tbuckley/cabot-search huggingface dataset:
Quality of life (QOL) for breast cancer patients receiving aprepitant versus placebo for prevention of chemotherapy induced nausea and vomiting
Authors: B. C. Zee, W. Yeo, F. K. Mo, W. Lau, A. Poon, L. Chan, W. M. Ho
Journal: Journal of Clinical Oncology (2008)

20549 Background: A Phase III randomized, double-blind placebo controlled trial was done to determine if there is a favourable QOL outcome for patients receiving aprepitant for the prevention of chemotherapy-induced nausea and vomiting (adriamycin 60 mg/m2 + cyclophosphamide 600 mg/m2). Methods: 80 breast cancer patients were entered with 40 in the study treatment arm (aprepitant 125mg; ondansetron 8mg x 2 doses; dexamethasone 20mg on day 1 and aprepitant 80mg QD day 2–3) and 40 patients in the control arm (ondansetron 8mg x 2 doses; dexamethasone 12mg on day 1, and ondansetron 8mg every 12 hours on days 2–3). The QLQ-C30 and FLIE were completed prior to chemotherapy and at the end of day 5. A change score from baseline to day 5 was used in the analysis. Results: The average nausea scores captured by 100 mm visual analog scale between placebo and aprepitant arms were not significant (16.5 vs. 12.8, p=0.554). However, in cycle 1 the QLQ-C30 NV subscale (40.3 vs 20.4, p=0.0066) and appetite loss (57.4 vs 33.3, p=0.0023) were significantly different in favour of aprepitant arm. There were no significant difference with respect to global QOL (-19.9 vs -12.2, p=0.1633). The FLIE nausea subscale (40.1 vs 30.6, p=0.3214) were not significant, but FLIE vomiting subscale (30.4 vs 3.1, p=0.0001) and FLIE overall score (35.3 vs 16.8, p=0.0289) were significant in favour of study treatment. For cycles 2 and 3, we have 36 and 38 patients in the control and study treatment arms respectively. Similar results were found in the FLIE subscales and overall score. Conclusions: There is a significant benefit for the study treatment with respect to QLQ-C30 QOL NV subscale, which is a combined measure on nausea and vomiting. FLIE overall score is an aggregate measurement of 18 items and reflects a significant benefit in favour of aprepitant arm. The majority of treatment effect was due to FLIE vomiting subscale but not FLIE nausea subscale reflecting that aprepitant may provide better control to vomiting than nausea. Study supported by Merck Sharp & Dohme (Asia) Ltd. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Sharp & Dohme (Asia) Ltd.
Hepatic intra-arterial chemotherapy in patients with advanced hepatocellular and biliary tract carcinomas using a temporary percutaneous catheter.
Authors: F. Spada, F. Orsi, G. Bonomo, S. Boselli, M. Squadroni, G. Di Meglio, K. Lorizzo, A. Farris, F. G. De Braud, N. Fazio
Journal: Journal of Clinical Oncology (2010)

e14622 Background: Hepatocellular and biliary tract carcinomas are chemoresistant and poor prognosis malignancies. After around 30 years of no drug approval, sorafenib was registered as a first line in patients with advanced hepatocellular carcinoma (HCC) with preserved liver function. In HCC systemic chemotherapy did not improve survival, while very recent evidence suggested a possible efficacy of gemcitabine/cisplatin in biliary tract carcinomas (BTC). Nevertheless several studies supported a higher activity when chemotherapy is performed ashepatic intra-arterial infusion. This study evaluated feasibility, activity and toxicity of hepatic intra-arterial chemotherapy (HIAC) in patients with advanced HCC and BTC. Methods: Between July 1997 and June 2003, 43 consecutive patients with advanced unresectable tumor (28 HCC and 14 BTC) were enrolled. A 3-day HIAC, with 5-fluorouracil 1,000 mg/m2/day over 3 days as a continuous infusion, cisplatin 10 mg/m2 twice daily and mitomycin-C 2 mg/m2 twice daily on days 1-3, every 6 weeks until tumor progression or unacceptable toxicity, was performed through a radiologically placed temporary percutaneous catheter. Results: Ninety-nine cycles were delivered (median per patient: 2, range: 1-4). A partial response was observed in 4/14 BTC (28%), and 7/28 HCC (25%). Seven out of 14 (50%) BTC and 10/28 (36%) HCC had a stable disease (SD). Twenty HCC patients (46%) had a chronic liver disease. Twenty-seven patients (63%) were pre-treated. Manageable catheter-related complications were observed in 10 patients (23%). Most relevant grade 3-4 toxicities included neutropenia (2%), thrombocytopenia (5%) and transaminitis (12%). Febrile neutropenia was observed in one patient. No toxic deaths were observed. Conclusions: This study showed that HIAC with 5-fluorouracil, cisplatin and mitomycin-C, administered through a radiological temporary percutaneous catheter, represents a feasible, active, and well tolerated therapy in patients with advanced HCC and BTC. This treatment could be studied in selected patients with advanced HCC progressive on or not eligible for sorafenib and in patients with liver-dominant metastatic BTC. No significant financial relationships to disclose.
Polyfunctional Tumor Antigen-specific T Cells Generated in Vitro from Human CD34 Positive Precursor Cells Transduced to Express T Cell Receptor αβ Chains Fused to CD28-CD3ζ Signaling Cassette
Authors: Yasmine Van Caeneghem, Glenn Goetgeluk, Sylvia Snauwaert, Fritz Offner, Reno Debets, Tessa Kerre, Bart Vandekerckhove
Journal: Blood (2014)
Phase I study of NGR-hTNF administered at high doses in refractory patients with solid tumors.
Authors: M. Simonelli, A. Santoro, P. A. Zucali, L. Rimassa, F. De Vincenzo, T. Pressiani, M. C. Tronconi, C. Carnaghi, A. Lambiase, C. Bordignon
Journal: Journal of Clinical Oncology (2010)

e13091 Background: NGR-hTNF is a vascular targeting agent exploiting a tumor homing peptide (NGR) that selectively binds an aminopeptidase N overexpressed on tumor blood vessels. Previously, a phase I trial testing doses ranging from 0.2 to 60 μg/m2 established the maximum tolerated dose (MTD) of NGR-hTNF at 45 μg/m2 when given as 1-h infusion every 3 weeks (q3w), with dose-limiting toxicity (DLT) being characterized by transient infusion-time related grade 3 reactions. Here, we report further dose escalation by using both longer infusion time and mild premedication. Methods: Patients (pts) with refractory solid tumors received NGR-hTNF given at 60, 80, 100, and 125 μg/m2 as 2-h infusion q3w. Acetaminophen 1,000 mg was given before dosing. Four pts for each dose level (DL) were planned to be enrolled. Any drug-related grade 3 or 4 toxicity was deemed as DLT. Plasma samples for pharmacokinetics and pharmacodynamics (soluble TNF-receptors, sTNF-R1 and -R2) were tested over the first 3 cycles. To assess the biologic effects on tumor vascularity, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before and on treatment. Results: 12 pts (median age: 65 years, range, 37-71; PS 0/1: 7/5) with a variety of solid tumors were enrolled at the first 3 DLs and were assessed over 32 cycles (range, 1-6). The median number of prior treatment lines was 3 (range, 1-5). No DLTs were recorded at 60 (n=4), 80 (n=4), and 100 μg/m2 (n=4). Most drug related toxicities were grade 1 chills experienced by 7 pts (58%) over 16 cycles (50%). One grade 2 vomiting was noted at the highest DL explored. Both Cmaxand AUC increased dose-proportionally (p=0.0001). The levels of sTNF-R2 were significantly higher than those of sTNF-R1 (p=0.0001). However, the mean changes vs baseline did not significantly differ across DLs (p=0.18 for R1 and p=0.13 for R2), thus suggesting a plateau in the shedding kinetics. By DCE-MRI assessment, decreases in both the volume transfer coefficient (Ktrans) and the initial area under the contrast agent concentration time curve (IAUGC) were detectable in all DLs. Conclusions: NGR-hTNF can be safely escalated at doses higher than the MTD by using longer infusion time and mild premedication. Further dose escalation is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed
In Vivo Modulation of Mitochondrial Activity Determines HSC Engraftment and Post-Transplant Survival in Mice
Authors: Nicola Vannini, Olaia M. Naveiras, Vasco Campos, Eija Pirinen, Riekelt Houtkooper, Mukul Girotra, Aline Roch, Johan Auwerx, Matthias Lutolf
Journal: Blood (2012)
Leptin receptor expression in parathyroid cancer.
Authors: Zorka Inic, Snezana Jancic, Momcilo Inic, Ivan Paunovic, Svetislav Tatic, Vladan Zivavljevic, Ivana Inic, Milan Zegarac, Katarina Tausanovic
Journal: Journal of Clinical Oncology (2014)

e17060 Background: Epidemiology studies have shown that there is a strong, positive correlation between obesity and the incidence of several types of carcinoma. One of the most important mediators correlating between obesity and an increased risk of cancer is leptin, which is an adipokine whose major functions are regulating appetite and energy homeostasis. However, no previous studies have yet to examine leptin or its receptor expression in parathyroid cancer (PC). PC is a rare malignancy which accounts about 1% of the cases of primary hyperparathyroidism Methods: In this study, the expression of leptin receptors (OBRs) was examined in 10 parathyroid cancer samples using immunohistochemistry, for which their associations with clinicopathological parameters were also evaluated. Ten patients (six men, four women) underwent operations for parathyroid carcinoma and primary hyperparathyroidism (HPTH) at the Clinical Centre of Serbia. All patients had hypercalcemia (a mean of 3.55 mmol/l) and elevated parathyroid hormone (a mean of 1824 pg/ml). Results: The expression of leptin is associated with OBRs, which were observed in the tumor cell membrane and/or cytoplasm of these patients, at a positive rate of 40 %. The Mann-Whitney Test confirmed a statistically significant difference (p=0.033) in the gland's weight which was not possible to find in regard to parathyroid hormone, calcium, gland's size, multifocality or age, due to the size of the sample, although they were increased in this group. Conclusions: The results of the researches have found that the expression levels of leptin and OBRs are mutully associated and have a role in the development of a large variety of malignancies promoting angiogenic factors that increase cancer cell survival, proliferation, and migration. The results signify the expression of leptin and/or OBRs in parathyroid cancer to be associated with parathyroid weight and may be a potential target in parathyroid cancer.This is still the first report. Further research is necessary in order to determine the potential prognostic and thearapeutic implication of the leptin/OBRs system and whether a correlation exists with other clinicopathological features.
A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.
Authors: Amy Patricia Moore, Thach-Giao Truong, Kenneth Ted Thurn, Scott Thomas, Charles J. Ryan, Thierry Marie Jahan, Steven G. DuBois, John K. Chan, Hope S. Rugo, Eric Andrew Collisson, Paromita Raha, Stephanie Chen, Anne Reinert, Adil Daud, Pamela N. Munster
Journal: Journal of Clinical Oncology (2012)

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.
Oral pilocarpine to treat vaginal xerosis associated with chemotherapy-induced amenorrhea in pre-menopausal women
Authors: F. G. Le Veque, S. Hendrix
Journal: Journal of Clinical Oncology (2004)

8099 Background: Chemotherapy-induced amenorrhea frequently results in side effects common to those experienced in menopause; vaginal dryness (VD) and its related symptoms are prominent examples. Although many of these side effects respond to the use of estrogen replacement therapy (ERT), many cancer survivors choose to not chance the risks linked with ERT. Previous results in a placebo-controlled Phase III study treating xeroses associated with Sjögren's syndrome with oral pilocarpine (OP){Salagen® Tablets}demonstrated impressive improvement in VD, P≤0.02 (25% vs.14%):Vivino et al; Arch Intern Med. 1999;159. Methods: A 12-week, open-label pilot study was conducted using OP (5mg./qid) in pre-menopausal women with VD caused by the effects of high cumulative dose cyclophosphamide on ovarian function. Study enrollment required a minimum 2 month history of VD and 4 months status-post chemotherapy. The primary endpoint of this study was a global assessment of VD measured on a standard visual analog scale (VAS), at 6 and 12 weeks of treatment, or at final study visit if prior to week 12. Participants were asked to characterize their VD at these visits compared to their VD before treatment with OP; each participant acted as her own control. Results: The pre-study expectation was for a 25 mm (absolute) improvement in the participants' VAS by end of study. Four of four evaluable participants treated with OP experienced a marked clinical improvement in VD.Three responders recorded ≥40mm absolute gain in VAS, the fourth gained ≥28mm. Conclusions: OP, a well-tolerated muscarinic agonist was able to stimulate remaining mucus and other moisture producing cells in the vaginal mucosa & muscularis to the extent that a marked clinical improvement in VD was experienced by each of the study participants. The only AEs experienced were mild and of the known side effects of OP and did not interfere with treatment. These results warrant further investigation as a possible treatment for symptomatic relief of this difficult problem. No significant financial relationships to disclose.
Initial study of bone scan tumor area for early surrogate outcome assessment in patients with metastatic castration-resistant prostate cancer.
Authors: H. J. Kim, M. S. Brown, G. H. Chu, D. W. Gjertson, M. Auerbach, C. Poon, A. Vidovic, B. Ramakrishna, M. J. Morris, S. M. Larson, H. I. Scher, J. G. Goldin
Journal: Journal of Clinical Oncology (2011)

e15161 Background: Assessment of changes in tumor burden on bone scans is challenging. A computer-aided (CAD) system to measure overall tumor area on bone scans has been developed with pixel-level of 94.1% sensitivity 89.2% specificity, and 89.4% accuracy. We hypothesize that early changes in tumor area, determined by CAD, will be useful for predicting a patient’s progression rate. Methods: From an anonymized image database, 34 patients with castrate resistant prostate cancer undergoing one of two treatments (A and B) were randomly selected. Whole body standard of care scintigraphy was acquired in original DICOM format. Baseline and 14-week follow-up bone scans were analyzed with the CAD system. Early progressive disease (PD) was defined if the change in area was greater than 30% at 14 weeks. Multivariate Cox regression was use to test the PD effects on progression-free and patient survival rates, controlling for age and treatment. Results: At baseline, the median tumor area was 256 cm2 (267 cm2 for Treatment A and 250 cm2 for Treatment B) and 44% of patients were found to have PD at 14-week follow-up based on CAD assessment. Patients without PD had significantly longer progression-free beyond 14 weeks than subjects with PD: median 461 days vs. 135 days, p=0.04, hazard ratio= 3.0 (see table). The overall patient survival rates between non-PD and PD subjects were not statistically different (median 347 days vs. 284 days, p=0.42). Conclusions: Early changes in computer-aided measurements of overall tumor area on bone scans holds promise as a surrogate outcome in prostate cancer studies and may aid in new drug development. Multivariate Cox model for progression-free survival in metastatic castration-resistant prostate cancer patients. Variable Hazard ratio Standard error P value 95% confidence interval Age>65 yr 1.3 0.75 0.65 0.42–4.0 Treatment 0.69 0.39 0.51 0.22–2.1 Early progressive disease by CAD 3.0 1.59 0.04 1.1–8.5
Analysis of the cause of discordance between two radiologists on the assessment of radiographic response and progression for subjects enrolled in breast cancer clinical trials employing blinded independent central review.
Authors: K. Borradaile, R. Ford, J. M. O'Neal, K. Byrne
Journal: Journal of Clinical Oncology (2010)

6044 Background: The Food and Drug Administration (FDA) advocates blinded independent central review (BICR) of radiographic exams for oncology registration studies when the primary endpoint is based on tumor measurements. Current FDA guidance recommends multiple BICR readers evaluating each subject. This introduces the potential for discordance between readers on subject outcome resulting in adjudication by a third reader. There are no published metrics regarding the cause of discordance between BICR radiologists. Methods: BICR data was reviewed to identify 459 cases in which 2 readers were discordant in outcome. Cases were reviewed to determine the cause of discordance. Results: In 37% of cases (168/459) discordance resulted from differences inlesion selection. In 137 cases the difference was justifiable, but in 31, the choice of lesions by one reader was not thought to represent the overall extent of disease. In 30% of cases (139/459) discordance resulted from a difference in the perception of new lesions. In 88 cases the difference was justifiable, but in 51, one reader's assessment was deemed incorrect during review. In 13% of cases (58/459) discordance resulted from a difference in the qualitative assessment of nontarget disease progression. In 39 cases the difference was justifiable, but in 19, one reader's assessment was deemed incorrect. In 11% of cases (52/459) image quality issues resulted in a justifiable difference between readers. In 9% of cases (41/459) discordance resulted from a difference in lesion measurements between readers. In 37 cases the difference was justifiable, but in 4, one reader's measurements were deemed incorrect. In one case, discordance resulted from a lack of clinical information during the review. Conclusions: Some factors that cause discordance are process-driven or due to justifiable interpretation differences as was observed in 77% of cases (354/459). Separate from these factors are reader assessment errors such as those identified in 23% of cases (105/459). The BICR process of adjudication by a third reader identifies and mitigates these interpretive errors. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration RadPharm, Inc. RadPharm, Inc. RadPharm, Inc.
Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells
Authors: G. von Wichert, T. Edenfeld, G. Adler, T. Seufferlein
Journal: Journal of Clinical Oncology (2008)

22165 Background: Chromogranin A is a member of the granin family of acidic secretory glycoproteins that is found in secretory granules of many endocrine cells including neuroendocrine tumour cells. This hormone serves as a model system for autonomous hormone secretion by the so called functional neuroendocrine tumours of the gastrointestinal tract. The protein kinase D (PKD) family of serine threonine kinases has so far been implicated in the regulation of constitutive secretion in epithelial cells. Here we examined whether PKD2 expression and activity could also play a role in the release of secretory granules from the trans Golgi network (TGN) in neuroendocrine tumour cells and hence be a target to block autonomous secretion by these tumours. Methods: BON neuroendocrine tumour cells are the only established model for studying the biology of these rare type of tumours. We used invivo fluorescence microscopy in order to study the distribution and transport of hormone containing vesicles in these cells in response to stimulation with phorbol esters or in response to changes in the expression and/or activity of PKD2. In addition, secretion and activity/expression of PKD2 was quantitatively assessed by western blot analysis and immunoprecipitation- experiments. Results: Our data show that expression and catalytic activity of PKD2, and not of PKD1 and PKD3, are required for the release of chromogranin A containing secretory vesicles. Inhibition of PKD2 activity or siRNA knockdown of PKD2 resulted in a marked perinuclear retention of chromogranin A immunofluorescence in the trans Golgi network and led to a marked reduction in basal as well as phorbol ester stimulated secretion of chromogranin A into the supernatant of cells. Interestingly, PKD2 expression and activity were not required for the control of microtubulus-associated transport (speed and directionality) of hormon containing vesicels. Conclusion: PKD2 controls the release of secretory granules in neuroendocrine tumour cells at the level of the Golgi apparatus and could hence serve as a novel target to block hormone secretion in functional neuroendocrine tumours. No significant financial relationships to disclose.
Effects of granulocyte-macrophage colony-stimulating factor on in vitro growth of human solid tumors.
Authors: S E Salmon, R Liu
Journal: Journal of Clinical Oncology (1989)

Solid tumor biopsies from 33 patients were tested in vitro to evaluate the growth modulatory effects of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). In 29 of 33 studies (88%), addition of GM-CSF either had no effect on in vitro growth, or induced growth inhibition. While significant growth inhibition was observed in 10 studies, marked inhibition was only observed in three studies. However, all dose-response curves were usually flat, suggesting indirect effects. Moderate growth stimulation was observed in four instances, which may have been due to residual granulocyte-macrophage progenitors within the biopsies. We conclude that GM-CSF has little or no growth-modulatory effect on most nonhematopoietic neoplasms. The primary role of GM-CSF in patients with solid tumors appears to be in prevention or reversal of myelosuppression associated with therapy. Thus, while GM-CSF seems unlikely to have a role in monotherapy of cancer, it is also unlikely to have its utility compromised by enhancement of tumor growth.