tbuckley/cabot-search huggingface dataset:
The Cancer Stem Cell Fraction in Hierarchically Organized Tumors Can Be Estimated Using Mathematical Modeling and Patient-Specific Treatment Trajectories
Authors: Benjamin Werner, Jacob G. Scott, Andrea Sottoriva, Alexander R.A. Anderson, Arne Traulsen, Philipp M. Altrock
Journal: Cancer Research (2016)

Abstract Many tumors are hierarchically organized and driven by a subpopulation of tumor-initiating cells (TIC), or cancer stem cells. TICs are uniquely capable of recapitulating the tumor and are thought to be highly resistant to radio- and chemotherapy. Macroscopic patterns of tumor expansion before treatment and tumor regression during treatment are tied to the dynamics of TICs. Until now, the quantitative information about the fraction of TICs from macroscopic tumor burden trajectories could not be inferred. In this study, we generated a quantitative method based on a mathematical model that describes hierarchically organized tumor dynamics and patient-derived tumor burden information. The method identifies two characteristic equilibrium TIC regimes during expansion and regression. We show that tumor expansion and regression curves can be leveraged to infer estimates of the TIC fraction in individual patients at detection and after continued therapy. Furthermore, our method is parameter-free; it solely requires the knowledge of a patient's tumor burden over multiple time points to reveal microscopic properties of the malignancy. We demonstrate proof of concept in the case of chronic myeloid leukemia (CML), wherein our model recapitulated the clinical history of the disease in two independent patient cohorts. On the basis of patient-specific treatment responses in CML, we predict that after one year of targeted treatment, the fraction of TICs increases 100-fold and continues to increase up to 1,000-fold after 5 years of treatment. Our novel framework may significantly influence the implementation of personalized treatment strategies and has the potential for rapid translation into the clinic. Cancer Res; 76(7); 1705–13. ©2016 AACR.
Pathologic findings at orchiectomy following chemotherapy for disseminated testicular cancer.
Authors: A Greist, L H Einhorn, S D Williams, J P Donohue, R G Rowland
Journal: Journal of Clinical Oncology (1984)

Patients with testicular cancer who have disseminated disease at presentation do not always undergo orchiectomy for diagnosis of staging before initiation of chemotherapy. Between October 1978 and November 1982 orchiectomy was performed following cisplatin combination chemotherapy in 20 patients with disseminated germ cell tumors. There were three patients with residual carcinoma in the removed testis and six patients with teratoma. Therefore, in patients with evidence of a primary testicular neoplasm that was not resected initially, orchiectomy should be performed after chemotherapy. Furthermore, the testis may be a sanctuary site for germ cell malignancies during systemic treatment.
Expanding the antimalarial toolkit: Targeting host–parasite interactions
Authors: Jean Langhorne, Patrick E. Duffy
Journal: The Journal of Experimental Medicine (2016)

Recent successes in malaria control are threatened by drug-resistant Plasmodium parasites and insecticide-resistant Anopheles mosquitoes, and first generation vaccines offer only partial protection. New research approaches have highlighted host as well as parasite molecules or pathways that could be targeted for interventions. In this study, we discuss host–parasite interactions at the different stages of the Plasmodium life cycle within the mammalian host and the potential for therapeutics that prevent parasite migration, invasion, intracellular growth, or egress from host cells, as well as parasite-induced pathology.
Rectal cancer: Pattern of care in the elderly
Authors: G. Kichenadasse, A. R. Townsend, K. B. Pittman, K. Patterson, J. H. Stephens, M. Borg, N. A. Rieger, P. J. Hewett, D. J. Rodda, T. J. Price
Journal: Journal of Clinical Oncology (2008)

17563 Background: Though rectal cancers are common in the elderly, such patients are under treated due to presumed indolent nature of disease and expected toxicity. It is essential to audit the actual treatment delivered in the community as this is a useful way to assess the provided health care against the backdrop of clinical trials. This study describes the pattern of care among elderly rectal cancer patients at our center. Methods: We performed an audit of elderly (≥ 80 years) with rectal cancers diagnosed between the period of December 1997 and December 2006. Emphasis was on the actual treatment delivered to the patients. Results: There were 55 patients (males-33; females-22) identified with median age of 84 years (range 80–93 years). Disease stage was known in 42 patients (Duke A - 7, Duke B- 17, Duke C - 11, Duke D- 7). Majority (83.6%) had surgery for the primary. Surgical resection was the only treatment for all (except one) Duke A patient. Among Duke B patients, all had primary resection, 5 (30%) received pre or post operative radiotherapy ± chemotherapy (RT±CT); while the remaining 12 (70%) received neither. Surgery for the primary was performed in all Duke C cases; only 4 (36.6%) received post-operative RT±CT and none had pre-operative RT±CT. Duke D patients were heterogeneous - 2 never had their primary resected; instead received palliative radiotherapy, 4 had surgery alone and the other received surgery/RT and CT. At last follow-up, 20 (36.3%) were alive; median overall survival (OS) - 20 months, 5-year OS of 15.4%. Conclusions: It appears that most elderly undergo surgical resection, but adjuvant therapy is being offered only to a small proportion (<40%) of the eligible patients. Several factors including patient, family and physician related factors could be involved in decision process. No significant financial relationships to disclose.
Authors’ reply to Gupta:
Authors: Sheng-Chia Chung, Johan Sundström, Chris P Gale, Adam Timmis, Tomas Jernberg, Harry Hemingway
Journal: BMJ (2015)

In answer to Gupta,1 we performed additional sensitivity analyses to investigate the influence of ethnicity on the variation in 30 day mortality after acute myocardial infarction (AMI) in UK hospitals.2

Ethnicity information was not documented in the …
Albuminuria in children with obstructive sleep apnea
Authors: Vasiliki Varlami, Emmanouel Alexopoulos, Georgia Malakasioti, Vasiliki Theologi, Eleni Theophanous, Athanasios Kaditis, Efthimia Daskalopoulou, Konstantinos Gourgoulianis
Journal: European Respiratory Journal (2011)

Increased excretion of albumin in urine has been considered a surrogate marker of endothelial dysfunction in adults with obstructive sleep apnea (OSA). Aim of this study was to evaluate urinary excretion of albumin in children with OSA.   Methods:  Albumin-to-creatinine ratio (ACR) was calculated in a morning urine specimen collected from children with or without OSA. An assay appropriate for detection of microalbuminuria was used.   Results:  Twenty seven subjects with moderate-to-severe OSA (5.6±2.1 y.o.; AHI 9.1±3.7 episodes/h), 71 subjects with mild OSA (6.2±2.3 y.o.; 2.4±1 episodes/h) and 31 children without habitual snoring (6.7±2.4 y.o.; 0.6±0.3 episodes/h) were studied. Subjects with moderate-to-severe OSA had similar ACR to those with mild OSA (p=0.072) and significantly higher ACR relative to subjects without habitual snoring (p=0.007): median 0.38 (0-14.3) mg/g vs. 0.31 (0-13) vs.0 (0-3.26), respectively. There was significantly increased risk for having ACR>0 in children with moderate-to-severe or mild OSA compared to children without habitual snoring after adjustment for age and gender: OR (95% CI) 6.4 (1.8-23.3) or 2.7 (1.1-6.9) vs. 1.0.   Conclusions:  Children with OSA are at increased risk for having detectable morning abuminuria.
Engineering antibodies to enhance efector functions
Authors: D. F. Carmichael, J. R. Desjarlais, G. A. Lazar, W. Dang, O. Vafa, J. Vielmetter, S. Karki, B. Dahiyat
Journal: Journal of Clinical Oncology (2005)

2551 Background: Despite great progress, the clinical success of therapeutic anti-tumor antibodies against proven targets is still partial. Bringing immune effector functions to bear on target cells is a primary method of antibody mediated tumor cell killing. Published analyses of clinical outcomes in cohorts of patients treated with anti-tumor antibodies show that, all else being equal, patients with higher Fc:Fc-gamma-Receptor IIIa interactions have a survival advantage over patients with weaker receptor binding. Xencor has engineered the Fc to improve Fc-gamma-R binding. Importantly this approach can be used to improve the effector potency of any antibody regardless of the receptor phenotype of the patient. This translates to enhanced specific target cell killing in vitro and in vivo. Methods: Variants of human IgG1 at the constant region Fc:Fc-gamma-receptor interface were made and tested for their ability to interact with various Fc-gamma-receptors, especially Fc-gamma-receptor IIIa. These were further analyzed for potency and efficacy using in vitro ADCC assays. The data presented here compare the variant and wild type human IgG1 Fc grafted onto an anti-CD20 (Rituxan, rituxumab) or anti-Her2 (Herceptin, trastuzumab) Fab. Finally, some were tested for in vivo activity against CD20 bearing cells in a primate B-cell depletion model. Results: Hundreds of high activity variants have been developed and characterized with respect to binding against a panel of Fc-gamma-receptors (including R IIIa), C1q and FcRn. Shown are the results for a case study that has been advanced to the primate B-cell depletion model. Conclusions: XmAb antibodies improve effector functions. The improvement may be conferred on any antibody by grafting the engineered Fc to a desired Fab. In vivo efficacy and available clinical evidence suggests the XmAb technology will impart substantial clinical benefit when used with therapeutic anti-tumor antibodies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Xencor Xencor
Akt-mediated YB-1 phosphorylation induces resistance for chemotherapy of gastric cancer
Authors: E. Oki, Y. Kakeji, E. Tokunaga, R. Yoshida, A. Egashira, N. Sadanaga, M. Morita, K. Taguchi, M. Kuwano, Y. Maehara
Journal: Journal of Clinical Oncology (2007)

4554 Background: Y-box-binding protein 1 (YB-1), a member of the DNA-binding protein family which contains a cold-shock domain, has pleiotropic functions in response to stimuli of the AKT/PI3K signal pathway. We have previously described a pathway that involves PTEN/AKT/PI3K, thereby mediating chemoresistance in gastric cancer patients. We studied the Akt-mediated YB-1 phosphorylation and resistance to anti-cancer drugs for the treatment of gastric cancer. Methods: Primary gastric carcinoma tissue and the corresponding normal mucosa were both obtained from 81 gastric cancer patients who underwent surgery in the Department of Surgery II at Kyushu University Hospital from the years 1996 to 2000. YB-1 nuclear expression was investigated by immunostaining while AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. LOH of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite markers in the same samples. Results: We found the activated AKT to be associated with an increased resistance to multiple chemotherapeutic agents, including those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). The YB-1 nuclear expression was recognized in some patients and they closely correlated with a high expression of phosphorylated AKT. A high level of AKT phosphorylation (activated AKT) correlated closely with the LOH of PTEN (p &lt; 0.0008), and the prognosis of patients who had LOH of PTEN was significantly poor in comparison to the other patients. Conclusions: The results of this study indicate that AKT activation and LOH of PTEN mediated the YB-1 activation, thus suggesting that they play an important role in conferring broad-spectrum chemoresistance in gastric cancer patients. These findings thus support the carrying out of new clinical trials for investigations of combination chemotherapy using conventional drugs with a new generation of signal transduction inhibitors. No significant financial relationships to disclose.
Death in the United States: Changes From 1969 to 2013
Authors: Jill Jin
Journal: JAMA (2016)

Americans are becoming healthier, living longer, and losing fewer years of life to preventable disease. How Many People Are Dying?A study published in the October 27, 2015, issue of JAMA looked at death certificates gathered by the Centers for Disease Control and Prevention from all 50 states between 1969 and 2013 and provides information on the rates and causes of death in the United States.From 1969 to 2013, the overall death rate in the United States decreased by more than 40%.In 1969, about 1279 people per 100 000 died.In 2013, this number decreased to 730 people per 100 000.These rates are age standardized, meaning they are adjusted for the fact that over the years, the US population has been getting older, so there are many more elderly Americans (in whom death is more common) now than in 1969.Another way of looking at the overall health of the nation is to look at trends in premature deaths by estimating the years of "potential life" lost.Between 1969 and 2013, the years of potential life lost decreased by more than 50%, from 135 per 1000 years to 64 per 1000 years.
Pharmacokinetics of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in cerebrospinal fluid (CSF) of a patient with breast cancer with carcinomatous meningitis.
Authors: M. Castro, L. Li, T. E. Stallings
Journal: Journal of Clinical Oncology (2010)

e13559 Background: Triple-negative breast cancer (TNBC) carries a high risk for brain metastasis and is associated with poor survival. A key role has emerged for PARP1 in the repair of DNA damage, particularly in cancers associated with BRCA1 dysfunction, including TNBC. BSI-201, a small molecule inhibitor of PARP1, has demonstrated significant antitumor activity when added to gemcitabine and carboplatin in treatment of metastatic TNBC. BSI- 201 was provided through a single patient IND to a patient with metastatic TNBC who developed carcinomatous meningitis as the only site of initial relapse. Methods: The patient had an Omaya reservoir inserted to facilitate intrathecal (IT) chemotherapy. The patient received IT methotrexate, which was switched to liposomal-cytarabine due to arachnoiditis. The patient received BSI-201 (5.6 mg/kg IV, biweekly) throughout IT treatment. CSF was sampled via the Omaya reservoir, and BSI-201 and its metabolites were measured prior to dosing and up to 2 hours post-infusion. Results: BSI-201 exposure in the CSF was ∼120 ng/mL at end-of-infusion. BSI-201 was rapidly eliminated from the CSF (t1/2 ∼ 10 min), with a longer-lived metabolite (t1/2 ∼ 21min). Overall exposure of the CNS was estimated to be ∼8% of the total systemic AUC for BSI-201, and Cmax in CSF was ∼7.5% of plasma Cmax. The patient responded to treatment for 5 months before developing disease progression in the bone and a second primary breast cancer. The burden of tumor cells in the CSF was reduced by > 95% throughout treatment. No evidence of systemic or neurologic toxicity from BSI-201 beyond what is normally observed with chemotherapy occurred. Conclusions: BSI-201 and its key metabolites cross the blood-brain barrier with BSI-201 AUC and Cmax in CSF of ∼10% of plasma values. This observation provides a basis for further examination of the role of BSI-201 in the treatment of this metastatic complication. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BiPar Sciences
Chromosome Pulverization in Chinese Hamster Cells Induced by Sendai Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Hatao Kato, Avery A. Sandberg
Journal: JNCI Journal of the National Cancer Institute (1968)

A chromosome pulverization phenomenon was induced in Chinese hamster cells by infecting cultures with Sendai virus. Striking cellular responses to virus, in terms of chromosome pulverization and syncytium formation, were observed as early as 30 minutes after treatment of the cells with virus. It is suggested that syncytial formation is a prerequisite for the induction of chromosome pulverization. After an initial response, the cells appeared to lose promptly the high susceptibility to pulverization-inducing factors. The latter were proved to be present constantly in the culture medium during the culture period. The syncytium formation depended on virus dosage, but the pulverization phenomenon occurred at a constant ratio and pattern, regardless of the dosage of virus. It is likely that only a definite proportion of cells in the culture may be able to participate in the induction of the pulverization phenomenon.
Tumor location does not impact return of renal function following partial nephrectomy
Authors: J. Pettus, D. Sharp, Y. Ofer, A. Bach, P. Russo
Journal: Journal of Clinical Oncology (2006)

14511 Background: To study the impact of tumor location on the glomerular filtration rate (GFR) changes following partial nephrectomy. Methods: We reviewed our institutional database to identify patients who underwent partial nephrectomy between 1/1995 and 7/2005. Preoperative CT and/or MRI studies were reviewed to characterize tumors as either central or peripheral. Central tumors were defined as those involving the collecting system or renal sinus; all others were categorized as peripheral. We used the Abbreviated Modification of Diet in Renal Disease study equation to estimate GFR preoperatively, in the early postoperative hospital stay, and at 1 and 12 months after surgery. Multivariate models were fit to determine the association of tumor location with changes in GFR at each time period after controlling for age, sex, tumor size, American Society of Anesthesia Score, ischemic time, operative time, and blood loss. Results: A total of 616 patients (265 central and 351 peripheral tumors) were available for analysis. Patients with central tumors were younger compared to those with peripheral tumors (62 vs. 59, p = 0.014), had longer intraoperative renal ischemia (40 vs. 30 min, respectively, p &lt; 0.001), and had longer operations (201 vs. 184 min, respectively, p = 0.01). Although baseline GFR did not differ between the groups, a significantly larger decrease in GFR was found in patients with central compared to peripheral tumors in the early postoperative period (−16 vs. −11 cc/min/1.73 m 2 , p = 0.013) and 1-month follow-up (−10 vs. −6 cc/min/1.73 m 2 , p = 0.017). The GFR change was similar at 1-year follow-up, −10 and −11 cc/min/1.73m 2 (p = 0.586) for central and peripheral tumors, respectively. On multivariate analysis, tumor location was not significantly associated with the change in GFR at any of the time intervals after adjusting for size, ischemic time, operative time, age, sex and comorbidity. Conclusions: Patients with centrally located tumors have a more pronounced short-term decrease in GFR, which reflects a longer operative time and ischemia duration. Tumor location does not appear to impact the long-term renal function. This suggests that renal sparing surgery should not be withheld from this subset of patients. No significant financial relationships to disclose.
Infection With Human Immunodeficiency Virus-1 Increases Expression of Vascular Endothelial Cell Growth Factor in T Cells: Implications for Acquired Immunodeficiency Syndrome-Associated Vasculopathy
Authors: G. Ascherl, C. Hohenadl, O. Schatz, E. Shumay, J. Bogner, L. Eckhart, E. Tschachler, P. Monini, B. Ensoli, M. Stürzl
Journal: Blood (1999)
Delay of chemotherapy through use of post-progression erlotinib in patients with <i>EGFR</i>-mutant lung cancer.
Authors: Geoffrey R. Oxnard, Peter Lo, David Michael Jackman, Mohit Butaney, Stephanie Heon, Bruce E Johnson, Lecia V. Sequist, Pasi A. Janne
Journal: Journal of Clinical Oncology (2012)

7547 Background: 1 st -line tyrosine kinase inhibitor (TKI) therapy for patients (pts) with EGFR-mutant lung cancer prolongs progression free survival (PFS) and improves quality of life. When pts develop acquired resistance to TKI, chemotherapy is the only approved systemic treatment. Anecdotal evidence suggests that change of therapy can be delayed in some pts through continued TKI beyond progression (PD), but the effectiveness of this approach has not been quantified. Methods: Through an IRB-approved mechanism, pts with advanced lung cancer and EGFR sensitizing mutations treated on 3 prospective trials of 1 st -line erlotinib were identified. Only pts with RECIST PD while on erlotinib were studied. Time from PD until use of an alternate systemic therapy (or death) and characteristics at PD (development of new extra-thoracic metastases or cancer-related symptoms) were assessed. Results: 42 eligible pts were identified with the following characteristics: median age 70, 86% female, 93% non-Asian, 50% never-smokers, 83% adenocarcinoma, 100% EGFR-mutant (55% exon 19, 36% exon 21, 9% exon 18). Median PFS on erlotinib was 13 months. After PD, alternate systemic therapy was delayed &gt;3 months in 19 pts (45%; 95%CI: 31%-60%), through a combination of post-PD erlotinib (16 pts), radiation (6 pts), and/or surgery (3 pts), or on observation alone (2 pts). These 19 pts commonly had exon 19 deletions and were more likely to have no cancer-related symptoms at PD (Table), and had a median post-PD survival of 29 months. Alternate systemic therapy was delayed &gt;12 months in 8 pts (19%). Conclusions: In a subset of pts with EGFR-mutant lung cancer and acquired resistance to TKI, chemotherapy can be delayed with the aid of post-PD TKI and local treatment modalities. This indolent PD is likely due to ongoing tumor EGFR dependence. In pts who are tolerating TKI and have asymptomatic progression, we recommend this palliative treatment strategy as an option for delaying chemotherapy and maximizing quality of life. [Table: see text]
Malignant pericardial effusion treated with IFN alpha 2b
Authors: A. Apodaca-Cruz, G. Vazquez-Islas, F. Lara-Medina, A. Mohar, M. Cuellar, D. Gallardo-Rincon
Journal: Journal of Clinical Oncology (2005)

2595 Background: patients with malignant pericardial disease may be asymptomatic or may present with a number of manifestations, pericardial effusion is the more common, pericardial tamponade account for at least 50% of all reported cases that require intervention, overall median survival of patients with MPCE is less than 6 months. Interferon has demonstrated activity in patients with pleural effusion and could be well tolerated in MPCE Objective: to treat patients with MPCE with IFN alpha 2b after pericardiocentesis recurrence. Methods: we administered interferon alpha 2b 10 millions into pericardial cavity, for patients with recurrent MPCE, considering as complete response when the MPCE disappear at least for a month, partial response in the case of disappearing in less than a month, and non response when it did not disappear, the response was evaluated by clinical and radiological findings (CT scan). Results: we treated 56 patients with MPCE since January 1996 to January 2004, 40 women and 16 men, mean age 45 years (range 17–73 y) breast cancer was the most common cause (39 pt); lung cancer (10); cervical cancer (2); LNH (3); primary mediastinal tumors (2). In 20 patients was necessary the administration of INF: 14 with breast cancer, two with lung cancer; three with primary mediastinal tumor; and one with cervical cancer. Four patients received two doses of interferon and in one patient three. We got 13/20 (65%) CR; 2/20 (10%) PR; 5/20 (25%) NR. Toxicity: we did not have any toxicity grade 3 or 4. Conclusions: the administration of IFN alpha 2b should be followed explored as an option for patients with recurrent MPCE. l No significant financial relationships to disclose.