tbuckley/cabot-search huggingface dataset:
The value of the number of nodes removed (or the ratio of involved nodes) as a prognostic factor in breast cancer
Authors: I. Germain, A. Fortin, A. Dagnault, T. T. Vu, M. Larochelle
Journal: Journal of Clinical Oncology (2004)

611 Background: To assess the prognostic value of the number of nodes removed and the ratio of positive nodes after breast conservative approach. Methods: A retrospective study including all breast cancer patients treated by conservative surgery between 1970 and 1997 at the Hotel-Dieu de Quebec. Kaplan-Meier and Cox multivariate analysis using known prognostic variables for distant metastases were performed in three groups: N0, N1–3 and N>3 positive nodes. Results: For the 1615 N0 patients, ten-year metastases free survival (10 year-MFS) was 75 % and 85% when <4 nodes and when ≥ 4 nodes were removed, p=0.0001. In a Cox model, the number of nodes removed (HR=0.64, p=0.002) ranks third after T stage (Hazard ratio:2.2, p<0.00) and age≥40 (HR=0.57, p=0.001). For the 919 N1–3 node positive patients, 10 year-MFS was 70 % and 61% when <8 nodes and when ≥ 8 nodes were removed, p=0.03. For the same group, 10 year-MFS were 70 % and 60% when the ratio of positive nodes was <0.25 and ≥0.25, p=0.0002. In a Cox model done on this group, ratio ranks third(after age and grade III) with a HR of 1.6, p=0.02. The number of positive nodes and the number of nodes removed were not independent prognostic factors. For the 444 N>3 node positive patients, 10 year-MFS was 47% and 46% when <10 nodes or ≥ 10 nodes were removed, p=0.5. For the same group, 10 year-MFS was 54%, 46 %, and 36% when ratio was <0.5, between 0.5–0.8 and ≥0.8, respectively, p=0.0009. In a Cox model done on this group, ratio is an independent prognostic factor(p=0.01) with T stage(p=0.01), number of positive nodes(p=0.01) and age(p=0.01). Compared to a ratio < 0.5, the HR of distant metastases was 1.26 and 1.5 when the ratio was 0.5–0.8 and ≥8, respectively. Conclusions: In N0 patients, the number of nodes removed (<4 vs. ≥4 ) is a prognostic factor. In N+ patients, ratio( <0.25 vs.≥0.25) for N1–3 and ratio (<0.5, 0.5–0.8 and ≥0.8) for N>3 positive nodes is an independent prognostic factor for distant metastases. No significant financial relationships to disclose.
Megakaryocytes compensate for Kit insufficiency in murine arthritis
Authors: Pierre Cunin, Loka R. Penke, Jonathan N. Thon, Paul A. Monach, Tatiana Jones, Margaret H. Chang, Mary M. Chen, Imene Melki, Steve Lacroix, Yoichiro Iwakura, Jerry Ware, Michael F. Gurish, Joseph E. Italiano, Eric Boilard, Peter A. Nigrovic
Journal: Journal of Clinical Investigation (2017)

The growth factor receptor Kit is involved in hematopoietic and nonhematopoietic development. Mice bearing Kit defects lack mast cells; however, strains bearing different Kit alleles exhibit diverse phenotypes. Herein, we investigated factors underlying differential sensitivity to IgG-mediated arthritis in 2 mast cell–deficient murine lines: KitWsh/Wsh, which develops robust arthritis, and KitW/Wv, which does not. Reciprocal bone marrow transplantation between KitW/Wv and KitWsh/Wsh mice revealed that arthritis resistance reflects a hematopoietic defect in addition to mast cell deficiency. In KitW/Wv mice, restoration of susceptibility to IgG-mediated arthritis was neutrophil independent but required IL-1 and the platelet/megakaryocyte markers NF-E2 and glycoprotein VI. In KitW/Wv mice, platelets were present in numbers similar to those in WT animals and functionally intact, and transfer of WT platelets did not restore arthritis susceptibility. These data implicated a platelet-independent role for the megakaryocyte, a Kit-dependent lineage that is selectively deficient in KitW/Wv mice. Megakaryocytes secreted IL-1 directly and as a component of circulating microparticles, which activated synovial fibroblasts in an IL-1–dependent manner. Transfer of WT but not IL-1–deficient megakaryocytes restored arthritis susceptibility to KitW/Wv mice. These findings identify functional redundancy among Kit-dependent hematopoietic lineages and establish an unanticipated capacity of megakaryocytes to mediate IL-1–driven systemic inflammatory disease.
First report of a phase I/II study of DFP-10917, a nucleoside analog, given by continuous infusion (CI) in patients (pts) with relapsed or refractory acute leukemia.
Authors: Hagop M. Kantarjian, Elias Jabbour, Guillermo Garcia-Manero, Tapan M. Kadia, Courtney Denton Dinardo, Naval Guastad Daver, Gautam Borthakur, Nitin Jain, Jane Waukau, Monica Kwari, Barry Douglas Anderson, Kenzo Iizuka, Cheng Jin, William Plunkett
Journal: Journal of Clinical Oncology (2015)

7077 Background: DFP-10917 has a unique mechanism of action upon prolonged administration at a low dose. Under such administration, DFP-10917 is converted to its nucleotide form and then incorporated into DNA in tumors to cause DNA strand breaks resulting in G2/M phase-arrest by cell-checkpoint regulators and ultimately the apoptosis of tumor cells. Methods: In phase I, DFP-10917 was administered by 7-day CI followed by 21 days rest (stage 1) or 14-day CI followed by 14 days rest (stage 2) in pts with relapsed or refractory acute leukemia in order to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of CI DFP-10917. Results: In stage 1, 27 pts received a 7-day CI of DFP-10917 at 8 escalating doses ranging from 4 to 35 mg/m2/day. At the 35 mg/m2 dose level, one patient experienced a DLT of grade 3 diarrhea during cycle 1. Two other pts treated at the 35 mg/m2 dose level completed cycle 1 study treatment without DLT. The starting dose for stage 2 was calculated as 2/3rds the cumulative 7-day DFP-10917 dose at the MTD of 30 mg/m2/day divided by 14-day resulting in a dose of 10 mg/m2/day x 14 days. In stage 2 of phase I, 4 pts received 10 mg/m2/day x 14-day CI DFP-10917 with DLTs of prolonged hypo-cellularity in 2 pts. At the 6 mg/m2/day x 14-day dose level, 1 of 6 evaluable pts in a cohort experienced a DLT of prolonged hypo-cellularity, and the MTD/RD was defined as 6 mg/m2/day x 14-day CI. Initial efficacy assessments include leukemia responses observed in 7 of 10 pts (70%) receiving the 14-day DFP-10917 CI; three were bone marrow complete responses, and four were partial response. Patients have received up to 7 cycles of DFP-10917 CI to date with ongoing responses. Conclusions: The MTD/RP2D of DFP-10917 in relapsed AML was established for 14-day CI at 6 mg/m2/day, and the phase II study was initiated based on an acceptable safety profile. In phase II, the therapeutic efficacy of the DFP-10917 will be evaluated in relapsed or refractory acute myeloid leukemia (AML), or pts aged ≥ 60 years with newly diagnosed AML. Enrollment of the phase II study is ongoing.Clinical trial information: NCT01702155. Clinical trial information: NCT01702155.
SWOG S0820/PACES (Preventing Adenomas of the Colon with Eflornithine and Sulindac): A randomized, double-blind, placebo-controlled phase III clinical trial.
Authors: Jason A. Zell, Joseph M. Unger, Garnet L Anderson, Elise D. Cook, Robert S. Krouse, M Peter Lance, Lori M. Minasian, Leslie Ford, Powel Brown
Journal: Journal of Clinical Oncology (2015)

TPS3627 Background: After standard treatment for stage 0-III colorectal cancer (CRC), patients remain at increased risk for metachronous high-risk adenomas (HRAs) and 2ndprimary CRCs. Polyamines, in excess, are implicated in CRC carcinogenesis. In prior CRC chemoprevention clinical trials, low doses of polyamine-inhibitory agents eflornithine (E) and sulindac (S) demonstrated impressive efficacy. In the prior phase III clinical trial of colorectal adenoma (CRA) patients the combination E+S vs. placebo for 3-years resulted in > 92% reduction in risk of HRAs. Utility of these agents in colon cancer survivors, however, is unknown. Methods: Eligibility:Patients age > 18 with colon or rectosigmoid adenocarcinoma, stage 0, I, II, or III are eligible. Patients with major cardiovascular risk factors (MI, CVA) are excluded, as are patients with hearing loss > 30dB at 4K Hz and below. Daily low dose aspirin is allowed. Study Design: Patients are enrolled 9-15 months postoperatively for a 3-year duration in the randomized, double-blind, placebo-controlled Phase III trial. The intervention consists of eflornithine 250mg or matching placebo 2 tablets daily and sulindac 150mg or matching placebo one tablet daily. Baseline and end-of-study audiograms are required. Using a 2x2 factorial design, we will conduct 3 formal comparisons, each at the 2-sided, alpha = .0167 level with > 80% power. We tested the marginal effects of E &S, and the combined effect of E+S compared to placebo only. 1488 patients will be accrued over 5 years. Optional study components include pharmacogenetic, pharmacokinetic, & diet/lifestyle studies. The DSMC last met in October of 2014 and suggested that the trial continue as planned. Endpoints: The primary objective is to assess whether eflornithine 500 mg or sulindac 150mg are effective in reducing the 3-year event rate, defined as HRA or 2nd primary CRC, in Stage 0- III colon cancer patients. Hypothesis: In stage 0-III colon cancer patients during postoperative year 1-4, one or both of the single active agents will produce a 35% decrease in the rate of HRAs + 2nd primary CRCs; combination E+S will result in a 58% decrease compared to placebo alone. Clinical trial information: NCT01349881.
Timely antibiotic administration in febrile neutropenia.
Authors: Ignatius Nyatsanza, Irum Khan, Jennifer Windhorst, Nicole Gerardo, Kasandra Cadman, LeeAnn Valero, Eileen Knightly, Lawrence Eric Feldman, William Galanter, Neeta K. Venepalli
Journal: Journal of Clinical Oncology (2017)

204 Background: The University of Illinois currently lacks a standard process to ensure timely antibiotic administration for patients with febrile neutropenia. The Infectious disease society of America (IDSA) guidelines recommend administration of antibiotics within two hours. Given the variability in patient encounters, we sought to implement an early identification and interventional strategy in the ambulatory setting for febrile neutropenic patients. A retrospective chart review over 10 weeks demonstrated that of 40 patients diagnosed with neutropenia 15 % (N = 6) had febrile neutropenia. Of these 6 patients, 50% (N = 3) received antibiotics within the IDSA time frame. We aimed to increase the percentage of febrile neutropenic patients receiving antibiotics within 2 hours from 50% to 100% in 8 weeks. Methods: A focus group at our quarterly morbidity mortality and improvement conference brainstormed a list of causes of delay in antibiotic initiation based on an index case discussion. A task force generated a pareto chart after affinity sorting the prior list, and created actual and ideal process maps, from identification of neutropenic patients to patient disposition. A standard operative protocol (SOP) was developed involving the creation and implementation of an electronic provider generated neutropenia check list triggering specific actions per IDSA recommendations, and a standardized order set including STAT cultures, and STAT antibiotics. Results: The febrile neutropenia SOP will be piloted over an 8 week period starting in early November in four ambulatory settings. The primary outcome data is the time from event to antibiotic administration. Process data will include time from event to antibiotic order, time from antibiotic order to administration and compliance with high risk neutropenic check list. We plan to assess our interventions every 3-4 weeks, and pilot at least 2 PDSA cycles within the next 8 weeks. Conclusions: Although febrile neutropenia is a recognized medical emergency with clear guidelines on treatment, not all patients may receive antibiotics within the appropriate time frame. It is therefore imperative for institutions to be aware of their level of IDSA compliance and implement appropriate quality improvements as required.
Genomic heterogeneity of circulating tumor cells in castration-resistant prostate cancer (CRPC) revealed by single-cell sequencing.
Authors: Allison Welsh, Daniel Costin Danila, Aseem Anand, Jude Kendall, Charles L. Sawyers, Martin Fleisher, Michael Wigler, James B Hicks, Howard I. Scher
Journal: Journal of Clinical Oncology (2013)

5030 Background: Circulating tumor cells (CTC) provide an opportunity to sample multiple metastatic tumor sites through a single blood draw – a ”fluid biopsy.” NextGen DNA sequencing provides the means to obtain detailed genetic information from captured cells prior to and during treatment. Here we demonstrate the use of DNA sequencing to interrogate genome-wide copy number variations (CNV) at the single-cell level in CTC isolated from pts with CRPC. Methods: Pre- and post-treatment blood samples were obtained from pts treated at MSKCC. EpCAM+ events were collected singly and in groups by cytometric flow sorting and were subjected to DNA amplification and Illumina NextGeneration sequencing. Parallel samples were assayed using the Veridex CellSearch method to ensure the presence of malignant cells. Results: Samples with up to 50 EpCAM+ events analyzed in bulk displayed CNV patterns expected from published CRPC data. Subsequent single cell analyses showed that the method could reliably detect common genomic markers in CRPC, including AR amplification, PTEN and RB1 loss, and the TMPRSS-ERG fusion. Individual genomic CNV profiles obtained from 125 single cells isolated from 15 patients were then analyzed. Using unsupervised clustering, cells from each pt showed a closely related lineage structure, consistent with an evolution from a common ancestor. The degree of genomic heterogeneity within CTC from an individual pt was highly variable, with R 2 correlation coefficients ranging from &gt;0.92 (nearly homogeneous) to &lt;0.75 (mixed populations). Two pts harbored separate subpopulations with both amplified AR and non-amplified AR cells and another displayed mixtures of genetic markers that changed over the course of treatment. Conclusions: The observed variation in complexity of CTC populations in CRPC pts underscores the importance of being able to sample and analyze multiple cells from an individual pt on multiple occasions and with real time analytics. Doing so is essential to understand and identify mechanisms of resistance so that they can be targeted effectively. Supported by STARR Cancer Consortium, NCI SPORE in Prostate Cancer; Department of Defense; Prostate Cancer Foundation.
Prognostic and predictive value of a low estrogen receptor expression in breast cancer: A retrospective study from a reference center.
Authors: Caroline Diorio, Antoine Bouchard-Fortier, Caty Blanchette, Louise Provencher
Journal: Journal of Clinical Oncology (2013)

627 Background: Threshold of estrogen receptors positivity in breast cancer has been lowered to ≥1% of stained cells by immunohistochemistry testing. This change was based on experts’ recommendations from the 2009 St Gallen International Expert Consensus and from the 2010 guidelines of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP). However few studies support these guidelines and the benefit of treating weakly positive estrogen receptor tumors (1-9%) is unknown. Methods: We identified 2221 breast cancer patients with estrogen receptors tested by ligand-based assay, treated and followed in our institution between 1976 and 2008. Date and cause of death were identified through linkage to Quebec Mortality File. A multivariate Cox proportional-hazards model was used to assess the effect of estrogen receptor levels on breast cancer mortality in patients who received hormonal therapy (tamoxifen). Results: In patients with low estrogen receptors, 17% (383 patients) were within 0-3 fmol/mg of cytosol and 12% (266 patients) were within 4-9 fmol/mg of cytosol. Patients with estrogen receptor levels of 0-3, 4-9, 10-19, 20-49, and ≥50 fmol/mg of cytosol had a 20-year breast cancer survival rate of 56%, 56%, 63%, 71% and 60% respectively. From the 2221 patients, 661 (29.8%) received hormonal therapy. In these patients, estrogen receptor levels of 0-3, 4-9, 10-19, 20-49 and ≥50 fmol/mg of cytosol were associated with lower breast cancer mortality (HR (p-value) of 1.00 (reference), 0.59 (0.09), 0.19 (&lt;0.0001), 0.26 (&lt;0.0001) and 0.31 (&lt;0.0001) respectively); with significant mortality reduction only for estrogen receptor levels ≥10 fmol/mg of cytosol. Conclusions: A weak expression of estrogen receptors (&lt;10 fmol/mg) in breast cancer is associated with increase breast cancer mortality. Our results did not show a significant benefit to treat these patients with hormonal therapy as oppose to those with estrogen receptor levels ≥10 fmol/mg of cytosol. To further support these findings, a similar study should be repeated in patients with estrogen receptors tested by immunohistochemistry.
Phase II neoadjuvant and adjuvant chemotherapy for localized esophageal carcinoma
Authors: B. Ardalan, A. Livingstone, D. Franceschi, S. Spector, G. Walker, P. Ganjei-Azar, A. Burnett, M. Lima, L. Sparling
Journal: Journal of Clinical Oncology (2004)

4147 Background: Patients (Pts) with localized esophageal carcinoma were evaluated for toxicity, operative mortality/morbidity, and overall survivorship in a regimen that did NOT contain radiation therapy. Methods: Pts with T3N1M0 esophageal carcinoma confirmed by endoscopic ultrasound and CAT scan were eligible for this study. Our therapy consisted of combined Cisplatin100 mg/m2, Paclitaxel (Taxol) 125mg/ m2, Fluorodeoxyuridine (FUdR) 150 mg /Kg or 80 mg/Kg, and Leucovorin 500mg /m2. Chemotherapy was given for 16 weeks prior to surgery. Adjuvant chemotherapy was administered for the patients whose pathology at the time of the surgery demonstrated microscopic disease. Results: 33 pts (29 males, 4 females) with adenocarcinoma (n=30) or squamous cell carcinoma (n=3) were enrolled. 26 pts (78%) were symptomatic with dysphagia at the time of enrollment on the study. 28 pts completed two cycles of neoadjuvant chemotherapy, 19 (68%) showed improvement of dysphagia. There were 9 instances of grade 3 or 4 hematological toxicity. There were 11 instances of non-hematological grades 3–4 toxicities: fatigue (4), nausea (1) diarrhea (2) and stomatitis (4). Of 33 R0 resections, 5(15%) had no gross disease, 2 (6%) had no microscopic residual disease. Major surgical complication occurred in 5(15%) of 33 pts. Operative mortality was 1 of 33 pts. Conclusions: Our regimen of preoperative and postoperative chemotherapy without radiation for esophageal carcinoma has produced a rapid relief of dysphagia, acceptable toxicity and durable response rates. No patient developed local recurrence, however, 14 pts developed distant metastasis, the sites included: 1 rectum and mediastinal lymph node, 2 brain, 2 liver and lung, 1 liver and spleen, 3 bone, 4 liver, lung, and brain, and 1 lung. Seventeen pts died after being followed for a median of 12 months (range 2 to 43 months), while 16 others remain alive with median follow up of 39 months (range 5 to 60 months). Median survival was estimated to be 42 months with a 95% lower confidence bound of 14 months. The Kaplan-Meier estimates of 1- and 3-year survival were 75% (95%CI: 60–90%) and 50% (95%CI: 32 to 68%). No significant financial relationships to disclose.
Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145).
Authors: Craig L. Slingluff, Gina R. Petroni, Lynn Dengel, David W. Mullins, William W. Grosh, Geoffrey R. Weiss, Robert M Strieter, Patrice Neese, Carmel Nail, James W Patterson, Walter C. Olson, Kimberly A. Chianese-Bullock
Journal: Journal of Clinical Oncology (2013)

TPS3118^ Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8 + CXCR3 + T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3 + T cells. Methods: This pilot clinical trial is enrolling patients (n=14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm 3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 &amp; CXCL11) and the magnitude of infiltration of CD8 + CXCR3 + T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3 + CD25hi CD4 + (putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.
Low-level radioactive wastes. Council on Scientific Affairs
Journal: JAMA (1989)

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