tbuckley/cabot-search huggingface dataset:
A phase I trial of a pharmacodynamically-conceived decitabine/thioguanine combination in patients with advanced myeloid malignancies.
Authors: Todd Louis Rosenblat, Joseph G. Jurcic, Mark L. Heaney, Azra Raza, J. Gregory Mears, Ruth Santos, Diana Carrillo, Jacquelyn Gonzales, Katherine Harwood, Martin Santos, Rong Zhang, Glorymar Ibanez, Leah Hogdal, Jennifer Leigh Crombie, Hakim Djaballah, Joseph M Scandura, Anthony G. Letai, Mark G. Frattini
Journal: Journal of Clinical Oncology (2015)

e18025 Background: Using a chemosensitivity screening assay, we showed that combination decitabine and thioguanine was active in primary leukemia cells from patients with relapsed/refractory acute myeloid leukemia (AML). To test the safety and activity of this combination, we are performing a Phase I dose escalation trial of thioguanine and decitabine. Methods: Patients with untreated AML > 60 yrs who are not candidates for standard induction therapy, those with relapsed/refractory AML, advanced myelodysplastic syndromes, and chronic myelomonocytic leukemia (CMML) are eligible. Thioguanine 80 or 120 mg/m2/day was given on Days 1-12 of each induction course for up to two cycles and Days 1-7 of maintenance cycles. Decitabine 20 mg/m2 was given IV on Days 3-12 during induction cycles and on Days 3-7 during maintenance cycles. A 3+3 dose escalation scheme was used. Biologic activity was assessed by patient-specific pharmacodynamic measures including an in vitro chemosensitivity assay, genome-wide analysis of DNA methylation, and BH3 profiling. Results: Nine patients (median age, 67 yrs; range, 56–83 yrs) with newly diagnosed AML (n=2), transformed AML (n=1), relapsed/refractory AML (n=5), and newly diagnosed CMML (n=1) were treated to date with thioguanine 80 mg/m2 (n=6) or 120 mg/m2(n=3). Median cycles administered was 3 (range, 1-8). Dose-limiting toxicities (acute renal failure and persistent myelosuppression) were seen in 2 patients. Grade 3 toxicities included neutropenic colitis, bacteremia, and pneumonia. Responses included 1 CR, 2 CRi, 2 MLFS (morphologic leukemia-free state), 1 marrow CR, and 1 PR for an overall response rate of 78%. Chemosensitivity assay results for thioguanine on pretreatment mononuclear cells directly correlated with clinical outcomes. BH3 profiling on pre-treatment myeloblasts showed that apoptotic priming corresponded to initial clinical response. Conclusions: Combination decitabine and thioguanine was well-tolerated and highly active. In vitro chemosensitivity testing and BH3 profiling predicted clinical outcomes. Accrual continues to determine the maximum tolerated dose.
First double-blind placebo-controlled, multicenter, randomized trial of stabilized natural sulforaphane in men with rising PSA following radical prostatectomy.
Authors: Bernard G Cipolla, Eric Mandron, Jean Marc Lefort, Yves Coadou, Emmanuel Della Negra, Luc Corbel, Romuald Le Scodan, Nicolas Mottet
Journal: Journal of Clinical Oncology (2014)

5032 Background: Sulforaphane (SF) is a natural compound present in cruciferous vegetables. It has demonstrated molecular targets. Its main problem is its instability in its free form. We have assessed the efficacy of a natural, stabilized SF in recurrent prostate cancer patients (pts) after radical prostatectomy (RP) ± adjuvant or salvage external radiotherapy (RT). Methods: In this multicenter trial, 81 pts, mean age 69 ± 6 years with a rising prostate-specific antigen (PSA) >0.2 ng/ml (and <5 ng/ml) after RP ± RT, without metastasis, a Gleason score ≤7, a PSA doubling time (PSADT) >5 and <36 months (M) participated in a double-blind, randomized, placebo (P) controlled study. Treatment consisted in 60 mg daily SF during six-months (M0-M6). A two months washout period (M6 to M8) followed. Clinical and biological assessments were performed at M0, M1, M3, M6 and M8. The study was designed to detect a 0.012 log(ng/ml)/month decrease in Log PSA slope in the SF arm compared to P. Results: Baseline parameters did not differ between the 2 groups considering pathological stage and Gleason score, PSA, PSADT, Log PSA slope and serum testosterone. Three non-complying pts were excluded. The ITT population was 78 patients (40 P and 38 SF). Log PSA slope in the SF group (0.0298±0.0096) was significantly lower between M0 and M6 (p=0.036, 0.0285 log(ng/ml)/month =-49%) than in the P group (0.0583±0.0093) and most particularly (-83%) between M3 and M6 (p=0.011). The difference in PSA levels observed at M6 between the two groups was preserved during the washout period. A 78 % PSA DT increase was observed in the SF group (21.9 vs 12.1 months) compared to P. The mean change in PSA levels between M6 and M0 was significantly lower in the SF group compared to P (0.099±0.341 vs 0.620±1.417 ng/ml; p=0.03). Testosterone levels did not differ between the two groups. Observance was excellent (96% in each group). Safety was very good with a few more GI tract side effects in the SF arm (17 vs 10). Conclusions: The stabilized SF used in this study was shown to significantly delay PSA progression after RP ± RT. These encouraging results both on efficacy and safety indicate more extensive studies of this SF. Clinical trial information: ID-RCB: 2011- A00347-34.
Whole-Exome Sequencing of Waldenström Macroglobulinemia Transformation into Aggressive Lymphoma
Authors: Sara Alonso, Cristina Jiménez, Miguel Alcoceba, María García-Álvarez, Isabel Prieto-Conde, M. Carmen Chillon, M. Eugenia A. Sarasquete, Noemi Puig, Maria-Victoria Mateos, Enrique M. Ocio, Marcos González, Ramon Garcia-Sanz
Journal: Blood (2016)
ETIOLOGY OF OROYA FEVER
Authors: Hideyo Noguchi, Raymond C. Shannon, Evelyn B. Tilden, Joseph R. Tyler
Journal: The Journal of Experimental Medicine (1929)

With a view to determining the mode of infection in Carrion's disease, a study of the blood-sucking insects found in the districts of Peru where the disease prevails has been carried out, through the cooperation of The Rockefeller Institute and the Rockefeller Foundation. The material studied included ticks, mites, midges, lice, fleas, bedbugs, mosquitoes, buffalo gnats, horse-flies, "sheep ticks," 3 species of Streblidae, and 3 species of Phlebotomus, including Phlebotomus verrucarum Townsend and two new species which have been named Phlebotomus noguchii and Phlebotomus peruensis. The insects were collected without the use of chemicals, were prepared for transportation in such a manner as to prevent drying, and were shipped under conditions of refrigeration to New York, where they were inoculated into monkeys. The plan followed was to inject saline suspensions of the crushed insects intradermally into rhesus monkeys and to make cultures of the blood of the animals at intervals of 1 to 6 weeks after inoculation. The only class of insects in which the presence of Bartonella bacilliformis could be detected were phlebotomi. No cutaneous lesions were induced in monkeys injected with the crushed insects, but in the case of four different lots of phlebotomi the blood of the animals so injected yielded cultures of Bartonella bacilliformis which produced typical verrucous lesions on inoculation into other monkeys. The morphology and cultural characteristics of the Bartonella strains obtained from phlebotomi proved identical with those of strains isolated from human blood and skin lesions. Monkeys which had recovered from infection with the phlebotomus strains resisted inoculation with a human strain of Bartonella bacilliformis, and, conversely, monkeys which had passed through an infection induced by the human strain resisted inoculation with the strains obtained from phlebotomi. The experimental observations described in this paper lead us to conclude that certain phlebotomi act as insect vectors of Oroya fever and verruga peruana. The phlebotomi which have been shown quite certainly to carry the Bartonella bacilliformis are those of the species Phlebotomus noguchii. Phlebotomus verrucarum is also probably a vector, while Phlebotomus peruensis remains doubtful in this respect.
Exercise for cancer-related fatigue and putative functional, inflammatory, and metabolic mechanisms in patients receiving chemotherapy: A URCC CCOP research base phase III RCT.
Authors: Karen Michelle Mustian, Michelle Christine Janelsins, Luke Joseph Peppone, Lisa Sprod, Oxana Palesh, Charles Stewart Kamen, Anita Roselyn Peoples, Charles E. Heckler, Samer S. Kasbari, Anthony Joseph Scalzo, Pavan S. Reddy, Benjamin Esparaz, Gary R. Morrow
Journal: Journal of Clinical Oncology (2013)

TPS9651 Background: Up to 100% of cancer patients report cancer-related fatigue (CRF) during chemotherapy which co-occurs with impaired cardiopulmonary (CPF) and neuromuscular function (NMF), chronically up-regulated inflammatory responses, and low metabolic energy expenditure. CRF interferes with completion of treatment, increases cancer morbidity and mortality, and impairs quality of life (QOL). Exercise is one of the most promising treatments available for CRF, but no large multicenter phase III RCTs have confirmed these findings and little is known about the mechanisms through which exercise may impact CRF. Methods: We are conducting a nationwide multicenter phase III RCT (N=692) through the URCC CCOP Research Base with 23 CCOP affiliates. The primary aim is to determine if exercise will significantly improve CRF, and secondarily, CPF, NMF, inflammation, energy expenditure, and QOL compared to standard care in cancer patients receiving chemotherapy. The exercise intervention is our standardized, individually-tailored, home-based walking and progressive resistance program, “Exercise for Cancer Patients” (EXCAP, 7 days/wk, 6wks). To be eligible, patients must: 1) have a confirmed diagnosis of cancer with no leukemia or metastasis, 2) be chemotherapy naïve and scheduled to start, 3) not be receiving concurrent radiation, 4) have a KPS of &gt;70, 5) be ≥21 years of age, 6) have no contraindications to exercise or functional testing, and 7) not be currently exercising. CRF and all secondary outcomes are assessed at baseline (pre-chemotherapy), 3 weeks (mid-intervention), and 6 weeks (post-intervention). Measures include: 1) CRF-Brief Fatigue Inventory, 2) CPF-6-minute walk test, 3) NMF-handgrip dynamometry, 4) inflammation-serum ELISA levels, 5) energy expenditure-actigraphy, and 6) quality of life-Functional Assessment of Chronic Illness Therapy. The DSMC reviewed the trial in October of 2012 and suggested it continue as planned. 532 participants have been enrolled in 36 months. Funding: NCI U10CA037420, U10CA37402-28, K07CA120025, K07CA132916, 1R25CA102618, ACS MRSG1300101CCE. Clinical trial information: NCT00924651.
Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients.
Authors: Robert Charles Newton, Peggy A Scherle, Kevin Bowman, Xiangdong Liu, Gregory Lawrence Beatty, Peter J O'Dwyer, Thomas Gajewski, Jill Bowman, Richard Schaub, Lance Leopold
Journal: Journal of Clinical Oncology (2012)

2500^ Background: The ineffectiveness of the immune system to control tumor growth is, in part, a result of immunosuppression imposed by negative regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme that catabolizes the first and rate-limiting step in the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been shown preclinically to play an important role in tumor-mediated immunosuppression. In cancer patients (pts), elevated IDO1 levels are associated with poor prognosis and shortened survival in a number of tumor types. Here we describe the pharmacodynamic (PD) assessment of INCB024360, a novel inhibitor of IDO1. Methods: Plasma samples were obtained from consented pts in study INCB 24360-101, a phase I dose-escalation study in patients with advanced malignancies. Trp and Kyn levels in plasma were determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells was also monitored. Results: Using anti-IDO1 specific antisera and archived tumor samples, we found IDO1 expression in various human tumors, including ovarian, colorectal, breast and prostate. Consistent with this result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were detected in archived plasma samples from pts, indicative of higher IDO1 activity in cancer pts. To date, 23 pts have been treated with the selective IDO1 inhibitor INCB024360. When plasma samples from patients were collected pre- and post-INCB024360 treatment, significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected. As an additional biomarker measurement, whole blood samples collected from pts at various times after dosing were stimulated ex vivo with interferon-γ and lipopolysaccharide to increase IDO1 activity and also showed dose-dependent decreases in IDO activity. With the current dose regimens and assays we have successfully achieved sustained inhibition of &gt;90% at a well tolerated dose of INCB024360. Conclusions: This is the first demonstration of PD activity of an IDO1-specific inhibitor in cancer pts. Our study also confirms that IDO1 is frequently activated in cancer pts. The methods described will be used to establish a phase II dose.
Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative
Authors: Leonard A. Levin, Joan W. Miller, Donald J. Zack, Martin Friedlander, Lois E.H. Smith
Journal: Ophthalmology (2017)

The National Eye Institute launched the Audacious Goals Initiative (AGI) in 2013 with the aim "to restore vision through the regeneration of neurons and neural connections in the eye and visual system." An AGI Town Hall held at the Association for Research in Vision and Ophthalmology Annual Meeting in 2016 brought together basic, translational, and clinical scientists to address the clinical implications of the AGI, with a particular emphasis on diseases amenable to regenerative medicine and strategies to deal with barriers to progess. An example of such a barrier is that replacement of lost neurons may be insufficient because damage to other neurons and non-neuronal cells is common in retinal and optic nerve disease. Reparative processes such as gliosis and fibrosis also can make it difficult to replenish and regenerate neurons. Other issues include choice of animal models, selecting appropriate endpoints, ethics of informed consent, and regulatory issues. Another area critical to next steps in the AGI is the choice of target diseases and the stage at which early development studies should be focused. For example, an advantage of doing clinical trials in patients with early disease is that supporting cellular and structural constituents are still likely to be present. However, regenerative studies in patients with late disease make it easier to detect the effects of replacement therapy against the background of severe visual loss, whereas it may be harder to detect incremental improvement in visual function in those with early disease and considerable remaining visual function. Achieving the goals of the AGI also requires preclinical advances, new imaging techniques, and optimizing translational issues. The work of the AGI is expected to take at least 10 years but should eventually result in therapies to restore some degree of vision to the blind.
Phase I/II trial of intravenous liposomal doxorubicin and whole abdomen hyperthermia in patients with refractory ovarian cancer
Authors: A. A. Secord, E. Jones, C. A. Hahn, L. J. Havrilesky, J. T. Soper, A. Berchuck, D. L. Clarke-Pearson, L. R. Prosnitz, M. W. Dewhirst
Journal: Journal of Clinical Oncology (2004)

5089 Background: A phase I/II study of liposomal doxorubicin combined with whole abdominal hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase liposomal extravasation into tumor xenografts resulting in enhanced cytotoxic effects. Methods: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) liposomal doxorubicin 40 mg/m2 as a 1-hour infusion followed by whole abdominal hyperthermia. Quality of life (QOL) was performed at baseline, prior to each cycle, and every 3 months following treatment. Results: All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2–8) and 6 patients had been previously treated with liposomal doxorubicin. There were 3 partial responses for a response rate of 10% and 8 patients (27%) had disease stabilization. The median time to progression was 3.4 months (range, 1.3 to 20.7) and the median survival was 10.8 months (range, 2.7 to 27.2). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only 4 (13%) experienced grade 3/4 PPE toxicity. None of the patients had grade 3/4 thermal toxicity due to hyperthermia. QOL was stable in patients responding to therapy. Conclusions: Therapy with intravenous doxorubicin and whole abdominal hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer has modest activity and stabilized quality of life. Whole abdomen hyperthermia was well tolerated in this population. Work supported by a grant from the NIH CA42745. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Pharmacia Aventis; GlaxoSmithKline; Pharmacia
Role of trastuzumab in infracentimetric HER2-positive breast cancer: The southern Italy experience.
Authors: Vincenzo Adamo, Giuseppina R. R. Ricciardi, Barbara Adamo, Michele Caruso, Hector J. Soto Parra, Carmelo Iacono, Angela Prestifilippo, Antonio Russo, Vittorio Gebbia, Nicolo Borsellino, Livio Blasi, Giuseppe Lavenia, Pietro Spadaro, Francesco Verderame, Giovanni Tuccari
Journal: Journal of Clinical Oncology (2014)

e11512 Background: HER2 positive (HER2+) disease is relatively uncommon in early infracentimetric breast cancer (BC) accounting for approximately 10% of cases. Trastuzumab (T) based-adjuvant therapies have shown benefit in patients (pts) with HER2+ tumors with diameter ≥1 cm or positive lymph nodes, based on evidence from large clinical trials. Nowadays, scant data concerning the role of trastuzumab in infracentimetric HER2+ disease have been reported. The aim of this study is to identify the pattern of use of T and risk of recurrence in this setting. Methods: This observational, multicenter, retrospective study was conducted in 13 oncology centers in Sicily from 2005 to 2011. Multifocal and metastatic tumors were excluded. Results: Among our case series, 96 pts were included. Median age was 54 years (range 36-77). Tumor stage: T1a 29 (30.2%) and T1b 67 (69.8%). Nodal status: N0 73 (76%). Histological type: Ductal 91 (95%), Lobular 4 (4%) and Medullary 1 (1%). Histological grade: G1 3 (3.1%); G2 55 (57.3%); G3 38 (39.6%). The Ki67 index was ≥13% in 66 (69%). Hormonal Receptor Status (HR): positive 59 (61.4%). Surgery: quadrantectomy in 84 (87.5%) and mastectomy in 12 (12.5%). All 59 pts HR positive received hormonotherapy, 38 were treated with aromatase inhibitors and 21 with LHRH agonists plus tamoxifen. Sixty-eight pts (71%) received T in combination and/or after adjuvant chemotherapy (mostly anthracyclines/taxane-based regimens). Only 2 cases reported asymptomatic and transient left ventricular ejection fraction decrease below 20% after T. Ninety pts were evaluable for relapse-free survival (RFS) analysis. At a median follow-up of 32.0 months, there were 7 metastatic recurrences and 1 loco-regional, 4/28 (14.3%) in the non-T treated group and 4/62 (6.4%) in the T-treated group. The subgroup analysis revealed that HR-negative status was associated with a poorer RFS in HER2+ disease compared to HR+ status. Conclusions: Our study suggests that infracentimetric HER2+ with HR negative status is associated with a poor outcome and may benefit from T-based therapies. Therefore, our data underline the importance of the biological assessment for driving the treatment choice.
Long-term progression-free survival (PFS) in patients under sunitinib treatment: A SOG_GU experience.
Authors: Francisco Javier Afonso, Ovidio Fernández Calvo, Emilio Esteban, Elena Fernández Gabriel, Sergio Vazquez-Estevez, Urbano Anido, Martin Lázaro Quintela, Lucía Santomé, Manuel Ramos Vazquez, Begoña Campos Balea, Luis Leon Mateos, Jose-luis Firvida, Luis Anton Aparicio
Journal: Journal of Clinical Oncology (2012)

e15067 Background:A multicenter retrospective analysis was performed in patients (pts) with metastatic RCC treated with sunitinib who achieved long-term PFS defined as ≥18 months. Methods: 46 pts (87% male) treated with sunitinib in first (74%) or subsequent lines were included. Median age was 59 years, most common histology was clear cell (93.5%), 89% had undergone prior nephrectomy, 28.3% were metastatic at diagnosis and 58.7% presented one site of metastasis, 28.3% two sites and 13% three or more and 12 (26%) had bone metastases. Good, medium, and poor prognosis (MKSCC) was presented in 30.4%, 67.4% and 2.2% of pts respectively. Median time from diagnosis to sunitinib treatment was 2.23 years and median duration of therapy was 27 months. At the time of analysis 37% were still receiving sunitinib. Reasons for discontinuation were progressive disease (83%), toxicity (10.3%) and death (3.4%). Results: Incidence of adverse events was as expected, with asthenia, hand food syndrome (HFS), hypertension, and mucositis as main toxicities. Efficacy results are described in the table. No significant differences in PFS with prior or nonprior history of hypertension, diabetes, or hyperlipidemia were observed. The emergence of drug-related toxicities, lack of bone metastasis, and being nonmetastatic at the time of diagnosis were independenly associated with a trend towards an improvement in PFS (p=NS)(see table). Conclusions: A comparison with a sunitinib-refractory population is planned and will provide additional information about prognostic biomarkers for long term response. [Table: see text]
Case 8-2017
Authors: David R. Boulware, A. Tariro Makadzange
Journal: New England Journal of Medicine (2017)

A 39-year-old man with non–insulin-dependent diabetes mellitus was admitted to a hospital in Zimbabwe because of a severe headache. Evaluation of the cerebrospinal fluid revealed a white-cell count of less than 5 per cubic millimeter. Diagnostic tests were performed.