tbuckley/cabot-search huggingface dataset:
SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC
Authors: F. Cappuzzo, T. Ciuleanu, L. Stelmakh, S. Cicenas, A. Szczesna, E. Juhasz, E. Esteban Gonzalez, O. Molinier, G. Klingelschmitt, G. Giaccone
Journal: Journal of Clinical Oncology (2009)

8001 Background: Erlotinib (E), a small-molecule EGFR TKI, is proven to extend survival versus placebo (P) in 2nd/3rd-line advanced NSCLC. The phase III SATURN study (BO18192) was initiated to evaluate E as maintenance therapy after standard 1st-line platinum-based chemotherapy (CT) in advanced NSCLC. Methods: Patients with no evidence of disease progression after 4 cycles of CT were randomized to receive either E 150 mg/day or P until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) in all patients and the co-primary endpoint was PFS in EGFR immunohistochemistry-positive (IHC+) patients. Results: A total of 1,949 patients entered the CT phase, of whom 889 were randomized to E (n=438) or P (n=451). Median age was 60 years for both arms. Baseline characteristics for E and P arms (%): male/female: 73/27 and 75/25; adenocarcinoma + BAC/squamous-cell/other: 47/38/15 and 44/43/13; stage IIIB/IV: 26/74 and 24/76; Caucasian/Asian/other: 84/14/2 and 83/15/2; ECOG PS 0/1: 31/69 and 32/68; current/former/never smoker: 55/28/18 and 56/27/17. PFS (by investigator assessment; confirmed by independent review) was significantly prolonged with E versus P in all patients (HR 0.71 [95% CI 0.62–0.82]; p&lt;.0001) and in EGFR IHC+ patients (HR 0.69 [95% CI 0.58–0.82]; p&lt;.0001). Subgroup analyses will be reported. Response rate was 12% with E versus 5% with P. Disease control rate (complete response + partial response + stable disease &gt;12 wks) was 40.8% with E versus 27.4% with P (p&lt;.0001). OS data are not yet mature. E was well tolerated: the majority of treatment-related adverse events (AEs) were grade 1/2. AEs reported in ≥10% of all patients were rash (60% with E versus 9% with P) and diarrhea (20% with E versus 5% with P); again, most were grade 1/2. Only 2.3% of patients receiving E had a serious treatment-related AE and 2.8% withdrew due to a treatment-related AE. Conclusions: The SATURN study met its primary and co-primary endpoints with high statistical significance. Erlotinib in the 1st-line maintenance setting is well tolerated, and significantly improves disease control and delays progression versus placebo across patient subgroups. [Table: see text]
Phase I dose escalation trial of biweekly pemetrexed in combination with docetaxel in advanced solid tumors
Authors: L. L. Garland, L. Cranmer, G. Gerstner, R. Walker, Y. Obregon, S. Ebbinghaus
Journal: Journal of Clinical Oncology (2007)

13019 Background: Pemetrexed (PEM) and docetaxel (DOC) are cytotoxic agents with a broad range of activity in solid tumors and relatively non-overlapping toxicities. We are conducting a single site dose escalation trial of biweekly dosing of PEM + DOC in advanced solid tumor patients (pts) to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and preliminary antitumor activity for the combination. Eligible pts have had 0–1 prior therapies, a performance status of 0–1, and creatinine clearance of =45 ml/min. Methods: Escalating doses of PEM (10 min infusion, d1 and 15) and DOC (1 hr infusion, d1 and 15) are administered q 28 days. Pretreatment vitamin supplementation consists of 1 mg IM vitamin B12 repeated q 9 weeks and daily oral folate 350–1,000 mcg. DLT is defined as grade 4 neutropenia =5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3–4 non-hematological toxicity in cycle 1. Results: To date, 12 pts ages 40–70 have been enrolled at 3 dose levels. Tumor types (N pts) include leiomyosarcoma (3); schwannoma (1); synovial sarcoma (1); transitional cell carcinoma of the bladder (1) and non-small cell lung carcinoma (NSCLC) (6). One patient was withdrawn for early progressive disease. Grade 3/4 treatment-emergent toxicities for 11 pts include neutropenia (3), anemia (1), mucositis (1), hyperglycemia (1), anorexia (1), weight loss (1), hyponatremia (1), pain (1), dehydration (1), fatigue (1), and thromboembolism (1). In addition, one pt had grade 5 pneumonitis during cycle 3. Dose level 3 has been expanded due to DLT in 1 pt. Antitumor activity for 11 evaluable pts includes 2 confirmed partial responses (by RECIST) in uterine leiomyosarcoma after adjuvant AIM therapy and pretreated NSCLC; stable disease in 5 pts; and progressive disease in 4 pts. Conclusion: Biweekly dosing of PEM + DOC is feasible and shows activity in a number of advanced solid tumors. The MTD has not been reached. *Pt with early progression replaced [Table: see text] No significant financial relationships to disclose.
Mechanical restriction to tidal volume expansion partially determines intensity of physical activity in COPD
Authors: Eleni Kortianou, Maroula Vasilopoulou, Zafeiris Louvaris, Ioannis Nasis, Stavroula Spetsioti, Vasilis Andrianopoulos, Giorgos Kaltsakas, Nikolaos G. Koulouris, Ioannis Vogiatzis
Journal: European Respiratory Journal (2013)

Aim : We investigated whether the intensity of movement outdoors adopted by each individual COPD patient during walking, is determined by the degree of mechanical restriction to tidal volume expansion.

Methods : Eighteen COPD patients (FEV1 %pred: 48±14) underwent an indoor treadmill walking test at a speed corresponding to each individual patient’s average outdoor walking intensity that was captured by the DynaPort Minimod accelerometer during a preceded 7-day period. Chest wall volume variations were computed breath-by-breath by Optoelectronic Plethysmography.

Results : Outdoor walking intensity ranged from 1.5 to 2.3 m/s² and it was significantly related to: i) the breathing pattern adopted by each individual patient (breathing frequency: 24±1breaths/min, r=-0.48; VT/Ti: 1.4±0.08, r=0.51; VT/Te: 1.1±0.1, r=0.6); ii) the degree of dynamic lung hyperinflation (2.16±0.15 L, r=0.55) and iii) the magnitude of both tidal volume expansion (1.68±0.14 L, r=0.58) and minute ventilation (40.2±2.4 L, r=0.84). Variations in minute ventilation with increasing movement intensity were primarily determined by variations in individual patients’ tidal volume expansion (r=0.77).

Conclusions : For each individual patient outdoor movement intensity is determined by the breathing pattern and the degree of mechanical restriction to tidal volume expansion that the patient exhibits during walking.

This work was funded by Innovative Medicines Initiative Joint Undertaking (IMU-JU #115011) and by Thorax Foundation.
Inhibition of Inflammation and Mucus Production By Bordetella Pertussis Whole-Cell Vaccine in a Murine Model of Allergic Rhinitis
Authors: Marcelo Vivolo Aun, Fernanda Arantes-Costa, Francine Maria Almeida, Thayse Regina Brüggermann, Beatriz Mangueira Saraiva-Romanholo, Isabella S. Genaro, Milton Arruda Martins, Jorge Kalil, Pedro Giavina-Bianchi
Journal: Journal of Allergy and Clinical Immunology (2016)
Combining ovarian function suppression (GNRH analog) and chemotherapy with epirubicin (E) cisplatin (C) and fluorouracil as continuous infusion (FUci) (ECF regimen) as primary treatment for premenopausal women with endocrine responsive breast cancer
Authors: R. Torrisi, M. Colleoni, G. Peruzzotti, M. Medici, R. Ardito, P. Veronesi, G. Viale, T. De Pas, F. Nolè, A. Goldhirsch
Journal: Journal of Clinical Oncology (2004)

9645 Background: Chemotherapy is an established primary treatment for patients with large breast cancer. Although premenopausal patients with endocrine responsive tumors might benefit from the addition of ovarian suppression to chemotherapy, no data are available on their combined use. Methods: We investigated the efficacy in terms of clinical response (CR) and pathological complete responses (pCR) of the ECF regimen (E 25 mg/m2 i.v. Day 1&2; P 60 mg/ m2 i.v. Day 1; CIfu 200 mg/ m2 Days 1 through 21, all q 21 days) for 6 courses, in association with a 28-day GnRH analogue, administered either as a subcutaneous or intramuscular injection from start of chemotherapy in premenopausal women with T2-T4a-d N0–2 M0 ER and/or PgR positive breast cancer, all treated in one institution. FSH, LH and 17-β-estradiol were measured every 21 days starting from day 1 of chemotherapy. Results: Thirty-six patients were enrolled from 09/1999 to 12/2001. Median age was 40 years (range 26–52). Chemotherapy was administered for at least 3 courses in all patients (range 3–6). Thirty out of 31 patients evaluable for endocrine assessment had documented ovarian suppression after administration of a GnRH analogue. Median time to ovarian suppression was 28 days (range 20–43). Clinical response (complete or partial) was observed in 27 out of 36 patients (75%) and a pCR was observed in 4 pts (11 %). Nine (25%) patients had stable disease and no progression was observed. Twenty-one patients were submitted to quadrantectomy + axillary node dissection and 15 had a radical mastectomy. Conclusions: The combination of ECF and a GnRH analogue is associated with a high response rate. Results favorably compare with previous series of patients with endocrine responsive disease treated with chemotherapy alone, where no pCRs were observed. The concurrent combination of chemotherapy and GnRH analog dose not seem similar to concurrent tamoxifen and chemotherapy, for which evidence of a detriment on efficacy is documented, and appears suitable for further investigations. No significant financial relationships to disclose.
Merit of nagging policy makers as part of a comprehensive campaign to effect change
Authors: Anthony A Laverty, Simon Capewell
Journal: BMJ (2015)

McCartney raises several important points on the futility of nagging patients to be more physically active.1 Her alternative to nagging patients is to nag policy makers. This strategy has merits, particularly if part of a comprehensive campaign.

Examination of any guides on how to influence policy finds that relationship building is key. The public health and medical communities …
Intensity modulated radiation therapy (IMRT) may reduce the oesophageal toxicity of hypofractionated accelerated 3-D radiation for non small cell lung carcinoma
Authors: P. Thirion, C. Kelly, C. O' Shea, C. Collins, O. Holmberg, M. Michael, M. Pomeroy, D. Hollywood, C. Faul, J. Armstrong
Journal: Journal of Clinical Oncology (2004)

7233 Background: Several groups are assessing the feasibility of increasing the radiobiological impact of 3-D radiation for NSCLC by using high dose per fraction dose escalation. We report the most mature data of any trial using 3Gy /fraction (72 Gy/24 fractions). Methods: 30 pts with NSCLC with KPS>70% and wt loss <10% in 3 months, with inoperable stage I/II (11 ) or unresectable stage IIIa/b, no effusion (19 ). Initial chemotherapy was used in 13 pts. No more than 30% of the combined lungs could receive >=25 Gy (V25) and the max. dose to the cord was < 61%. No oesophageal dose limits were used. Results: 8 CR and 11 PR in 27 evaluable pts. Median time to local progression, progression and survival: 18.6, 17.3 and 12.6 months. No grade-4 acute toxicity occurred. 2 pts had grade-3 acute oesophageal toxicity and 1 pt a grade 3 acute lung toxicity. 26 pts were evaluable for long-term toxicity (median follow-up 9.5 months). Late grade-1 lung toxicity occurred in 5 pts. Late oesophageal toxicity was clinically dominant: grade 1 in 2 pts, grade 2 in 1 pt and grade 3 in 1 pt. There was a significant association between late toxicity and length of circumferential oesophagus receiving 97% of the prescribed dose. If this length was <1cm late oesophageal toxicity occurred in 0/16 vs. 4/10 if it exceeded 1cm. p< 0.05. We redesigned the treatment of patients with oesophageal toxicity and length of circumferential oesophagus receiving 97% of the prescribed dose >1cm, with IMRT to see if this length could be reduced. For 3 of 4 patients IMRT reduced the length without exceeding lung constraints. Conclusions: Oesophageal toxicity was the main toxicity of clinical concern, with 20% of pts experiencing acute or long-term toxicity. The trial continues with new oesophageal dose-volume constraints. IMRT may have the potential to avoid excessive irradiation of focal parts of the oesophagus. No significant financial relationships to disclose.
Analysis of the clinical implications of c-kit expression in small cell lung cancer patients (SCLC)
Authors: A. Carrato, C. Camps, R. Sirera, M. J. Safont, J. Garde, P. Bayo, A. Berrocal, C. Caballero, A. Juarez, A. Blasco
Journal: Journal of Clinical Oncology (2005)

7164 Background: c-kit is a growth factor receptor that plays a crucial role in the biology of cancer. The aim of this study was to determine the incidence and role of c-kit overexpression as a prognostic marker in patients with SCLC. Methods: A retrospective study with 70 patients diagnosed of SCLC was performed. Relevant clinical information was obtained from chart review (age, performance status -PS-, weight loss, tumor stage and response to therapy). c-kit expression was analyzed in formalin-fixed and paraffin-embedded tumor tissues immunohistochemically. Results: Mean age of the cohort was 62.5 years [40–80] and 96% were males. 35 patients presented extended disease (ED) at diagnosis and 35 patients limited disease (LD). c-kit expression was observed in 58.7% of the patients. c-kit was observed in 44.4% in LD and 55.6% in ED (p=0.402). All patients were former o actual smokers. Weight loss was present in 52.3% at diagnosis. Patients with a PS between 0–2 represented 85.7% of the c-kit positive group and 90% in the c-kit negative one. 36 patients received a median of 4 cycles of first-line therapy (52.2% vs 47.8% in c-kit positive and negative group respectively). The most used schedule was platinum plus etoposide and the most common second-line agent was topotecan. Radiotherapy of the primary tumor was administered in 42.9% of the patients in the c-kit positive group and in 30% in the negative one (p=0.107). In LD and comparing the c-kit positive group vs the negative one: Complete Response (CR) and Partial Response (PR) was observed in 75% versus 60%.and Stable Disease (SD) or Progressive Disease (PD) in 25% vs 40%, (p=384). Mean time to progression (TTP) was 11.7 vs 5.9 months respectively (p=0.26) and overall survival (OS) was 24.5 vs 17.5 months (p=0.17). In the EE group CR +PR was observed in 40% vs 33% and SD + PD in 60% vs 67%, (p=547). TTP was 5.9 vs 8.9 months respectively (p=0.72) and OS was 5.9 vs 11.8 months (p=0.65). Conclusions: c-kit is expressed in about 60% of the patients with SCLC. Our findings do not suggest a significant association between c-kit expression and survival either in the ED or LD group. New studies with longer cohorts are needed in order to define its prognostic value. No significant financial relationships to disclose.
Plasma Membrane and Intracellular Lipid Synthesis in Tumor Cells Rendered Sensitive to Humoral Immune Killing After Treatment With Metabolic Inhibitors<xref ref-type="fn" rid="FN2">2</xref>
Authors: S I Schlager, S H Ohanian
Journal: JNCI Journal of the National Cancer Institute (1979)

Line 10 guinea pigs hepatoma cells are resistant to killing by antibody and guinea pig complement. Metabolic inhibitors (adriamycin and actinomycin D) that increase the sensitivity of the cells to antibody-complement (C) killing were examined for their effects on the ability of the cells to synthesize and incorporate specific lipids into plasma membrane and intracellular membrane fractions. Drug-treated cells that had been rendered sensitive to antibody-C killing were inhibited in their incorporation of newly synthesized phosphatidylcholine and cholesteryl ester into the plasma membrane, as well as incorporation of phosphatidylcholine, cardiolipin, cholesteryl ester, and triglyceride into certain intracellular organelles including mitochondria, endoplasmic reticulum, nuclear membrane, or microsomes. Drug-treated cells recultured in the absence of the drug regained their ability to resist antibody-C killing and to synthesize and incorporate lipids into plasma and intracellular membranes. These data suggested that agents modifying the sensitivity of the tumor cells to humoral immune killing have a concomitant effect on plasma membrane and intracellular lipid synthesis.
Abstract P052: The Effect of Re-designing Workflow and Introducing Automated Blood Pressure Devices in Community-based Primary Care Clinics
Authors: Romsai T Boonyasai, Greg P Prokopowicz, Jeanne Charleston, Kathryn A Carson, Gary J Noronha, Edgar R Miller, Lisa A Cooper
Journal: Circulation (2012)

BACKGROUND: Prior studies report that poor technique and terminal digit preference (TDP) can distort blood pressure (BP) estimates in clinical settings. These limitations may bias population BP estimates, increase clinician workload, and contribute to clinical inertia. HYPOTHESIS: We hypothesized that BP measurement training with an automated blood pressure measurement (aBPM) device would reduce TDP, reduce the number of times clinicians repeat staff-obtained measurements, and reduce average BP estimates within each site. METHODS: We replaced aneroid BP measurement devices in 6 community-based primary care clinics with aBPM devices (Omron HEM-907XL) and trained clinic staff with a standardized BP measurement protocol using 1 hour presentations and follow-up visits. We report mean weekly BP measured in the 8 weeks pre- and 4 weeks post-intervention at the first intervention site. Results are analyzed using chi-squared and paired t-tests. RESULTS: Clinic staff recorded 5796 BP readings in the 8 week pre-intervention period and 2321 readings in the 4 weeks post-intervention period. TDP and clinician workload improved after the intervention. Pre-intervention, 1941 of 4833 (40.2%) of systolic BP and 2199 of 4833 (45.5%) of diastolic BP ended in zero, in contrast to 216 of 2158 (10.0%) of systolic and 219 of 2158 (10.2%) of diastolic readings post-intervention (P&lt;.001 for both SBP and DBP). Clinicians repeated BP obtained by staff in 963 of 5796 (16.6%) of visits pre-intervention but only in 163 of 2321 (7.0%) of visits post-intervention (P&lt;.001). TDP persisted when clinicians repeated staff-obtained BP readings post-intervention: 58 of 163 (35.6%) systolic and 65 of 163 (35.7%) diastolic BP ended in zero (P=.32 for SBP and P=.35 for DBP in comparison with pre-intervention BP readings). Overall, BP estimates changed modestly following the intervention. Post-intervention, mean systolic BP rose 1.4 mmHg (P=.004) and diastolic BP declined 3.1 mmHg (P&lt;.001). Among clinician-repeated BP readings, systolic BP rose 2.4 mmHg (P=.12 for pre/post change) and diastolic BP declined 0.4 mmHg (P=.72 for pre/post change). CONCLUSIONS: A standardized BP measurement protocol used with an aBPM device in community-based primary care settings can reduce TDP and clinician workload but is associated with only modest change in population BP estimates.
Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma
Authors: J. H. Kim, H. Y. Kim, C. W. Jung, S.-H. Lee, K. Kim, W. S. Kim, Y. S. Park, Y.-H. Im, W. K. Kang, K. Park
Journal: Journal of Clinical Oncology (2005)

4602 Backgrounds: Somatic inactivation of the von Hippel-Lindau (VHL) gene is the most frequent genetic event observed in clear cell renal cell carcinomas (CC-RCCs). However, the prognostic relevance of somatic VHL alteration and its target, hypoxia inducible factor (HIF)-1α, has not been defined. We investigated the genetic changes in the VHL gene and HIF-1α and studied their clinical implications in patients with sporadic CC-RCC. Methods: Patients who underwent nephrectomy were eligible if they had pathologically confirmed CC-RCC that was not associated with VHL disease or familial RCC. Tumor tissues were selected from paraffin blocks on the basis of hematoxylin and eosin (H&E)-stained sections. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis was performed to detect VHL mutations and genetic changes in HIF-1α, which were followed by automated direct sequencing. VHL hypermethylation was examined by methylation-specific PCR. Results: A total of 56 patients were enrolled and somatic VHL alterations were detected in 16 (29%); intragenic mutation in eight, hypermethylation in five, and both alteration in three. The mutation types were missense in five patients, silent in three, nonsense in two, and frameshift in one. Somatic VHL alterations were not significantly associated with progression-free survival (PFS) or overall survival (OS). However, patients with a ‘loss-of-function’ VHL mutation showed significantly decreased PFS (P=0.016) and OS (P=0.046). Although the association between VHL alteration and response to immunotherapy was not significant (P=0.486), The CC-RCCs with missense mutation seem to have had better responses to immunotherapy. The Pro582Ser change in HIF-1α was detected in six patients (11%) and was positively correlated with the development of metastases (P=0.023). Concluions: This study did not show an association between somatic VHL alteration and prognosis in patients with sporadic CC-RCC. However, it suggests that the therapeutic and prognostic implication of somatic VHL alteration may be different according to the mutational subtype and that the Pro582Ser change in HIF-1α may contribute to the development of metastases. No significant financial relationships to disclose.
Phase I trial of anti-sense oligonucleotide vascular endothelial growth factor (VEGF-AS, Veglin) in patients with relapsed and refractory malignancies
Authors: A. M. Levine, D. I. Quinn, G. Gorospe, H. J. Lenz, A. Tulpule
Journal: Journal of Clinical Oncology (2004)

3008 Background: Vascular endothelial growth factor (VEGF) is critical for tumor angiogenesis and is an autocrine growth factor in some cancers. Elevated tumor/serum VEGF levels predict poor survival in cancer patients (pts). A novel VEGF-antisense coumpound (VEGF-AS, Veglin) has been developed, targeting VEGF-A,-C and -D. In vitro and in vivo studies with Veglin show inhibition of VEGF receptor binding and expression, resulting in tumor growth inhibition. Methods: For the first 4 levels of this phase I dose escalation trial, pts received a single course of Veglin given IV over 2 hours for 5 consecutive days at 15, 22.5, 30, and 37.5 mg/m2. Subsequent pts were given repeat cycles of Veglin for 5 days every 2 weeks (8 cycles, max) at doses of 47, 59, 74, and 85 mg/m2. 3 pts were accrued to each dose level. Results: To date, 19 males and 7 females, median age 57 years, (range 19–83) were accrued. All failed standard therapy including systemic chemotherapy in 24 (92%), biologics/ immunotherapy in 13 (50%), and radiation in 9 (35%). The most common tumor types accrued were lymphoma (NHL) in 5; sarcoma in 4; renal and AIDS-related Kaposi's sarcoma in 3 each; colon and lung in 2 each. All pts completed the initial 5 days of Veglin. Plasma VEGF levels declined in 56% of pts.Veglin infusions were well tolerated with no dose limiting toxicities observed at doses up to 85 mg/m2. One case of grade 3 anemia has occurred; there was no grade 3 or 4 neutropenia or thrombocytopenia. No perturbation in coagulation or complement profiles have been seen. Non-hematologic side effects were grade 1 or 2 and included fatigue, hypotension, and perioral numbness (all <20% of pts). The maximum tolerated dose has not been reached. \(\underline{\mathrm{Response\ data}}\): There has been anti-tumor activity in 2 patients with AIDS-related KS (one biopsy-proven CR at level 1), in 1 pt with renal cell (PR), and 1 pt with tumor cutaneous T-cell NHL (PR). Conclusions: Veglin is well tolerated at doses up to 85 mg/m2with no dose limiting toxicities. Veglin has shown evidence of anti-tumor activity, even at the lowest dose studied. Updated clinical and pharmacokinetic information will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vasgene Corporation; The Whittier Foundation