tbuckley/cabot-search huggingface dataset:
The complete phase Ib clinical trial: A method to accelerate new agent development
Authors: D. D. Von Hoff, J. A. Nieves, L. K. Vocila, S. D. Weitman, E. Cvitkovic
Journal: Journal of Clinical Oncology (2007)

2562 Background: The usual clinical development plan for a new agent (NA) includes a phase I monotherapy trial. However, because many new agents are eventually developed as part of a combination, additional phase I trials assessing the new agent in combination with a standard agent are usually performed (usually as individual phase Ib studies). Our hypothesis was that within a single protocol, several combination phase I trials could be conducted simultaneously. Methods: The design of the protocol is (assuming the new agent is synergistic with an anthracycline, a tubulin interactive agent, an antimetabolite, an angiogenesis inhibitor or an antibody to EGFR): patients with advanced cancer are treated with the combination deemed most likely to be of help-with a choice of a) anthracycline + NA; b) tubulin interactive + NA; c) antimetabolite + NA; d) angiogenesis inhibitor + NA; e) antibody to EGFR + NA. The standard agent is started at full dose with 3 patients placed at 1/3 full dose of NA, 3 patients at 2/3 dose of NA, and 3–6 patients at full dose of the NA in the combination. Results: Our experience with the complete phase Ib trial has found several advantages over conducting separate phase I trials. The advantages include: (a) a very rapid follow-up on preclinical data in one study; (b) a saving of time and expense in the start up; (c) accrual is rapid because many patients in a practice are likely to be eligible (e.g. the standard agent is the standard of care); (d) patients are often less pretreated; (e) the trial generates information for more informed selection of follow-up randomized phase II or III trials. Conclusions: Utilizing a Complete phase Ib trial design is feasible. Our initial experience has suggested that this approach is safe and highly efficient with several potential advantages over multiple sequential combination phase Ib studies. No significant financial relationships to disclose.
Elevation of Infiltrating Mononuclear Phagocytes in Human Colorectal Tumors
Authors: C Allen, N Hogg
Journal: JNCI Journal of the National Cancer Institute (1987)

The distribution of infiltrating monocytes-macrophages and T-lymphocytes in 45 primary colorectal tumors and 8 metastatic lymph nodes has been investigated by immunoperoxidase labeling with monoclonal antibodies (MoAbs). The number of lymphoreticular cells observed in tumor tissue, staged according to Dukes classification, was compared with paired normal tissue and between staged groups by statistical analysis. T-lymphocytes were not significantly elevated above the normal in either Dukes B or C stage tumors, although the IL-2 receptor (MoAb Tac) was expressed by varying numbers of T-cells in both groups. Mononuclear phagocytes increased numerically in both Dukes B (1.5-fold, P-value <.01) and Dukes C tumors (2.5-fold, P-value <.001) as compared to those in the uninvolved gut. In addition, the number of both total (MoAbs 3.9, 24) and stimulated mononuclear phagocytes expressing the C3b receptor (MoAb E11) was greater in metastasizing than in nonmetastasizing tumors (P-value <.01). Thus the T-cell-to-monocyte ratio was altered from 2:1 in normal tissue to 1:1 in advanced tumors. The stromal environment around tumor cells in lymph nodes was similar to that of the primary tumor, but there was a reduction in the proportion of cells expressing the C3b receptor; unlike the primary tumor, there was virtually no infiltration of the tumor epithelium. Although there is a significant alteration in the mononuclear phagocyte population within colorectal tumors, there is no histologic evidence for a cytotoxic role for these cells.
Serum cytokine profile in metastatic renal cell carcinoma (RCC) patients undergoing immunotherapy
Authors: B. Wolf, T. Schwaab, A. Schwarzer, J. Y. Smith, K. M. Smith, J. L. Fisher, C. A. Foster, N. A. Crosby, J. D. Seigne, M. S. Ernstoff
Journal: Journal of Clinical Oncology (2008)

16061
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MLN8237, a novel selective aurora A kinase (AAK) inhibitor, in patients (pts) with advanced solid tumors
Authors: A. Cervantes-Ruiperez, M. E. Elez, S. Roselló, T. Macarulla, E. Rodríguez-Braun, Y. Lee, J. Ecsedy, H. Liu, H. Fingert, J. Tabernero
Journal: Journal of Clinical Oncology (2009)

2565 Background: MLN8237 is a second-generation, selective AAK inhibitor, designed to avoid benzodiazepine-like effects (somnolence) observed with another agent, MLN8054. This phase I trial examines the safety, PK, and PD of MLN8237 administered orally (PO) in pts with advanced solid tumors. Methods: Pts received MLN8237 PO once daily (QD) or twice daily (BID) for 7 days (d) followed by a 14d recovery period. Tumor and skin biopsies were done serially to evaluate bioactivity measured by mitotic index and chromosome and spindle abnormalities in mitotic cells. Doses were increased in cohorts of 3–6 pts until dose-limiting toxicity (DLT) evaluated in the first cycle was seen in ≥2 pts in a cohort. Results: As of 12-Dec-08, 27 pts received MLN8237 (median 2 cycles, range 1–10+); median age was 57 yr (range 31–78). The first cohort received 5mg QD. Higher QD doses were safe in another Phase 1 study (Infante et al, EJC Suppl 2008;6[12]:90), so subsequent cohorts in this study started at 80mg QD (Table). DLTs at 60–100mg PO BID included neutropenia, pancytopenia, stomatitis, and somnolence. Somnolence (of any grade) was seen with QD dosing, but was reduced with divided doses each &lt;100 mg. Antitumor activity was seen in a pt in cohort 4 with a large treatment-resistant pleomorphic liposarcoma. Preliminary PK analyses showed dose-dependent increases in AUC 0–24 and C max . Consistent with Aurora A inhibition, increased mitotic index in skin and tumor biopsies after MLN8237 dosing was coupled with decreased bipolar spindles and aligned chromosomes in mitotic cells from tumor biopsies. Conclusions: At the doses and schedule evaluated, MLN8237 is tolerable with BID dosing x7d and exhibits favorable PK, PD, and clinical antitumor activity. Additional planned cohorts include extended dosing for 14–21d in 28–35d cycles. The results support future phase 2 development. [Table: see text] [Table: see text]
Patient-Reported Outcomes (Pros) in Patients (Pts) with Advanced Non-Small Cell Lung Cancer (Nsclc) Receiving Afatinib (A) Monotherapy Followed By a + Paclitaxel (A + P) Vs Investigator'S Choice of Single-Agent Chemotherapy (Ic): Lux-Lung 5 (Ll5)
Authors: D. Planchard, K. Park, J. Yang, J. Kim, F. De Marinis, Y. Chen, J. Feng, C. Chouaid, S. Lu, R. Wiewrodt, C. Zhou, J. Bennouna, X. Liu, J. Lungershausen, B. Wang, V. Chand, M. Schuler
Journal: Annals of Oncology (2014)
High-dose conformal radiotherapy and concomitant 5-FU, followed by gemcitabine for non-metastatic unresectable pancreatic carcinoma: A phase II prospective study
Authors: G. Van Tienhoven, W. L. Vervenne, V. J. Ooink, S. S. Phoa, M. J. Bruno, D. J. Gouma, M. C. Hulshof, D. J. Richel
Journal: Journal of Clinical Oncology (2004)

4181 Background: There are no standard treatment options for locally advanced pancreatic cancer (LAPC). External beam radiotherapy (RT) has frequently been used. The administered radiation doses from 45 to 65 Gy may be considered inadequate for gross tumor. Concomitant 5-FU appears to improve efficacy of RT. Methods: Treatment consisted of RT at a dose of 70 Gy, 2 Gy per fraction in 7 weeks concomitant with 5-FU, 200 mg/m2/24 h as a continuous infusion, day 1–5 every week. After chemoradiation 4 cycles of gemcitabine (Gem) 1000 mg/m2 days 1, 8 and 15/ q 4 weeks. Twenty-four patients were included. Mean age was 60 years (range: 35–74); 16 male/8 female. Local disease was confirmed by laparoscopy. Results: Treatment was well tolerated. Grade 3 toxicities during RT/5FU included neutropenia (1 patient), liver toxicity (1), nausea (1), vomiting (1). Seventeen out of 24 patients experienced fatigue (9 grade 1, 7 grade 2 and 1 grade 3). Grade 3 toxicities during Gem included thrombopenia (1), neutropenia (5), anaemia (1) and fatigue (3). Twenty-one completed RT/5FU; 3 (12.5%) discontinued because of disease progression. Six patients (25%) completed RT/5FU but did not start Gem because of disease progression. Fifteen patients (63%) started Gem. Nine of them did not complete 4 cycles, 6 (40%) because of disease progression during Gem, 2 because of toxicity, 1 for personal reasons. 6/24 (25%) of patients completed all planned treatment. Response rates: no radiological remissions (CR/PR) were observed. After RT/5FU 15 patients (71%) had stable disease. Median overall survival was 9 months (1–30). Median progression free survival was 4 months (1–21). Conclusions: This approach is safe and tolerable. However, the lack of efficacy and the treatment duration make this approach not feasible in this patient population. Although chemoradiotherapy is considered standard treatment in many centers, our data do not support this. No significant financial relationships to disclose.
Retrospective chart review of end-of-life (EOL) care in patients with metastatic lung cancer harboring EGFR mutations.
Authors: Jessica Ruth Bauman, Zofia Piotrowska, Emily Scribner, Brandon Temel, Rebecca Suk Heist, Lecia V. Sequist, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2014)

126 Background: Metastatic lung cancer is the leading cause of cancer-related death in the US. In the last decade, however, patients (pts) with EGFR mutations have benefitted from improved outcomes with EGFR-directed targeted therapy. We hypothesized that this improvement might impact EOL care. The objective of this chart review was to describe the care of EGFR mutant pts with attention to EOL care, health care utilization, and palliative care use. Methods: With IRB approval, we retrospectively reviewed medical records of pts at our center diagnosed with advanced EGFR-mutant lung cancer from January 2009 to June 2012. We limited the review to pts who had at least one cancer therapy at MGH, and to those who died by June 2014. Results: 44 pts were included. 30 pts (68%) were female. 32 pts (73%) received cancer-directed therapy within 30 days of death. Of these, 30 pts (68%) received oral chemotherapy and 5 (11%) received IV chemotherapy. 30 pts (68%) were hospitalized within 30 days of death. Over their entire disease course, the median number of hospitalizations was 2 (0-8), and the median number of total inpatient days was 12 (0-88). 21 pts (48%) had a palliative care outpatient visit and 34 (77%) had an inpatient palliative care consult at some point during their care. 24 pts (54%) enrolled on hospice prior to death, 15 (34%) were never on hospice, and the hospice status of 5 (11%) was unknown. Of the 39 pts with known hospice status, median length of stay was 6 days (0-206). 23 pts (52%) died at home with hospice or in an inpatient hospice, 16 (36%) died in the hospital, 2 (4%) died at home without hospice, and the location of death was unknown for 3 (7%). Conclusions: Pts with EGFR mutations had high rates of hospitalization and chemotherapy use in the last month of life, and many died in the hospital. Palliative care utilization was high, but it is unclear how this affected EOL care. Designing innovative care models to support this unique population and understand EOL decision-making should be a priority.
Providing intensive care
Authors: M. Nielsen, A. Sced, J. Pappachan
Journal: BMJ (1996)

Finally, Waugh suggests that photography might be added to screening by opticians and be carried out by opticians.This would probably incur an additional fee and is unlikely to be any more cost effective, and is more likely to be less comprehensive, than a system based on the practice register and recall and directly involving the primary care team.
Differential Susceptibility of AKR, C57BL/6J, and CF1 Mice to 1,2-Dimethylhydrazine-Induced Colonic Tumor Formation Predicted by Proliferative Characteristics of Colonic Epithelial Cells&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: E E Deschner, F C Long, M Hakissian, S L Herrmann
Journal: JNCI Journal of the National Cancer Institute (1983)

The proliferative characteristics of the colonic mucosae of various mouse strains were examined to determine their value in forecasting the differential susceptibility of each to 1,2-dimethylhydrazine (DMH)-induced tumor formation. The control labeling index (LI) was highest (9.9 +/- 2.6) and the proliferative compartment (PC) widest in the DMH-sensitive CF1 strain, whereas the LI was lowest (7.3 +/- 1.3) (P greater than 0.01) and the PC shortest in the AKR resistant strain. The size of the PC and the LI for moderately resistant C57BL/6J mice lay between these values (8.5 +/- 1.1). Pooled data from 1 week after the fifth and sixth injections and 12 weeks after the first injection of six showed elevated LI in the distal colons of all DMH-treated mice. Distribution analyses of [3H]thymidine-labeled cells indicated extension of the PC (Stage II abnormality) in all strains with a shift of DNA-synthesizing cells from the major zone or lower third to the middle and upper thirds of the crypt (Stage II abnormality) occurring primarily in the CF1 strain. Cytotoxicity measurements at 6 hours and compensatory DNA synthesis at 3 and 4 days after DMH injection (20 mg/kg body wt) revealed similar relative response levels in CF1 and AKR mice, which suggested induction initially of like numbers of mutations. Indigenous conditions shown to influence the expression of colonic neoplasia are the level of DNA synthesis and the dimensions of the PC within the mucosa.
Preregistration house jobs in general practice
Authors: N. Oswald
Journal: BMJ (1998)

# Preregistration house jobs in general practice {#article-title-2}

There was nothing wrong with my house job. I had a friendly team and a fair boss, and, although busy, I was not unduly bowed under by the pressure of it all. But I never professed to being a budding vascular surgeon, and two months into the job I began to wonder whether the rigid preregistration house year of six months medicine and six months surgery was really the most efficient way to train tomorrow's senior doctors. After a particularly hectic Friday night on call dealing with an intracerebral bleed, the usual run of non-specific abdominal pains, and a man who had inserted a light bulb into his rectum, I went to see a friend of mine who is doing part of her preregistration post in primary care and asked her a few questions about life as a house officer in general practice.

What are the advantages of your job? 

Many. It's a friendly working environment and I don't have a bleep, so no one disturbs me when I'm dealing with patients. Having a GP supervisor is like having a personal tutor on tap all the time. He is very keen on evidence based medicine and we can look up on the computer the latest information on the management of cases, particularly uncommon ones.

No bleepewhat bliss! But how do you have the time to look everything up? 

Twenty five minutes are allocated for each patient. I have a protected half day during the week and have time to study during the day between surgeries.

So do you see fewer patients than hospital preregistration house officers? 

No. I see about 15 patients a day, but 15 different patients every day, so in a week I see many more cases than I ever saw in hospital, where you are seeing the …
Phase I trial of ARRY-520 in relapsed/refractory multiple myeloma (RR MM).
Authors: J. J. Shah, A. D. Cohen, J. A. Zonder, J. L. Kaufman, S. M. Burt, B. B. Freeman, S. Rush, A. M. Ptaszynski, R. Z. Orlowski, S. Lonial
Journal: Journal of Clinical Oncology (2010)

8132 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. ARRY-520 is a potent, selective inhibitor of KSP, arresting cells in mitosis with subsequent onset of apoptosis. Malignancies, such as MM, depending on the survival protein MCL-1 rapidly undergo apoptosis following treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease Methods: This phase I study was designed to evaluate the safety, pharmacokinetics and pharmacodynamics of ARRY-520 administered intravenous (IV) on D1 and D2 q 14 days without/with granulocyte colony stimulating factor (G-CSF). Patients (pts) with RR MM or plasma cell leukemia with ≥ 2 prior lines of therapy (including a bortezomib and IMiD-based regimen, unless refusing or ineligible for this therapy) were eligible. Cohorts of at least 3 pts are being enrolled in a classical 3+3 dose escalation design. Pts are treated for 2 cycles for safety evaluation prior to dose escalation. Results: 13 pts have been treated to date, with a median age of 55 years (range 44-78) and a median of 4 prior regimens (range 3-13). All pts received prior bortezomib, 9 pts prior lenalidomide, 5 pts prior thalidomide, and 10 pts had an autologous stem cell transplant. Pts received ARRY- 520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7). Dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose without G-CSF. As neutropenia was the DLT, dose escalation with G-CSF support was initiated, and 3 pts have been treated to date at 1.5 mg/m2/day with G-CSF. The most commonly reported (> 1 pt) treatment-related adverse events include anemia, neutropenia and thrombocytopenia as well as fatigue and nausea. No mucositis or peripheral neuropathy were noted. The median number of cycles is 4 (range 1-15+). One pt experienced a partial response (ongoing in Cycle 15 at 1 mg/m2/day, 8 prior regimens, decrease of % plasma cells in the bone marrow from 30 to 0%). Conclusions: ARRY-520 shows promising signs of clinical activity and has been well tolerated in pts with MM. Enrollment is ongoing at 1.5 mg/m2/day with G-CSF support. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Array BioPharma Amgen, Array BioPharma, Bristol-Myers Squibb, Celgene, Facet Biotech, Genzyme, Johnson & Johnson, Millennium, Novartis Array BioPharma Celgene, Millennium Bristol-Myers Squibb, Celgene, Cepahlon, Facet Biotech, Gloucester Pharmaceuticals, Merck, Millennium, Novartis
Taxol and anti-stathmin therapy: Novel synergistic inhibitors of angiogenesis
Authors: Sucharita J. Mistry, George F. Atweh
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3024 

Stathmin, a founding member of a family of microtubule destabilizing proteins provides an attractive target for cancer therapy. Taxol is an effective anti-tumor agent whose activity is mediated through stabilization of microtubules that make up the mitotic spindle. Taxol also has anti-angiogenic effects manifested by inhibition of endothelial cell proliferation and differentiation. We had previously shown synergy in the anti-tumor activities of taxol and stathmin inhibition. We hypothesized that taxol and stathmin inhibition may also have synergistic anti-angiogenic activities. A replication deficient bicistronic adenoviral vector (Ad.Rz.GFP) that coexpresses green fluorescent protein (GFP) and an anti-stathmin ribozyme (Rz) was generated for efficient gene transfer and inhibition of stathmin expression. Transduction of human umbilical vein endothelial cells (HUVEC) resulted in GFP fluorescence in 80% of the cells. Northern blot analyses of RNA isolated from endothelial cells infected with Ad.Rz.GFP showed 74% inhibition of stathmin expression relative to uninfected cells or cells infected with control Ad.GFP virus. We then assessed the sensitivity of HUVECs to low doses of the recombinant adenoviruses (15 pfu/cell) and picomolar doses of taxol, both as single agents and in combination. Exposure of uninfected or control Ad.GFP infected cells to taxol (2-6 pM) resulted in a modest dose-dependent decrease in proliferation. In contrast, exposure of Ad.Rz.GFP infected cells to the same doses of taxol resulted in complete inhibition of proliferation. Thus, anti-stathmin therapy sensitizes endothelial cells to the anti-angiogenic effects of taxol. We also examined HUVEC differentiation into capillary-like structures on reconstituted extracellular matrix proteins (matrigel). Uninfected or control Ad.GFP infected HUVECs formed a complex network of long anastomosing tubes in the absence of taxol. When the same cells were exposed to 4 and 6 pM taxol, tube formation was modestly reduced to 89% and 78% respectively. In contrast, tube formation in Ad.Rz.GFP infected cells was reduced to 59% in the absence of taxol. Moreover, the tubes that formed were short and distorted in Ad.Rz.GFP infected cells compared to control cells. When Ad.Rz.GFP infected cells were exposed to 4 pM taxol, tube formation was further reduced to 30% and was completely aborted at 6 pM taxol. Thus, combination of anti-stathmin therapy and taxol results in synergistic inhibition of angiogenesis that is clearly greater than the sum of their individual effects. TUNEL analyses of Ad.Rz.GFP infected HUVECs after taxol exposure showed a very modest fraction (<2%) of apoptotic cells. This suggests that the observed inhibition of angiogenesis is not a reflection of cell death. If these observations are confirmed in vivo , this novel combination may provide an attractive therapeutic strategy that combines anti-tumor activity with anti-angiogenic activity.
Clofarabine in combination with a standard remission induction regimen in patients 18-60 years old previously untreated intermediate an bad risk actue myelogenous leukemia (AML) or high risk myelodysplasia (MDS): combined phase I/II results of the EORTC/Gimema AML-14A trial
Authors: Dominik L.D. Selleslag, Stefan Suciu, Giovanna Meloni, Petra Muus, Constantijn J.M. Halkes, Adriano Venditti, Safaa M. Ramadan, Hans Pruijt, Liv Meert, Marco Vignetti, Jean-Pierre Marie, Dominique Bron, Theo De Witte, Sergio Amadori, Roelof Willemze, Frédéric Baron
Journal: Blood (2014)