tbuckley/cabot-search huggingface dataset:
Phase II study of neoadjuvant bevacizumab and trastuzumab administered with albumin-bound paclitaxel (nab paclitaxel) and carboplatin in HER2+ locally advanced breast cancer
Authors: E. Raefsky, R. Castillo, A. Lahiry, D. S. Thompson, S. Hanson, C. Meng, D. Knauer, V. Trieu, N. Desai, D. A. Yardley
Journal: Journal of Clinical Oncology (2008)

627 Background: HER2 signaling up-regulates vascular endothelial growth factor (VEGF) resulting in subsequent tumor angiogenesis and tumor progression. SPARC is a known prognostic factor for poor survival and its expression increases with tumor aggressiveness. SPARC may mediate enhanced intratumoral accumulation of nab paclitaxel (nab-pac) via a SPARC-albumin specific binding activity. This multicenter phase II pilot study was designed to evaluate feasibility, toxicity, and preliminary efficacy of dual VEGF and HER2 receptor blockade with bevacizumab (B) and trastuzumab (T) in combination with neoadjuvant nab-pac and carboplatin. SPARC tumor assessments were performed at baseline. Methods: Eligibility: cT1–4, N0–3, M0 adenocarcinoma, FISH HER2+, normal LVEF, ECOG PS ≤2, adequate organ function, controlled hypertension (HTN), neuropathy ≤ G1, tumor tissue availability for SPARC testing. Treatment: Nab-pac 100mg/m2 weekly days 1, 8, 15 q28 days with carboplatin AUC of 6 day 1 q28 days x 6 cycles, B 5mg/kg qwk x 23 wks with T 4mg/kg loading dose followed by 2mg/kg qwk x 22 wks. Surgery ≥ 4 wks following last B. T at 6mg/kg and B 15mg/kg q3wk post op for a total of 1 year (B began ≥ 4 weeks post op). LVEF at baseline, 3, 6, 12, and 18 months. SPARC IHC was scored on a 0–3 level (0=absent, 1= weak, 2=moderate, 3=strong). Results: 25 pts are evaluable for toxicity. Histology: ductal 80%, lobular 12%. 48% ER-PR-. ECOG PS 0 - 90%. G3/4 toxicity in >5% of patients included: neutropenia 12 pts (48%) and hypertension 3 pts (13%). No LVEF dysfunction was noted. 4 pts went off study: 2 - pt wishes, 2 - toxicity (fatigue, reflux). 2 pts did not complete post op therapy (unrelated to treatment). Complete pathologic responses were noted in 5 pts and PRs in 3 pts. SPARC data were available for 19 pts (1 pt-level 0, 4 pts level 1, 10 pts level 2, 6 pts level 3). Conclusions: Neoadjuvant T plus B with nab paclitaxel and carboplatin is feasible with promising activity. No unexpected toxicities have been reported and there has been no early evidence of LVEF dysfunction. Correlation of SPARC tumor staining with pathologic responses as well as hormone receptor status will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech Abraxis, Genentech
Serum HER2 (sHER2) levels in early-stage HER2 <i>neu</i> (+) breast cancer (HER2+BC): Results from the NCCTG adjuvant Intergroup trial N9831
Authors: A. Moreno-Aspitia, A. C. Dueck, W. L. Lingle, L. Kutteh, K. Tenner, N. E. Davidson, S. Martino, P. Kaufman, W. P. Carney, E. A. Perez
Journal: Journal of Clinical Oncology (2008)

529 Background: sHER2 is a circulating oncoprotein cleaved from full-length, membrane-bound HER2. Previous data support that increased sHER concentration is an indicator of poor prognosis and predictor of poor response to chemotherapeutic and hormone treatment in metastatic breast cancer. The role of sHER2 level on the outcome of patients in the adjuvant setting has not been defined, which we evaluated in the context of N9831. Methods: The objectives were to analyze the association between baseline sHER2 and disease-free survival (DFS) in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) of N9831. Baseline serum samples of 1,423 pts from both arms were analyzed for sHER2 using the ADVIA Centaur HER2 assay (Siemens Diagnostics; Tarrytown, NY). Cut off value of 15 ng/mL was used as recommended by the manufacturer/FDA. Patients who cancelled prior to receiving therapy, ineligible pts, and pts whose HER2 status was not corroborated by central review are excluded from analysis. This study uses Cox models stratified by hormone receptor status and nodal status to assess the association between sHER2 levels and DFS. Results: Baseline characteristics between pts with sHER2 <15 ng/mL (N=1,234) and pts with sHER2 ≥15 ng/mL (N=189) demonstrated differences between groups by age, menopausal status (higher sHER2 levels in pts ≥ 50 yrs/post-menopausal), and hormone receptor status (lower sHER2 in hormone receptor + tumors). Hazard ratios between sHER2 groups within Arm A and within Arm C showed that pts with sHER2 ≥15 ng/mL had worse DFS than pts with sHER2 <15 ng/mL (A: HR=1.71, p =0.004; C: HR=1.42, p =0.22). Hazard ratios between arms within each sHER2 group demonstrated similar benefit from trastuzumab in each sHER2 group (<15: HR=0.66, p=0.006; ≥15: HR=0.60, p=0.10). Results remained consistent when including menopausal status and age in the Cox models. Conclusions: 13% of HER2+BC pts of this study had high levels of sHER2. In the standard chemotherapy arm, pts with high sHER2 had significantly worse DFS than pts without. In the concurrent trastuzumab arm, a similar trend was observed but did not reach statistical significance, potentially due to a smaller number of events. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Siemens Healthcare Diagnostics, Inc Genentech™ BioOncology
Abstract 312: Hospital Personnel Interactions With Wearable Cardioverter Defibrillators During Sudden Cardiac Arrest: A Case Series Review
Authors: Chingping Wan, Steven J Szymkiewicz
Journal: Circulation (2013)

Purpose: The wearable cardioverter defibrillator (WCD) automatically detects and treats lethal ventricular tachyarrhythmias (VT/VF). However, intervention during an event by medical personnel to resuscitate a patient may delay or even prevent WCD treatment during sudden cardiac arrest (SCA). This study assessed hospital staff and WCD interactions, and the impact on in-hospital SCA outcomes. Methods: All shockable SCA events experienced by patients wearing a WCD between 11/2003 and 4/2013 were identified and retrospectively retrieved from the manufacturer’s post-market database. A shockable SCA event was defined as all sustained VT/VF during a single 24-hour period. Only events that occurred during hospitalization or emergency room visit were reviewed in this study. Interactions with medical personnel included 1) belt disconnection or garment removal prior to WCD therapy or 2) use of response buttons (RBs) by someone other than the patient. Device recordings and customer call reports were reviewed for event details and 24 hour survival (acute survival). Results: A total of 209 in-hospital SCA events were included. Overall, 51 (24.4%) were on telemetry and 76 (36.4%) were witnessed. Acute survival was 82.8%. The WCD delivered at least 1 shock in 181 (86.6%) events with a median arrhythmia onset-to-shock (OS) time of 47 seconds (mean=90.4±307.48 seconds). When hospital staff used RBs (n=15, 7.2%), the OS time was longer (median=62.5 seconds, p&lt;0.01). Three (1.7%) conscious patients were advised not to use RBs during sustained VT. No WCD therapy occurred in 28 (13.4%) events due to belt disconnection in 18 (64.3%), VT/VF rate below the pre-programed threshold in 8 (28.6%), RBs use by hospital staff in 6 (21.4%), resuscitation efforts creating ECG interference in 5 (17.9%), and device damage in 2 (7.1%). Only 4 (14.3%) patients survived acutely when WCD therapy was prevented, although 13 received defibrillation from hospital defibrillators. Conclusions: WCD therapy during in-hospital SCA resulted in a high acute survival rate. Interventions during an event by medical personnel to resuscitate a patient reduced the number of WCD therapies delivered and may have affected acute survival.
Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies
Authors: H Bohlen, T Hopff, O Manzke, A Engert, D Kube, PD Wickramanayake, V Diehl, H Tesch
Journal: Blood (1993)
Perturbations in PI3K pathway and cyclin dependent kinase (CDK) pathway to predict complete responders in CRC patients treated with ADAPT therapy.
Authors: Edward H. Lin, Xiaowei Yan, John Dallas Scarborough, David Wu, Jing Tang, Lingheng Li, Douglas E. Wood, Shilpen A. Patel, Edward Y. Kim, Raymond Sze Yeung, Jonathan F. Tait, Colin C. Pritchard, Qiang Tian
Journal: Journal of Clinical Oncology (2014)

3610 Background: Aspirin or selective COX-2 inhibitor may improve overall survival (OS) in colorectal cancer (CRC) patients with PIK3CA mutations. However, routine use of anti-inflammatory agents in metastatic CRC patients remains controversial. We showed that 3-year maintenance celecoxib, also a stemness inhibitor coupled with capecitabine in a two-step ADAPT (activating dormant tumor cells and potentiate targeting) therapy led to 40% complete responders (CR) whose median survival reached 92.7 months in patients with unresectable stage IV CRC (Lin et al. AACR LBA254). We sought to determine genetic aberrations and related pathways as predictor of CR to ADAPT therapy. Methods: We retrospectively reviewed 50 consecutive stage IV CRC patients who had achieved CR with ADAPT therapy alone or in conjunction with metastectomy between 2006-2012 at University of Washington. All patients were tested for a panel of 199 cancer-related genes (UW Oncoplex) with Illumina deep sequencing platform Results: We select first 25 patients as training set to derive classifier for CR versus none CR that were at first blind to biostaticians. We found that genes involved in the PI3K pathway were significantly mutated in the CR group whereas CDK pathways were altered in the none CR group (p< 0.0001, sensitivity 91.7%, specificity 76.9%). CR events were independent of other worst prognostic factors including K-ras, B-raf, and p53. In vitro treatment of CRC cell lines with ADAPT drugs confirms strongest PI3K pathway inhibition effects (p = 0) and cell cycle pathway (p < 0.05). Validation set analysis will be reported at the meeting. Conclusions: Altered PI3Kand CDK pathways predict CR from ADAPT therapy in advanced unresectable CRC patients. Ongoing retrospective and prospective phase II ADAPT studies intend to validate these above findings. Funded by Gateway for Cancer Research and Lyon Foundation.
A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991
Authors: P. J. O’Dwyer, P. LoRusso, A. DeMichele, V. Gupta, A. Barbi, H. Dials, I. Chen, R. Courtney, K. Wilner, G. K. Schwartz
Journal: Journal of Clinical Oncology (2007)

3550 Background: PD-0332991 is a novel oral inhibitor of CDK 4/6, which is active against Rb positive tumors and has never before been tested in humans. A phase I dose escalation trial of PD-0332991 administered as a daily oral single agent was conducted to investigate safety, pharmacokinetics and pharmacodynamics in patients with advanced cancer. Methods: PD-0332991 was administered daily for 21 days in 28-day cycles (Schedule 3/1) to patients in successive dose escalating cohorts at doses from 25 mg to 150 mg QD. An alternative schedule of 14 days dosing in 21-day cycles (Schedule 2/1) was tested at 100 mg to 225 mg QD. Patients with advanced Rb positive solid tumors were enrolled in the study. Results: Fifty-seven patients have been enrolled into the study. The most common tumor types were: breast, colorectal, liposarcoma, and melanoma. The median age across the study was 57 years. For Schedule 3/1, the MTD/RP2D was determined to be 125 mg QD. For Schedule 2/1, the MTD/RP2D is still to be identified but the maximum administered dose (MAD) was determined to be 225 mg QD. Six DLTs have been observed, all relating to myelosuppression. The most common AEs were neutropenia, anemia, fatigue, nausea, constipation, vomiting and diarrhea. Concentrations were moderately variable (% CV range in AUC on Day 8 of Cycle 1 was 14–64%) with dose-dependent increases in exposure observed following PD-0332991 administration (mean AUC (0–10 hr) values were 724 and 1,500 ng.hr/mL at the 125 mg and 225 mg dose levels, respectively). The effect of food on PD-0332991 pharmacokinetics is currently being evaluated. In Schedule 3/1, there have been 6 patients with stable disease (= 10 cycles) with 3 patients (one each with breast cancer, colon cancer and ovarian cancer) with stable disease for at least 20 cycles. In Schedule 2/1, one patient has had stable disease for at least 10 cycles. Updated data will be presented. Conclusions: The principal and dose limiting toxicity of PD- 0332991 is myelosuppression. The RP2D for Schedule 3/1 is 125 mg QD. The MAD has been determined for Schedule 2/1 as 225 mg QD and the dose in this schedule has been de-escalated to 200 mg QD to evaluate the MTD. Tumor specimens, when available, from patients in both schedules are also being tested for pharmacodynamic modulation of phospho-RB protein. No significant financial relationships to disclose.
A randomized trial of intrapericardial (ip) bleomycin (BLM) after drainage for management of malignant pericardial effusion (MPE) in lung cancer patients (pts): Report of a Japan Clinical Oncology Group trial (JCOG 9811)
Authors: H. Kunitoh, T. Tamura, T. Shibata, M. Imai, Y. Nishiwaki, M. Nishio, A. Yokoyama, K. Watanabe, K. Noda, N. Saijo
Journal: Journal of Clinical Oncology (2007)

7710 Background: This trial was aimed to evaluate the safety and efficacy of ip BLM instillation as compared to pericardial drainage alone in pts with MPE. Methods: Pts ≤ 75 y.o. with pathologically documented lung cancer, who had received pericardial drainage for clinical MPE within 72 hours of the enrollment, were eligible. Pts with chemo-naïve small cell cancer, major organ failure, or severe co-morbidity were excluded. Signed consent form was obtained. Pts were randomized to either Arm A: observation alone after drainage, or Arm B: ip BLM of 15mg, followed by additional ip BLM 10mg q48hours. Drainage tube was removed when daily drainage was ≤20mL; the protocol therapy was judged as primary failure, with no regulations on post-therapy, if this criteria could not be met after 7 days from enrollment. MPE was followed at 1,2,4,6 and 12 months by echocardiography. The primary endpoint was survival with MPE control (effusion failure-free survival, EFFS) at 2 months, assumed to be 60% vs. 30%. The trial was designed to provide 80% power with 5% one-sided alpha, with 80 cases. Results: From Aug./99 to Jan./06, 80 pts were enrolled, with 79 eligible. M:F=51:29, median age 60 y.o. (range: 39–75), 75 nonsmall histology, 53 with prior chemotherapy, and 20 with prior radiotherapy. Median drainage volume was 600 mL (range: 130–1930). Cytology of the effusion was positive in 58/76 examined. EFFS ( table ) tended to favor Arm B, with hazard ratio of 0.64 (one-sided p=0.030 by logrank test, 95% C.I. 0.40–1.03). No additional acute toxicities or complications were observed for Arm B. There were 2 cases with late constrictive complications in Arm B, but none was severe. The median survival was 79 days (A) and 119 days (B) (not significant). Conclusions: Although the difference of EFFS at 2 months was not statistically significant, BLM ip after pericardial drainage appears to be safe and effective in allover for management of MPE. No significant financial relationships to disclose. [Table: see text]
Trastuzumab (T) and CNS metastases in women with HER-2 positive metastatic breast cancer (MBC)
Authors: S.-J. J. Dawson, N. F. Ranieri, R. D. Snyder, S.-A. A. McLachlan, W. I. Burns, G. M. Newnham, P. A. Francis, A. J. Dowling
Journal: Journal of Clinical Oncology (2005)

683 Background: A high rate of CNS metastases has been described in women with MBC over-expressing HER-2 who receive T-based therapy. The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with T, CNS metastases occurred: 1) more frequently than historical controls, and 2) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 patients with MBC cancer over-expressing HER-2 and treated with T and chemotherapy was performed. Results: 22/25 (88%) patients who initially responded to T had progressed by the time of analysis. CNS metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) patients had controlled systemic disease (CR=2, PR=6, SD=1, PD=2 patients). There were trends for patients with CNS metastases to have > 1 site of metastatic disease at the commencement of T therapy (P=0.06), and to be hormone receptor negative at initial diagnosis (P=0.14). The median time to diagnosis of CNS metastases after the commencement of T therapy was 30.8 months (range 16–49). The median survival after diagnosis of CNS metastases was 30.6 months (range 4–75). Conclusions: Historically, CNS metastases have been reported to occur in 10–16% of women with MBC, with a median survival of < 1 year. This study demonstrates a significantly higher rate of CNS metastases (39%) in HER-2 positive MBC patients treated with T. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was over 2 years. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Australian New Zealand Breast Cancer Trials Group, Genentech, Roche Roche
Undifferentiated epithelial-rich invasive malignant thymoma: complete response to cisplatin, vinblastine, and bleomycin therapy.
Authors: C Dy, F A Calvo, J P Mindán, L A Aparicio, S M Algarra, A Gil, F González, S Harguindey
Journal: Journal of Clinical Oncology (1988)

Two cases of complete remission plus one almost complete and another partial response of undifferentiated, invasive epithelial malignant thymoma using the combination of cisplatin, vinblastine, and bleomycin (PVB), are reported in four patients treated with this combination. Radiotherapy was instituted after completing the fourth course of chemotherapy in three patients. One patient died from intercurrent infection after the fourth cycle of combination chemotherapy. Three patients remain free of disease at the end of the treatment program. PVB appears to be highly active in this disease and deserves more extensive evaluation in multicenter clinical trials.
Multicenter phase II study of every-2 week gemcitabine and paclitaxel as first-line chemotherapy in patients with advanced urothelial tract cancer
Authors: F. Calabro, C. N. Sternberg, V. Lorusso, L. Frassinetti, G. Rosati, T. Sava, M. Guida, N. Giovannini, L. Manzione, E. Donato Di Paola, S. Alonso
Journal: Journal of Clinical Oncology (2005)

4583 Background: Patients (pts) with transitional cell carcinoma (TCC) of the urothelium are not always amenable to cisplatin based chemotherapy. We have previously reported a 60% RR in patients who have failed cisplatin based combination chemotherapy (M-VAC) using a convenient every 2-week outpatient regimen of Gemcitabine (G) and Paclitaxel (P) (Cancer 2001 Dec 15;92(12):2993–8). A multicenter trial was initiated in 5 Italian centers to evaluate this regimen as first line chemotherapy. Methods: 48 patients with histologically proven measurable disease (RECIST criteria), WHO PS 0–2, metastatic or inoperable TCC, with no prior systemic cytotoxic or biologic treatment, CrCl ≥ 40 ml/min, bilirubin < 20 μmol/l and signed informed consent were treated with G 2,500 mg/m2 in 30 min and P 150 mg/ m2 in 3 hrs Q 2 weeks. G-CSF was given for 5–7 days for ≥ G3 neutropenia toxicity. 6–12 courses were planned. The median age was 67 (52–77 years), WHO PS 1 (0–2). Metastases occurred in lung in 14 (29%), lymph nodes in 22 (46%), in bladder in 14 (29%), in bone in 8 (17%), and in liver in 6 (13%) of pts. 52% of pts had more than 1 site of disease and 10% had at least 3 sites of disease. Results: 266 cycles were administered. 33/48 pts are currently evaluable, as many pts are still receiving therapy. RR thus far is 42%, with 3 CR (9%) and 11 PR (33%). Hematologic toxicity was predominant but manageable. G-CSF was used in only 6% of cycles. Conclusions: In a multicenter study, G and P was a well-tolerated outpatient regimen. This regimen shows promise and may be considered in pts unable to receive cisplatin. It should be compared to a cisplatin-containing combination regimen in the future. Supported in part by Eli Lilly. No significant financial relationships to disclose.
Vaginal estrogens: A look at prescription trends in postmenopausal breast cancer (BC) survivors
Authors: M. Castiel, M. Krychman, E. Stier, N. Kauff, A. Amsterdam
Journal: Journal of Clinical Oncology (2004)

8185 Background: Non-hormonal therapies are available for the treatment of many of the sequelae of menopause. However, estrogen has clearly been shown to be the most effective agent for the treatment of menopause-induced urogenital atrophy. The use of systemic estrogen in BC survivors is highly controversial because of the theoretical risk of a BC recurrence or a second primary. Low-dose vaginal 17β-estradiol (LDVE) has been shown to be highly effective in treating menopausal urogenital atrophy in patients without cancer. In addition, multiple studies have demonstrated minimal systemic absorption of estrogen. However, there are no studies evaluating the use of LDVE in BC patients. Methods: A retrospective review was performed using all patients who were seen at Memorial Sloan-Kettering Cancer Center from January through November of 2003 for routine gynecologic examination and were given a prescription for LDVE. Results: Of the 200 patients who received prescriptions, 61 (31%) had a BC diagnosis and were menopausal at the time of visit. All patients complained of vaginal dryness, dyspareunia or both. The median age was 55 (30–78) and 55 (90%) were free of disease. 33 (54%) had a documented history of estrogen receptor (ER) positive tumors. Concurrent hormonal manipulation included selective ER modulators 22 (36%), aromatase inhibitors 4 (7%) or gonadotropin releasing hormone antagonists 2 (3%). Conclusions: Currently, LVDE remains the most efficacious therapy available for urogenital atrophy. BC survivors are eager to find solutions to improve quality of life, particularly when relating to sexuality and are responsive to estrogen-containing medications if the perceived risk is low. Proper counseling and stressing that safety data are not yet available is essential before prescribing LDVE. Further studies evaluating the impact of LVDE on quality of life are under way at MSKCC and safety studies should follow. No significant financial relationships to disclose.
Molecular cloning of a cDNA encoding cytochrome c of Stellaria longipes (Caryophyllaceae)--and the evolutionary implications.
Authors: X H Zhang, C C Chinnappa
Journal: Molecular Biology and Evolution (1994)

A cDNA clone encoding cytochrome c of Stellaria longipes was isolated and characterized. The nucleotide and predicted amino acid sequences were highly similar to those from other plant, fungal, and animal species. No significant polymorphism was observed among different genotypes (ecotypes). The S. longipes genome contained a low copy number of nucleotide sequences of cytochrome c. The gene expression of cytochrome c exhibited a certain degree of tissue specificity, with more transcripts in leaf than in stem. A phylogenetic analysis of the cytochrome c amino acid sequences revealed an unusual aspect of plant cytochrome c evolution.