker for monitoring breast cancer patients.
A phase I and pharmacokinetic study of rubitecan, an orally administered topoisomerase I (topo-I) inhibitor, combined with gemcitabine in patients with advanced cancer
Authors: E. Calvo, E. K. Rowinsky, A. W. Tolcher, Q. S. Chu, M. Beeram, L. Forero, K. L. Mettinger, E. Eastham, A. D. Goetz, A. Patnaik
Journal: Journal of Clinical Oncology (2004)

2099 Background: Rubitecan, an oral camptothecin analogue and potent inhibitor of topo-I, has demonstrated clinical activity in gemcitabine-sensitive malignancies, such as pancreas, breast, ovarian or urothelial tumors, as well as gemcitabine-resistant cancers. There is preclinical evidence of synergism between topo-I inhibitors and gemcitabine and nonoverlapping toxicities, which provide a rationale for their evaluation in combination. Patients (pts) and Methods: Escalating oral doses of rubitecan from a starting dose level of 1.0 mg/m2/day x 5 days every 7 days x 3 weeks, with a fixed dose of gemcitabine 1000 mg/m2 IV on days 1, 8 and 15, every 28 days, were administered to minimally-pretreated patients with advanced solid malignancies. Results: To date, 24 pts (median age 58, [30–75]; 13 male/11 female; pancreas/cholangiocarcinoma \(\frac{12}{3}\), colon [2], esophagus [2], unknown primary adenoca [2], other [3]) have received 94 courses (range 0–17) at rubitecan dose levels of 1.0 mg/m2/day (5 pts), 1.25 mg/m2/day (9 pts), and 1.5 mg/m2/day (10 pts) with full doses of gemcitabine. DLTs have been gr 3 vomiting (1 pt), and gr 3/4 thrombocytopenia (2 pts) at 1.25 mg/m2/day; and febrile neutropenia (1pt) and gr 3 transaminase elevation (1pt) at 1.5 mg/m2/day. Toxicities are mostly mild to moderate, except non dose-limiting gr 4 neutropenia (21%), gr 3 transaminitis (8%), gr 3 diarrhea (8%), and gr 3 fatigue, vomiting, cystitis, weight loss, and epistaxis (each 4%). Patient accrual continues at 1.0 mg/m2 of rubitecan. 9-NC and gemcitabine AUCs (n=14 pts) increased with increasing dose levels. No drug-drug interactions were identified. Overall clearance of 9-NC and Gemcitabine were 9382.5 mL/hr and 314.3 mL/hr, respectively. A partial response has been observed in 2 pts with pancreas cancer, 1 gemcitabine-refractory, and 1 pt with esophagus cancer. 9 pts have stable disease lasting 4+-18+ months (pancreas, cholangio, colon, lung, H&N). Conclusions: Disease-directed evaluations of this safe and feasible regimen are planned in upper GI malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Supergen Supergen