tbuckley/cabot-search huggingface dataset:
Phase I study of CNTO 95, a fully human monoclonal antibody to α<sub>v</sub> integrins, docetaxel, and prednisone in hormone refractory prostate cancer patients (HRPCP)
Authors: F. M. Chu, J. Picus, M. Mata, C. Kopacynski, B. Foster, Z. Lang, R. A. Beckman, R. Dreicer
Journal: Journal of Clinical Oncology (2007)

15595 Background: CNTO 95 has demonstrated preclinical antitumor activity through binding to multiple a v integrins, resulting in growth inhibition indirectly through anti-angiogenic effects as well as directly by inhibiting tumor cell proliferation. The target, a v integrins, has been demonstrated by immunohistochemistry in a large proportion of human prostate cancer tissues. Docetaxel and prednisone have become a standard of care for HRPCP. The primary objective of this study was to evaluate the safety of combining CNTO 95 with this standard. Methods: Patients received day 1 infusions of 75 mg/m 2 docetaxel together with twice daily oral prednisone in every 3 week cycles, with weekly infusions of either 5 or 10 mg/kg of CNTO 95 for 7 weeks beginning with the second docetaxel cycle, then CNTO 95 on the days of docetaxel thereafter. Patients were monitored for safety and PSA. Radiologic tumor assessments were performed at least every 4 cycles. Results: Six patients have received docetaxel and prednisone with CNTO 95 at either 5 mg/kg (n=3) or 10 mg/kg (n=3). In the 5 mg/kg group, 1 received 8 cycles then withdrew consent because of fluctuating PSA levels; 1 received 9 cycles then had soft tissue disease progression; and 1 has completed 9 cycles and remains on study treatment. In the 10 mg/kg group, all patients remain on study and have received 7, 6, and 6 cycles of treatment, respectively. There were no unexpected toxicities and only one Grade 3 toxicity (febrile neutropenia) attributed to docetaxel. A 50% decline in PSA occurred in 1 patient treated in the 10 mg/kg group. Conclusions: The combination of standard dose docetaxel and prednisone with 10 mg/kg of CNTO 95 was well tolerated and 3 new patients are planned to be treated with these doses on this study. Further study is warranted. [Table: see text]
Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease
Authors: Julien Adjedj, Bernard De Bruyne, Vincent Floré, Giuseppe Di Gioia, Angela Ferrara, Mariano Pellicano, Gabor G. Toth, Jozef Bartunek, Marc Vanderheyden, Guy R. Heyndrickx, William Wijns, Emanuele Barbato
Journal: Circulation (2016)

Background— The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, whereas the FFR value of 0.80 has been widely accepted to guide clinical decision making. However, revascularization when FFR is 0.76 to 0.80, within the so-called gray zone, is still debatable. Methods and Results— From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the 2 neighboring FFR strata (0.70–0.75 and 0.81–0.85) were included. Study end points consisted of major adverse cardiovascular events (death, myocardial infarction, and any revascularization) up to 5 years. Of 17 380 FFR measurements, 1459 patients were included. Of them, 449 patients were treated with revascularization and 1010 patients were treated with medical therapy. In the gray zone, the major adverse cardiovascular events rate was similar (37 [13.9%] versus 21 [11.2%], respectively; P =0.3) between medical therapy and revascularization, whereas a strong trend toward a higher rate of death or myocardial infarction (25 [9.4] versus 9 [4.8], P =0.06) and overall death (20 [7.5] versus 6 [3.2], P =0.059) was observed in the medical therapy group. Among medical therapy patients, a significant step-up increase in major adverse cardiovascular events rate was observed across the 3 FFR strata, especially with proximal lesion location. In revascularization patients, the major adverse cardiovascular events rate was not different across the 3 FFR strata. Conclusions— FFR in and around the gray zone bears a major prognostic value, especially in proximal lesions. These data confirm that FFR≤0.80 is valid to guide clinical decision making.
Discussing goals of care preoperatively in high-risk oncologic surgery.
Authors: Chris McGreevy, Anastasia Kunac, Ravi Chokshi, Janet Harris Smith, Debra Mazza, Anne C Mosenthal
Journal: Journal of Clinical Oncology (2015)

38 Background: Major oncologic surgery has a high incidence of perioperative morbidity. Despite these risks, most surgeons do not discuss goals of care prior to surgery. This study assessed the feasibility of a preoperative goals of care discussion for high risk oncologic surgery. Methods: Observational study of patients undergoing high risk surgery. Prior to surgery, patients were referred for consultation with a surgeon certified in both Palliative and Critical Care. Consultations followed a semi-structured template (table). Patient and conversation outcomes were assessed, and qualitative analysis of consult notes was performed to identify themes. Results: Twelve patients were approached and 11 participated. Mean time between consultation and surgery was 7 days (1-36). All patients named a health care proxy and expressed goals of care. Most (8/11) specified their preferences for life support. Themes included hope –surgery will return them to independence/home; fear – pain, anxiety; and faith–“it is up to God” as reason for not discussing suboptimal surgical outcomes. One patient declined surgery after discussion and transitioned to hospice. Ten survived to discharge: 6 to home (2 with hospice), 4 to rehab. Conclusions: Preoperative goals of care discussions are feasible for high risk oncologic surgery patients. Eliciting goals of care helped clarify wishes for life sustaining therapy. Goals of care discussions do not destroy hope, but can reveal unrealistic expectations for surgery and outcomes. [Table: see text]
Current status of targeted agents in advanced pancreatic cancer (APC): A pooled analysis of 2,361 patients (pts) enrolled in six phase III trials
Authors: E. Bria, P. Carlini, A. Gelibter, E. Ruggeri, A. Ceribelli, M. Pino, E. Terzoli, F. Cognetti, D. Giannarelli, M. Milella
Journal: Journal of Clinical Oncology (2006)

4126 Background: Molecular targeting of pathways that are deregulated in pancreatic cancer is a promising approach aimed at improving the dismal prognosis of APC pts. However, the clinical impact of novel “biological” drugs (ND) remains to be defined. Methods: All prospective phase III trials comparing single-agent Gemcitabine (G) with either a ND or a combination of ND and G (ND+G) were considered eligible. A pooled analysis was performed and event-based relative risk ratios (RR) with 95% CI were derived through both a fixed- and a random-effect model approach, exploring OS as the primary outcome and PFS and ORR as secondary outcomes. Heterogeneity between different trials was also taken into account. Results: Six trials involving 2361 pts were identified; ND tested included: FTI inhibitors (1 trial), MMP inhibitors (3 trials), EGFR inhibitors (1 trial), and anti-gastrin vaccine (1 trial). The analysis was conducted considering three different subgroups: 1) overall population (2361 patients, 6 trials), 2) ND+G vs G (1879 patients, 4 trials), and 3) ND vs G (482 patients, 2 trials). As shown in the table, no significant differences in either the primary outcome (OS) or the secondary outcome of PFS were observed in the overall population as well as in ND+G vs G trials, while a significant negative trend for ND was found in ND vs G trials with regard to both endpoints. Conversely the evaluation of the secondary endpoint of ORR significantly favored G in the overall population as well as in ND vs G trials, while a not significant negative trend for ND was observed in ND+G vs G trials. Conclusions: G remains the treatment of choice in APC pts. The ND tested, either alone or combined with G, do not seem to add any benefit over G. A better understanding of pancreatic cancer biology and further clinical evaluation of new agents and is needed to improve prognosis in APC pts. [Table: see text] No significant financial relationships to disclose.
Same day diagnosis of breast cancer: Method of validation
Authors: M. Graudenz, D. Duarte Filho, J. M. Zignani, E. C. Dias, L. P. Antunes, A. B. Junior, B. Weber, M. Caleffi
Journal: Journal of Clinical Oncology (2005)

782 Background: Microwave-assisted tissue processing is a rapid method of histological analysis, with an acceptable quality and great impact on the timeliness of diagnostic surgical pathology. Few data exist comparing pathological diagnosis accuracy and quality of microwave-processed biopsy tissue with that processed by conventional techniques. Methods: A prospective pilot study of 40 consecutive patients referred to core breast biopsy guided by ultrasound due to abnormal breast mammography/ultrasound/clinical findings was conducted. Inclusion criteria were BIRADS US classification≥III, breast tissue biopsy and informed consent. Exclusions: Patients with microcalcifications only at mammogram. Half of the biopsy fragments was processed routinely overnight (CO), while the other half was processed by the rapid microwave technique (MW). The H&E slides were compared for diagnosis accuracy and quality of preparation in a blinded fashion. Hormonal receptor (HR) expression in cancer biopsies was also analysed. Results: The mean age was 47y-o±11, mean tumor size 1.49cm±1.12 and mean number of biopsy fragments in the MW group (3.65±3 cm) versus CO group (3.81±1.33 cm). 26 cases were BI-RADS III; 9 IV and 8 V. No difference was found between the mean sizes of biopsy fragments in the MW group (3.65±3 cm) versus CO group (3.81±1.33 cm). No biopsy complications were observed in either group. Final pathological diagnoses were 15 invasive breast cancers, 27 benign/normal conditions and 1 atypical suspicious case. The diagnosis correlation between CO and MW was excellent (Pearson’s R=1,0); 8 MW-processed specimens (5MW and 3CO) were judged as suboptimal but none was unsatisfactory for evaluation. In the remaining cases, the material obtained by the 2 techniques was considered of identical quality. There was one false negative case, confirmed later as cancer in the setorectomy speciemen) diagnosed as normal/benign in both Methods: Correlation rate of HR detection by immunohistochemistry was weak (Pearson’s R=0,529) favoring CO Method: Conclusions: The H&E quality of rapidly processed sections was comparable to those obtained with CO processing. MW processing and H&E staining is appropriate for a quick and safe pathology diagnosis method for breast cancer. No significant financial relationships to disclose.
Reply to M.G. McNamara et al and T.H. Oo
Authors: Gary H. Lyman, Nicole M. Kuderer
Journal: Journal of Clinical Oncology (2016)

The recent publication of the long-awaited final results of the CONKO-004 (Prospective Randomized Trial of Simultaneous Pancreatic Cancer Treatment With Enoxaparin and Chemotherapy) of thromboprophylaxis in ambulatory patients with advanced pancreatic cancer (APC) has generated considered interest, as illustrated by the letters submitted by Oo and McNamara and colleagues. 1,2The authors of these letters raise several interesting and important issues, many of which were further discussed in our editorial published in the same issue of the Journal of Clinical Oncology along with CONKO-004 findings. 3,4owever, although the authors highlight inconsistencies and other limitations of the clinical trial, some of the concerns expressed deserve further discussion.In addition, the results and limitations discussed should be placed in the context of the recently updated guidelines on cancer and thrombosis from the ASCO. 5,6s mentioned in the editorial and highlighted by both Oo and McNamara et al, [1][2][3] several discrepancies are apparent between the final published results of CONKO-004 and the original presentation of the final results at the 2009 ASCO Annual Meeting. 7These variances include differences in reported patient eligibility, the number of symptomatic venous thromboembolism (VTE) events, and the number of major bleeding events reported in each arm of the trial.Both letters appropriately mention that the authors do not report the rates of VTE in the two separate chemotherapy regimens, which may be relevant given the recognized thrombogenicity of cisplatin.Importantly, however, any such post hoc subgroup analysis would be purely exploratory or hypothesis generating because regimen administration was driven by baseline performance status and renal function. 4Although Oo calls for greater focus on economic considerations in practice guidelines, current recommendation against routine thromboprophylaxis in ambulatory patients with cancer is based on the limitations of available evidence on efficacy and safety, and full consideration of the appropriate balance of benefits and harms in this setting. 6However, current guidelines do encourage careful selection of patients at particularly high risk for VTE, based on recognized risk factors and models who may be candidates for prophylactic anticoagulation based on favorable risk-benefit considerations. 6vailable data, including separate analysis of the CONKO-004 study population, suggests that the risk for VTE is considerably
A phase II study of accelerated high-dose thoracic radiation therapy (AHTRT) with concurrent chemotherapy for limited small cell lung cancer: RTOG 0239
Authors: R. Komaki, R. Paulus, D. S. Ettinger, G. M. Videtic, J. D. Bradley, B. S. Glisson, H. Choy
Journal: Journal of Clinical Oncology (2009)

7527 Background: Inter-group(IG) study 0096 showed that hyperfractionated and accelerated radiotherapy (HFXART) and concurrent etoposide/cisplatin(EP) improved 5-yr survival (26 %) for patients (pts) with limited small cell lung cancer (LSCLC) compared to daily treatment (TRT) with EP (16%), (p=0.04), HFXART/ EP still had high local failure (LF 40 %) and acute severe esophagitis (ASE) rate (27%). Radiation Therapy Oncology Group (RTOG) 0239 was developed to improve local control (LC) and overall survival (OS) without increasing ASE.Methods: Eligibility included limited stage SCLC, age ≥ 18; P.S. 0–1, with adequate hematologic, hepatic, and renal function. RT was given to large field to 28.8 Gy: 1.8 Gy/ fraction (Fx), 5 days (d) / wk for 16 Fx followed by BID with AP/PA fields in AM @ 1.8 Gy /Fx; boost with 2 nd treatment in PM @ 1.8 Gy/Fx on d: 23–26; then off-cord boost, 1.8 Gy, BID, x last 5 days for a total dose of 61.2 Gy in 5 wks. EP was started on day 1 of TRT with P, 60 mg/m 2 i.v; E, 120 mg/m 2 i.v.; E, 240 mg/m 2 p.o. d 2 and 3 or E 120 mg/m 2 i.v. / d on d 2 or 3. Repeat cycle every 3 wks x 2 cycles with RT, followed by adjuvant EP alone x 2 cycles. CR pts were asked to participate in the prophylactic cranial irradiation (PCI) study RTOG 0212. RTOG 0239 was designed to detect an improvement in the 2-year survival rate from 47% to 60% with less than 30% of ASE.Results: RTOG 0239 accrued 72 pts (71 eligible) from June 20, 2003 to May 23, 2006. The median follow-up time is 19.0 months for all pts, and 30.4 months for pts still alive. The median age was 63, 52% female, 58% Zubrod PS 0. The 2 -year survival rate was 37 % [95% CI: 25.6, 47.7]. 13 pts (18 %) experienced severe esophagitis. 2 treatment related deaths (2.8%) were reported. Response rates 2 months post RX showed CR 41%, PR 39%, SD 10% and PD 6%. Locoregional control rate at two years was 80%. RT compliance was 95 %.Conclusions: RTOG 0239, AHTRT/EP for LSCLC resulted in 37% 2-year OS, 80% 2 year LC and 18% ASE. Compliance with treatment was high and treatment-related death rate was similar to other chemoradiation regimens. Although 2-year OS did not achieve 60%, excellent LC and low ASE were achieved by RTOG 0239 which became one of 3 arms in an ongoing randomized trial of LSCLC RTOG0538/CALGB30610. [Table: see text]
Genotype and phenotype in hereditary and sporadic breast cancers
Authors: G. Giorgetti, E. Galizia, F. Bianchi, C. Ferretti, F. Corradini, L. Belvederesi, G. Piccinini, C. Loretelli, A. Santinelli, R. Cellerino
Journal: Journal of Clinical Oncology (2007)

10538 Background: BRCA1 protein is involved in distinct DNA-repair processes. Germline mutations in BRCA1 gene confer cancer susceptibility. A frequent mechanism for epigenetic inactivation is hypermethylation of the CpG island in promoters of tumours suppressor genes. BRCA1 promoter hypermethylation has been found in a variable percentage of breast cancers (15–30%). BRCA1-associated breast cancers are usually high-grade, poorly differentiated and stain negative for HER2/neu, oestrogen and progesterone receptors (ER, PgR). Many studies have shown that hereditary BRCA1 and basal-like sporadic breast tumours have a similar phenotype and gene expression signature. Methods: By clinical criteria, 223 patients were selected and, for each patient, the probability to carry a BRCA1 mutation was calculated using the software BRCAPRO and Manchester Score System. All patients were studied by direct sequencing and MLPA of BRCA1 Open Reading Frames (ORFs). Thirty sporadic breast carcinomas, from women undergone surgery for primary invasive breast carcinoma between 1995 and 2001, were selected on the basis of negative staining for ER, PgR and HER2/neu (“BRCA-like”). In these patients, Methylation Specific-PCR and Bisulfite Sequencing on genomic DNA (obtained from sections of paraffin-embedded tissues and modified with sodium bisulfite) were used to assess the methylation pattern of BRCA1 promoter. BRCA1 immunohystochemical analysis (IHC) was performed in all patients. Results: We identified 17 patients with deleterious germline mutations in BRCA1. In “BRCA-like” patients, 13 methylated and 17 unmethylated cases were found by methylation analysis of BRCA1 promoter. The BRCA1 IHC was performed in all available samples ( table 1 ). Conclusions: Hypermethylation of BRCA1 promoter was found in 43% of “BRCA- like” patients. Expression of BRCA1 seems to correlate with hypermethylation of its promoter. Further studies are in progress to better understand the possible role of BRCA1 promoter hypermethylation in sporadic breast cancers. [Table: see text] No significant financial relationships to disclose.
Opportunities for prevention in the practice of psychiatry
Authors: I Philips
Journal: American Journal of Psychiatry (1983)

There are opportunities for prevention in the practice of general psychiatry that are often overlooked by the psychiatrist. The author discusses three groups that lend themselves to preventive efforts--the hospitalized mentally ill parent, children of depressed parents, and children of divorce. He also enumerates aspects of intervention that may result in opportunities for prevention. The application of research findings to individual situations may often result in change and improve the practice of psychiatry.
Co-treatment with aurora kinase inhibitor MK-0457 and pan-histone deacetylase inhibitor vorinostat: A novel targeted treatment for AML and CML
Authors: C. Ustun, W. Fiskus, Y. Wang, R. Rao, P. Lee, R. Kolhe, P. Fernandez, A. P. Jillella, C. Buser, K. N. Bhalla
Journal: Journal of Clinical Oncology (2008)

11054 Background: MK-0457 (M) is a pan-Aurora kinase inhibitor that also inhibits Bcr-Abl, including mutant Bcr-AblT315I. Aurora kinases are chaperoned by hsp90. Vorinostat (V) is a pan-histone deacetylase inhibitor that induces growth arrest, differentiation and apoptosis of acute leukemia cells. By inducing acetylation and inhibition of hsp90, V depletes the levels of hsp90 chaperoned proteins. Methods: Mouse BaF3 cells with ectopic expression of wild-type Bcr-Abl or mutant Bcr-AblE255K or Bcr-AblT315I, cultured human AML HL-60, OCI-AML3, and CML K562, as well as primary AML and imatinib-refractory CML cells were treated with M (50 to 250 nM) and/or V (0.5 to 2.0 μM) for 24 to 48 hours. Cell cycle status, DNA endoreduplication (PI staining) and apoptosis (Annexin/PI staining) were determined by flow cytometry. Intracellular levels of Aurora A and B, survivin, unmutated and mutant Bcr-Abl, p-STAT5, p-CrkL and Bim were determined by immunoblot analyses. Results: Treatment with M decreased phosphorylated (P)-serine 10 on histone H3 and p-survivin, as well as induced DNA endo-reduplication and apoptosis of the cultured AML cells. M induced more apoptosis of BaF3 cells with either the wild-type or mutant Bcr-AblE255K or Bcr-AblT315I, versus the control BaF3 cells. Co-treatment with M and V versus either agent alone resulted in more attenuation of the levels and activity of Aurora kinases and synergistically induced apoptosis of the cultured AML cells. Co-treatment with V and M markedly attenuated the levels of p-Bcr-Abl, p-STAT5, p-CrkL and Aurora kinases, as well as increased Bim and synergistically induced apoptosis of K562 cells. Co-treatment with M and V also induced synergistic apoptosis of BaF3/Bcr-Abl, BaF3/Bcr-AblE255K and BaF3/Bcr- AblT315I cells. M and V versus either agent alone, caused more loss of cell viability of primary AML and imatinib-refractory CML cells. The combination was also less toxic to normal CD34+ progenitor cells. Finally, co-treatment with M and V also inhibited leukemia growth and prolonged survival of NOD-SCID mice engrafted with OCI-AML3 cells. Conclusions: Combined treatment with M and V is highly active and should be tested in patients with AML or resistant CML, especially with Bcr-AblT315I. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck & Co. Novartis Institute for Biomedical Research Inc. Merck & Co., Novartis, Novartis Institute for Biomedical Research Inc.
Angiogenic Switch As Predictor of Response to Chemotherapy+ Bevacizumab in Patients with Metastatic Colorectal Cancer
Authors: A. Cubillo, R. Álvarez, J. Rodriguez-Pascual, M. Muñoz, G. Pond, S. Perea, G. Sanchez, M. Martin, E. Garralda, E. De Vicente, Y. Quijano, M. Hidalgo
Journal: Annals of Oncology (2014)