tbuckley/cabot-search huggingface dataset:
Silver in situ hybridization compared with immunohistochemistry in assessing HER2/neu status in fine-needle aspiration cytology.
Authors: S. Nofech-Mozes, R. S. Saad, S. Noy, W. Hanna, Z. Ghorab
Journal: Journal of Clinical Oncology (2011)

10 Background: Fine needle aspiration (FNA) cytology is a common diagnostic tool in breast cancer used to establish diagnoses of primary, metastatic or recurrent lesions. In these settings, knowledge of the HER2/neu status is vital for optimal therapeutic decision. We examined the accuracy of HER2/neu testing in alcohol-fixed malignant aspirates. Methods: FNAs with known HER2/neu status on concurrent/subsequent surgical specimen were retrospectively identified to select a study group of malignant aspirates in cell blocks (CB) from 38 breast and 18 axillary lymph nodes. This group was enriched for HER2/neu positive cases. Sequential sections were studied by IHC using rabbit monoclonal antibody 4B5 and SISH INFORM HER2 DNA and Chromosome 17 (both by Ventana Medical Systems, Tucson AZ, USA). IHC and SISH were evaluated by two pathologists according to 2007 ASCO/CAP criteria and results were compared with HER2/neu status of paired concurrent/subsequent surgical specimen. Results: HER2/neu IHC on CB yielded 17/56 (30.6%) positive, 30/56 (53.6%) negative and 9/56 (16.1%) equivocal cases. HER2/neu SISH on CB revealed 25/56 (44.6%) amplified, 30/56 (53.6%) not amplified cases. In one case the test was uninterpretable. HER2/neu status on available on 54 surgical specimens (combined IHC and ISH results) was positive in 26 cases and negative in 28. The concordance between negative or positive IHC and SISH on cell blocks was 93.6%. SISH on cell blocks could predict the HER2/neu status in 98.2% of surgical specimens whereas after exclusion of equivocal results, IHC on cell clocks could predict it in only 91.1%. Of the 26 cases with positive HER2/neu status, IHC-CB revealed 3 cases that scored 1+ and one case that scored 0 on cell block. These cases would have been misclassified if HER2/neu was tested on CB by IHC alone. Conclusions: SISH is a reliable methodology for testing HER2/neu in alcohol fixed cytology specimens and is superior to IHC in its ability to accurately predict the final HER2/neu status. Alternatively, cases can be first tested with IHC and further tested with in situ hybridization when the score is under 3+ to avoid false negative results.
Phase I evaluation of the safety of conatumumab (AMG 655) in combination with AMG 479 in patients (pts) with advanced, refractory solid tumors.
Authors: S. P. Chawla, J. Tabernero, H. L. Kindler, E. G. Chiorean, P. LoRusso, M. Hsu, V. Haddad, B. A. Bach, J. Baselga
Journal: Journal of Clinical Oncology (2010)

3102 Background: Preclinical studies show that evasion of death receptor (DR)-mediated apoptosis may depend on intact growth factor signaling. DR agonists have not previously been combined with IGF-1R inhibitors in published clinical studies. The combination may yield synergistic targeted antitumor activity without added toxicity. This study combined 2 investigational, fully human monoclonal antibodies: conatumumab, a human DR5 agonist; and AMG 479, an IGF-1R antagonist. Methods: Eligible pts had locally advanced or metastatic chemotherapy refractory solid tumors, ECOG PS of 0 or 1, and adequate glycemic control if diabetic. Pts enrolled into 3 sequential dose cohorts and received conatumumab 1, 3, or 15 mg/kg IV and AMG 479 18 mg/kg IV on day 1 of each Q3W cycle. Dose escalation was based on <33% incidence of dose-limiting toxicities (DLT) during the first cycle. Study endpoints included: dose determination, adverse event (AE) incidence, DLT, anti-drug antibodies, and pharmacokinetics (PK) of both drugs. Results: Nine pts were enrolled (3 per cohort) and received treatment for a median (range) of 2 (1-8) cycles; 5 pts were female, 7 had ECOG PS=1, and median (range) age was 58 (24-66) years. Primary tumor types were: CRC (3 pts), soft tissue sarcoma [STS] (4 pts), pancreatic carcinoma (1 pt), and breast carcinoma (1 pt). Seven pts discontinued due to disease progression, 1 due to death. No DLT was observed during phase 1 dose escalation. Treatment-emergent serious AEs occurred in 3 pts: pneumonia in 1 pt and dyspnea and pericardial effusion in 2 pts; none were deemed treatment related. Four pts experienced a minor infusion reaction; all patients received all planned doses. Combining conatumumab and AMG 479 showed little impact on the PK of either drug. Three pts had stable disease for >120 days (2 STS, 1 pancreatic carcinoma) with progressive disease in 5 pts; the duration of stable disease was 42-217 days). One pt remained on therapy for >240 days. The recommended dose for phase 2 is AMG 479 18 mg/kg + conatumumab 15 mg/kg. Conclusions: Conatumumab combined with AMG 479 was well-tolerated and no drug-drug interactions were observed. Phase II development of this combination is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen Amgen Amgen
A randomized open-label, phase II study of lapatinib/capecitabine, lapatinib/vinorelbine, or lapatinib/gemcitabine in patients (pts) with ErbB2-amplified metastatic breast cancer (MBC) progressing after taxane treatment-GLICO-0801.
Authors: H. L. Gomez, S. P. Neciosup, Y. Neron do Nascimento, G. Ismael, C. H. Barrios
Journal: Journal of Clinical Oncology (2010)

TPS120 Background: Despite recent reports showing decreased mortality for breast cancer (BC) the disease continues to be a major public health problem. Different studies have demonstrated the value of lapatinib in combination with capecitabine in metastatic BC overexpressing ErbB2. There is enough rationale to design trials that use lapatinib in combination with other citotoxic drugs than capecitabine; these studies could support the employ of novel combinations and improve the outcome of these patients. The data generated will help to address the potential activity and safety of novel L + chemotherapy combinations in ErbB2 + MBC pts. Objectives: The primary objective of the trial is to determine the clinical benefit rate (CR+PR+SD for ≥24 wk) with the three combinations. Secondary objectives include: PFS, OS, ORR, DR, tolerability, and safety. The study aims to determine whether either, or both, L/vinorelbine or L/gemcitabine can be considered reasonable alternatives to the established L/Cap. Methods: Trial Design: GLICO-0801 aims to evaluate the potential role of different lapatinib-based chemotherapy combinations as 1st/2nd line treatment for ErbB2 amplified MBC progressing after taxane treatment. This is an open-label, randomized, international (Argentina, Brazil, and Peru), phase II trial that will include 165 pts and explores lapatinib (L) in two novel combinations: with gemcitabine or vinorelbine as well as with capecitabine (Cap). Inclusion Criteria:Pts with advanced, RECIST measurable ErbB2 positive MBC with documented progression after taxane treatment will be included. Pts may or not have received previous anti-ErbB2 therapy with trastuzumab (T). A maximum of one prior regimen for MBC will be allowed. Pts will be stratified according to liver metastasis, previous use of T and taxanes. Protocol Procedures/Timelines:Pts will be followed with standard imaging every 3 m until progression. The trial was initiated in Nov 2009 and as per Jan 8, 2010, 6 patients have been randomized. Completion of accrual is expected in 14 m. No significant financial relationships to disclose.
Ceritinib in Asian versus Caucasian patients (Pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) NSCLC: Subgroup analysis of the ASCEND-1 trial.
Authors: Daniel Shao-Weng Tan, Alice Tsang Shaw, Ranee Mehra, Enriqueta Felip, Laura Quan Man Chow, D. Ross Camidge, Johan F. Vansteenkiste, Sunil Sharma, Tommaso De Pas, Gregory J. Riely, Benjamin J. Solomon, Juergen Wolf, Michael Thomas, Martin H. Schuler, Geoffrey Liu, Armando Santoro, Margarida Geraldes, Anthony Boral, Alejandro Javier Yovine, Dong-Wan Kim
Journal: Journal of Clinical Oncology (2014)

8078^ Background: Prior results from the first-in-human phase I study (ASCEND-1) of the novel ALK inhibitor (ALKi) ceritinib (LDK378), demonstrated high response rates in crizotinib (CRZ)-naïve and CRZ-resistant patients, and established 750 mg/day as maximum tolerated dose. As inter-ethnic variations can lead to differences in treatment response in Asian vs Caucasian pts, we report here a subgroup analysis of the data for pts with ALK+ NSCLC receiving ceritinib at 750 mg/day. Methods: In ASCEND-1, adult pts with advanced ALK+ cancers received oral ceritinib once daily. Investigator assessment of efficacy is presented for pts who received a first dose of ceritinib ≥18 wks prior to the cut-off date (2 Aug 2013). Results: 246 pts with ALK+ NSCLC (82 Asian, 156 Caucasian, 8 other) received ceritinib 750 mg/day with median follow-up of 4.5 months (mos). 67% of patients had received ≥2 prior anticancer therapies. Between Asian and Caucasian pts baseline demographics were similar but ALKi pretreatment had been received by 47 (29%) and 108 (66%) pts, respectively. Among Asian vs Caucasian pts, 42.7% vs 51.9% had no dose reductions while 29.3% vs 38.5% and 24.4% vs 7.1% had 1 and 2 dose reductions, respectively. Duration of ceritinib exposure was similar between groups. A modest increase (<30%) in the pharmacokinetic parameters AUCtau and Cmax at steady-state was observed in Asian vs Caucasian pts. Grade 3/4 AEs were reported in 55% Asian pts and 72% Caucasian pts; 4 (5%) and 18 (12%) pts, respectively, discontinued due to AEs. Of 173 pts analyzed for efficacy the ORR was 69% (95% CI: 55.2, 80.9) in Asian pts (38/55) and 57% (95% CI: 47.3, 65.9) in Caucasian pts (67/118). The median duration of response (DOR) among responders was 10.1 mos (95% CI: 7.3, not reached) and 6.9 mos (95% CI: 4.5, 11.4) in the Asian and Caucasian pts, respectively. The observed differences between Asians and Caucasians for ORR and DOR were not explained by differences in ALKi pretreatment. Conclusions: Ceritinib 750 mg/day resulted in high and durable antitumor activity and manageable tolerability with low discontinuation rates in both Asian and Caucasian pts with ALK+ NSCLC. Clinical trial information: NCT01283516.
A phase IB, open label, safety and pharmacokinetic (PK) study of escalating doses of PTK787/ZK 222584 (PTK/ZK) in combination with paclitaxel and carboplatin in patients (Pts) with stage IC to IV epithelial ovarian cancer (EOC)
Authors: W. Schroder, M. Campone, S. Abadie, P. Witteveen, P. Viens, T. Jalava, M. Palacay-Radona, S. Bilic, D. Laurent, A. Du Bois
Journal: Journal of Clinical Oncology (2006)

5075 Background: Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) are important mediators of tumor growth and metastasis and their expression is associated with poor prognosis in EOC. PTK/ZK is a novel, oral, angiogenesis and lymphangiogenesis inhibitor that blocks tyrosine kinase signaling from all known VEGFRs. Methods: An open label, multicenter, phase IB dose escalation study evaluating PTK/ZK with chemotherapy as first line therapy in Pts with stage IC to IV EOC. Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of PTK/ZK were assessed; PK of PTK/ZK, carboplatin and paclitaxel was characterized. Paclitaxel was administered as a 3-hour infusion on day 1 of each 21-day cycle at a dose of 175 mg/m 2 . Carboplatin was given immediately after paclitaxel as a 30-min IV infusion to AUC of 5 mg min/mL. PTK/ZK was given once daily from day 3 to day 21 of each chemotherapy cycle. Cohorts of 3 to 6 Pts received doses of PTK/ZK at 250, 500, 750, 1000 or 1250 mg/day. Dose expansion in 21 additional Pts was conducted with 1250 mg/day without reaching MTD. After completion of chemotherapy, PTK/ZK was given continuously until disease progression. PK samples were collected in cycle 1 (without PTK/ZK) and cycle 2 (after PTK/ZK pre-treatment). Results: 42 Pts were enrolled. To date 39 Pts are evaluated for safety, 19 Pts for DLT, 35 Pts for PK and 21 Pts with residual disease for tumor response. No DLTs were reported. The most frequently observed grade 3/4 toxicity was neutropenia (31%), leucopenia (18%) and hypertension (10%). PTK/ZK did not aggravate chemotherapy related side effects. To date 67% of Pts had achieved CR/PR, 9% SD, 5% PD and 19% UNK. PTK/ZK exposure at steady state was similar in cycle 1 and 2. PTK/ZK had no impact on the systemic exposure of carboplatin. Paclitaxel exposure was decreased by an average of 18% in cycle 2 compared to cycle 1 for Pts treated with PTK/ZK 1250 mg/day. Conclusion: Combination of PTK/ZK with paclitaxel and carboplatin is feasible and shows favorable safety profile. The combination is active in EOC and deserves further evaluation. [Table: see text]
Abstract 16424: Cardiac CT as Accurate as Transesophageal Echocardiography for the Detection of LAA Thrombus in Patients With Atrial Fibrillation: A Meta-Analysis
Authors: Jorge Romero, Syed A Husain, Iosif Kelesidis, Javier Sanz, Hector Medina, Mario J Garcia
Journal: Circulation (2012)

Objectives: To evaluate the diagnostic accuracies of cardiac computed tomography (CCT) assessing left atrial/left atrial appendage thrombi (LA/LAA) in comparison with transesophageal echocardiograp...
Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: is cure possible in a small subgroup?
Authors: T Philip, J M Zucker, J L Bernard, P Lutz, P Bordigoni, E Plouvier, A Robert, H Roché, G Souillet, E Bouffet
Journal: Journal of Clinical Oncology (1991)

The objectives of this study were to determine (1) the role of selection before bone marrow transplantation (BMT), (2) the role of vincristine, melphalan, and total body irradiation (TBI) as consolidation of induction therapy for stage IV over 12 months at diagnosis, and (3) the role of immunomagnetic purging in metastatic neuroblastoma. Among 72 consecutive unselected patients, 10 were not grafted (four died at induction: two in complete remission [CR], two in partial remission [PR]); three had bone marrow progression before harvest; one had uncontrolled progression; and two had parental refusal). Sixty-two patients were grafted (23 in CR/very good PR [VGPR] and 39 in PR). Among the 62, 33 were consolidated with at least 90% excision of their initial tumor excised (53.2%), 15 with catecholamine secretions (24.2%), 22 with minor bone marrow involvement (35.5%), and 31 with positive bone scan (50%). Median observation time is 59 months. Progression-free survival (PFS) for the 10 excluded patients was 20% at 2 years and 0% at 4 years. PFS for the grafted population (n = 62) is 40% at 2 years, 20% at 4 years, and 13% at 7 years. No difference was observed between patients grafted in CR/VGPR or in PR. However, a group of 19 children was grafted resulting in complete normalization of metastasis (regardless of primary-site tumor status). In this group, PFS at 59 months was 38% with no relapses up to 7 years post-BMT. A group of 31 patients with no bone involvement at BMT was also identified. PFS at 5 years is 30% compared with 12% for bone-positive patients at BMT. Moreover, the 11 children presenting at diagnosis with no bone involvement (Evans stage IVS or stage C Memphis) and consolidated with BMT had PFS at 5 years of 50% with no late relapses. A subgroup of stage IV neuroblastoma patients older than 1 year of age at diagnosis may be curable with this therapeutic approach, and the use of multivariate analyses to search for prognostic factors is warranted in currently existing international registries.
Stereotactic body radiotherapy (SBRT) and medical inoperability of early stage non-small cell lung cancer
Authors: K. N. Franks, A. Bezjak, S. Pearson, B. C. Cho, D. Payne, A. Sun, T. K. Waddell, F. A. Shepherd, S. Keshavjee
Journal: Journal of Clinical Oncology (2006)

17074 Background: Early stage NSCLC is commonly diagnosed in elderly patients who often have significant medical co-morbidity. SBRT is emerging as a treatment alternative that can provide 80–97% local control for peripheral tumors. We performed a literature review and a retrospective review of 24 patients referred to Princess Margaret Hospital for consideration of SBRT to assess what criteria were used to determine patient selection for this new treatment. Methods: Published papers reporting treating stage I NSCLC with SBRT were reviewed. Clinical and demographic characteristics of patients referred for consideration of SBRT over the last 15 months were analyzed. All patients were assessed by experienced thoracic surgeons to determine their operability status. Patients were retrospectively scored as average or high risk for surgery on the basis of accepted PFT guidelines (FEV 1 and DLCO &lt;40% predicted); Charlson Index of Comorbidity (CCI) was calculated (score &gt;2 associated with impaired survival). Results: Of 13 papers reporting Stage 1 SBRT results, 8 included details of medical inoperability. 2 papers had strict guidelines for PFTs, in addition to other criteria. In 6 studies reporting 276 pts, the most common reason for inoperability was non-specific medical comorbidity (60%). Our cohort (24 patients) referred for SBRT (median age 75, range 57–89) had a mean tumour size of 2.32cm (S.D. 1.11); 50% of patients had a good (0–1) Zubrod Performance status. Based upon PFT tests alone 10 patients (42%) were high risk and 5 (21%) average risk for surgery. The CCI score was ≥3 in 10 patients (42%). 3 patients who scored average risk and CCI ≤2 were deemed medically inoperable due a single severe medical comorbity. In 23/24 pts the surgeon recommended against surgery; one patient refused surgery. Conclusions: With an aging population and increased detection due to incidental finding or screening, it is important to know that there is effective alternative therapy for patients deemed too high risk for surgical resection. Comorbidity is an important factor influencing surgical mortality; defining explicit criteria for inoperability remains a clinical challenge. No significant financial relationships to disclose.
A study of physician investigator (PI) disclosure of alternatives of care and prognostic information to advanced cancer patients (ACP) enrolling in phase I trials
Authors: C. Daugherty, N. E. Kass, D. Roter, S. Larson, J. Sugarman, K. Kasza, M. J. Ratain, F. J. Hlubocky
Journal: Journal of Clinical Oncology (2009)

6508 Background: ACP in phase I trials have been described as having an inadequate understanding of several elements of informed consent. However, actual PI disclosure of alternatives to trial participation and prognostic information, and subsequent ACP understanding of these elements, have not been described. Methods: Clinical encounters between 131 ACP entering phase I trials and 25 oncologists at three institutions (University of Chicago; Johns Hopkins; and Duke University) were audio-taped. ACP completed follow-up questionnaires one week later to assess understanding of informed consent elements. Audiotapes were analyzed using the Roter Interaction Analysis System (RIAS) and specifically coded for terms associated with trial alternatives and patient prognosis. Results: To date, 85 encounters have been analyzed. Average encounters length: 30.4 min (range: 5.7–77.8 min). For ACP: median age 60y (33–83); 55% female; 88% Ca; 55% &lt;college educ; 52% income &lt;$60,000. The PI was recorded as discussing options other than anticancer treatment in 47% of encounters. The terms “palliative” or “hospice” were used in 1% and 2.3% of encounters respectively. In 29% of encounters the PI described the option of “doing nothing”. The PI used the terms “death” or “terminal” in 5.8% encounters. The PI was never recorded using the term “dying”. Within these encounters, no ACP was recorded as using any of the following terms: “palliative,” “hospice,” “terminal,” “death,” “dying.” Within follow-up interviews, 30% reported no alternatives to trial participation were discussed; 1% reported that palliative care/hospice was discussed. Based on coding of qualitative responses, 53% of ACP said that either their prognosis was excellent or they didn't know their prognosis. An association was found between recorded physician statements regarding general prognosis and ACP subsequently reporting having discussion regarding life expectancy (59% v. 33%, p = 0.04). Conclusions: PI communication and subsequent measured understanding regarding alternatives to trial participation and prognosis remain inadequate in the setting of phase I trial enrollment. [Table: see text]
Cardiac safety of pegylated liposomal doxorubicin (PLD) in combination with trastuzumab (T) in patients with metastatic breast cancer (MBC): Results from a multicenter phase II study
Authors: E. Stickeler, D. O. Watermann, J. Woll, M. Foeldi, G. Gitsch
Journal: Journal of Clinical Oncology (2007)

1106 Background: Combination therapy of doxorubicin and trastuzumab is highly effective for Her2 positive MBC but characterized by frequent cardiac toxicity (CT). PLD can significantly reduce CT compared to conventional doxorubicin. Patients and Methods: 15 patients were enrolled in a phase II trial to evaluate cardiac safety of T (4 mg/Kg loading dose day 2, followed by weekly 2 mg/Kg) in combination with PLD (40 mg/m 2 IV bolus day 1, q 28 d). 75% of pts. presented with more than 1 metastatic site and 40% for second line treatment. PLD was administered for 6 or 9 cycles, respectively, T until disease progression. To assess CT, all pts were evaluated with electrocardiogram (ECG) and echocardiograms (E) for Left Ventricular Ejection Fraction (LVEF) at baseline, every cycle during PLD and T, and every three months during T therapy alone. CT was defined as appearance of signs/ symptoms of congestive heart failure and/or an absolute decrease in LVEF &gt; 10 units (below 50%) or decrease in LVEF &gt; 15 units (above 50%). Results: Four pts. received 6 cycles, 4 pts. received 9 cycles of PLD, 4 pts discontinued treatment due to PD, 3 pts. due to toxicity. After a median follow up time of 15.4 months, 6 pts. (42.9%) demonstrated a clinical benefit and median OS was 16.2 months. Non cardiac side effects were mild with only 3 CTC Grade 3 events of 247 treatment cycles (1.2%). Three pts. developed minor ECG changes without pathological significance and 5 pts. had minor changes in their E with slight diastolic (n=3) or systolic (n=2) dysfunction. During follow-up, 3 pts. were diagnosed with pathological E findings, including 1 slight decrease of LVEF, one diffuse hypokinesia and one strong decrease in LVEF.The median LVEF in the study cohort was 66.1% at baseline, 62.7% after 6 cycles of therapy, 64.4% at the first follow up and did not change significantly until the 5 th examination. Conclusions: This study supports the combination of PLD and H in pts. with HER2 overexpressing metastatic breast cancer as a safe and feasible therapy. Due to the promising clinical response rates in this prognostically unfavorable group, this combination should be evaluated in larger studies as a potential regimen for adjuvant treatment of breast cancer. No significant financial relationships to disclose.