tbuckley/cabot-search huggingface dataset:
Trastuzumab with triple chemotherapy (DOC) in patients with advanced gastroesophageal cancer: A phase I dose-finding trial.
Authors: Katrine R. Schoennemann, Mette K. N. Yilmaz, Lene Baeksgaard, Helle Anita Jensen, Lene Weber Vestermark, Tine Plato Hansen, Per Pfeiffer
Journal: Journal of Clinical Oncology (2014)

108 Background: Trastuzumab (T) improves efficacy of doublet chemotherapy (TOGA trial) in HER2 positive patients with advanced gastro-esophageal (GE) cancer but safety and efficacy with triple chemotherapy is presently unknown. We initiated a dose-finding trial to establish a safe 4 drug combination of docetaxel (D), short-time infusion of oxaliplatin (O), continuously capecitabine (C) and trastuzumab (T). Methods: This phase I, dose-finding trial was approved by the local etic committee. All pts had histologically confirmed GE adenocarcinoma. Therapy was given day 1 with escalating doses of D (42mg/m 2 to 51 mg/m 2 as a 60 minutes infusion), O (100 mg/m 2 as a 30 minutes infusion) and C (1,250 mg/m 2 /day continuously). DOC was repeated every 3 weeks for a maximum of 6 courses. T was given as a loading dose (8 mg/kg) followed by 6 mg/kg every 3 weeks until PD or unacceptable toxicity. Toxicity was evaluated according to NCIC-CTC 3.0. DLT was evaluated after the first course and defined as non-haematological toxicity grade ≥ 3, neutropenia grade 4 more than 7 days or febrile neutropenia. Response was evaluated by the investigator according to RECIST 1.0 every 9th weeks. Data was updated September 1, 2013. Results: From May 2010 to October 2012 we included 11 pts. Median age was 62years (range 32-73), 5/11 pts had PS 0, all pts had metastatic disease. Neutropenia grade 3-4 was observed in two pts, one had febrile neutropenia grade 3 after four courses. Two pts had grade 3 vomiting, fatigue, or nausea, respectively and one patient had diarrhoea grade 3. Only one pt developed a DLT (grade 3 vomiting, nausea and fatigue). Dose-intensity, after six courses, in all 11 pts was: D = 89%, O= 88% C = 81% and T = 100%. Median number of DOC was 6; all pts continued T to a median of 12 courses and one pt is presently receiving T. Partial response was obtained in 9 pts (81%). Progression free survival was 8.8 months and overall survival was 16.5 months. Five pts are presently alive. Conclusions: DOC-T in HER2 positive GE pts is safe and easily administered in an out-patient setting. The recommended doses for further evaluation are: D 51 mg/m 2 , O 100 mg/m 2 , C 1,250 mg/m 2 . Efficacy is very promising and deserves evaluation in larger trials. Clinical trial information: NCT01295086.
Evolution of the T1 retroposon family in the Anopheles gambiae complex.
Authors: N J Besansky
Journal: Molecular Biology and Evolution (1990)

The T1 family of retrotransposable elements is interspersed and moderately repeated in five member species of the Anopheles gambiae sibling-species complex and has diverged little since the radiation of the complex. T1 includes two closely related but independent subfamilies, defined by the presence or absence of linked sets of restriction sites, in all but one species, although the relative abundance of the subfamilies differs within each. Sequence analysis of a 349-bp region from 21 clones isolated from A. gambiae confirmed the bipartite organization by revealing 19 coordinated nucleotide differences between the two subfamilies--T1 alpha and T1 beta. Sequence divergence is not only greater between than within subfamilies, but divergence within T1 beta is less than that within T1 alpha. Between-species comparisons of genomic consensus restriction maps revealed that T1 alpha is fixed for species-diagnostic differences in all species. With one exception, these subfamilies account for approximately 70% of detectable T1 copies in the genome. The results support retroposition as the dominant mechanism underlying the evolution of the T1 family.
A new prognostic model (MPI) for patients with myelofibrosis
Authors: K. Strasser-Weippl, M. Steurer, M. Kees, F. Augustin, A. Tzankov, N. Zojer, J. Thiele, H. Gisslinger, H. Ludwig
Journal: Journal of Clinical Oncology (2004)

6621 Background: Several prognostic models for patients with myelofibrosis with myeloid metaplasia (MMM) have been developed, with the LILLE score1 now most commonly used. The latter and other previous scoring systems, however, showed limited power to consistently separate patients with intermediate and poor prognosis. Methods: We have studied 107 patients with MMM (median age 68, range 24–87) and correlated clinical parameters at the time of diagnosis with survival by multivariate analysis. Results: Hemoglobin and age at diagnosis was found to be significantly associated with prognosis (p<0.1x10-5, p<0.1x10-6, respectively). These data were used to establish a prognostic index (myelofibrosis prognostic index, MPI) in a training group. One risk point was allotted for each Hb<10 g/dl and age> 60 years, respectively. The relevance of the MPI was confirmed in the test group and in the overall cohort of patients (Table 1). Median survival was not reached in the good prognosis group and was 64 and 34 in the intermediate and poor group respectively (p<0.1x10-6) . Next, previously published prognostic models were evaluated in our cohort of patients. The application of the LILLE model did not result in sufficient separation of patients with an intermediate or poor prognosis (Table 1). Conclusions: We have established a new, simple prognostic index (MPI) which discriminates three prognostic groups with highly significant different survival. Our data also confirm a previous report by Kvasnicka et al. who have shown the prognostic relevance of age and hemoglobin before, but used in addition leukocyte and platelet counts for separation of patients into different prognostic subgroups. No significant financial relationships to disclose.
Risk-stratified treatment of patients with metastatic germ cell tumor with progression after first-line therapy.
Authors: Orvar Gunnarsson, Wei-Ting Hwang, Christian Michael Squillante, Katherine L. Nathanson, Edward A. Stadtmauer, David J. Vaughn
Journal: Journal of Clinical Oncology (2015)

398 Background: The optimal management of patients with metastatic germ cell tumor (GCT) who experience progression after first-line (FL) therapy is controversial. A risk-stratified approach was introduced in 2005. Favorable risk patients received 4 cycles of paclitaxel, ifosfamide, cisplatin (TIP); unfavorable risk patients received 2 cycles of TIP followed by 2 cycles of high-dose chemotherapy [(HDCT); carboplatin and etoposide with autologous stem cell support]. Favorable risk was generally defined as gonadal primary and relapse &gt; 6 months after CR or marker negative PR to FL therapy; all others were unfavorable risk. The aim of this study is to present survival outcome of this risk-stratified approach at a single institution. Methods: A chart-based retrospective review was conducted on all patients with metastatic GCT who experienced progression after FL therapy from 2005 to 2013. Data were collected on baseline demographics and disease characteristics. Progression-free survival (PFS) and overall survival (OS) were calculated for favorable and unfavorable risk patients. Results: 37 patients were identified and included for analysis. Patients characteristics: Caucasian 92%; median age 27 years; gonadal primary 84%; non-seminoma, 81%. 16 (43%) favorable risk patients received TIP x 4; 21 (57%) unfavorable risk patients received TIP x 2 followed by HDCT x 2. The median time for follow-up was 16 months. Favorable risk patients: 2- and 4-year PFS of 60% and 45%; 2- and 4-year OS of 74%. Unfavorable risk patients: 2- and 4-year PFS of 41% and 27%; 2- and 4-year OS of 55% and 34%. Both IGCCCG risk classification at initial diagnosis and IPFSG risk classification at relapse had prognostic validity for OS (log rank p ≤ 0.05) but not PFS (log rank p = 0.065–0.080). Conclusions: Risk-stratified treatment of patients with metastatic GCT with progression after FL therapy may result in the best risk/benefit ratio. However, the optimal management of these patients is still not known and prospective randomized comparisons are needed.
Influence of Various Viruses on the Heterotransplantability of Human Cells
Authors: R. E. Kissling, Betty V. Addison
Journal: JNCI Journal of the National Cancer Institute (1964)

A variety of viruses were examined for their ability to modify the survival of human diploid cells after heterotransplantation into hamster cheek pouches. Cells infected with any adenovirus used (#1, 2, 3, 7, 12, and 16), or vaccinia, REO-2 viruses, or cytomegalovirus survived longer than uninfected cells. However, the degree of autonomy upon transplantation was not equal to cells of known malignant origin. The possible role of certain viruses in helping to establish autonomy of cells is discussed. Some viruses examined [varicella, simian virus 40 (SV40), measles, parainfluenza-3, and rubella] did not influence the survival of cells after heterotransplantation under the conditions of this experiment.
Effect of screening on the detection of good and poor prognosis breast cancers.
Authors: Y. Shieh, L. Esserman, E. J. Rutgers, M. Knauer, V. Retel, S. Mook, A. Glas, S. C. Linn, F. E. van Leeuwen, L. van't Veer
Journal: Journal of Clinical Oncology (2010)

1520 Background: 25 years of population-based screening have led to a sustained increase in the incidence of breast cancer, largely due to an increase in the rate of node-negative disease. A concomitant drop in the rate of node-positive disease has not been observed. To determine if screening has led to the emergence of more low-risk cancers, the NKI 70-gene prognosis signatures (PS) of cancers from a prescreening cohort were compared to those of a screening cohort. Methods: Patients were selected if they had node-negative breast cancers for which the 70-gene PS was generated as part of 2 validation studies in the prescreening era (EVS and NKI studies, pre 1992), or a prospective validation trial from the screening era (RASTER, 2004-6). For the prescreening and screening cohorts, the proportion of tumors classified by the 70-gene PS as low vs. high risk was compared. The distributions of PS index scores, a continuous measure, were also determined. An ultralow-risk group was defined using the index scores and corresponds to the threshold where no distant metastases were observed in the original validation set. Results: In the prescreening era, 46% (102/222) cancers detected in women 49-69 years of age were molecularly low risk. In the screening era, 58% (119/205) of cancers in women 49-60 were low risk, and of the screen-detected cancers, 67% (63/94) were low risk. No difference was observed in the under-40 age group: 25% (17/68) and 30% (17/56) were low risk in the prescreening and screening eras, respectively. A significant shift to index scores corresponding to biologically lower-risk tumors was seen in women with screen-detected cancers. Ultralow-risk cases constituted 10% of cases in women 49-60 during the prescreening era, compared to 30% of screen-detected cancers. Conclusions: There has been a substantial increase in the proportion of good prognosis cancers in women 49-60 (who are screened), but not in young women < 40 yrs (who are unscreened). Screening preferentially detects low-risk tumors and likely contributes to the detection of tumors that would otherwise not come to clinical attention. Due to this possible consequence of screening, physicians should embrace tools to classify risk and adjust their treatment strategies accordingly. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agendia Agendia
Ultrasound-guided percutaneous dilational tracheostomy versus bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients (TRACHUS): a randomized noninferiority controlled trial
Authors: André Luiz Nunes Gobatto, Bruno A. M. P. Besen, Paulo F. G. M. M. Tierno, Pedro V. Mendes, Filipe Cadamuro, Daniel Joelsons, Livia Melro, Maria J. C. Carmona, Gregorio Santori, Paolo Pelosi, Marcelo Park, Luiz M. S. Malbouisson
Journal: Intensive Care Medicine (2016)
An engineered multicomponent bone marrow niche for the recapitulation of hematopoiesis at ectopic transplantation sites
Authors: Mónica S. Ventura Ferreira, Christian Bergmann, Isabelle Bodensiek, Kristina Peukert, Jessica Abert, Rafael Kramann, Paul Kachel, Björn Rath, Stephan Rütten, Ruth Knuchel, Benjamin L. Ebert, Horst Fischer, Tim H. Brümmendorf, Rebekka K. Schneider
Journal: Journal of Hematology & Oncology (2016)

Bone marrow (BM) niches are often inaccessible for controlled experimentation due to their difficult accessibility, biological complexity, and three-dimensional (3D) geometry. Here, we report the development and characterization of a BM model comprising of cellular and structural components with increased potential for hematopoietic recapitulation at ectopic transplantation sites. Cellular components included mesenchymal stromal cells (MSCs) and hematopoietic stem and progenitor cells (HSPCs). Structural components included 3D β-tricalcium phosphate (β-TCP) scaffolds complemented with Matrigel or collagen I/III gels for the recreation of the osteogenic/extracellular character of native BM. In vitro, β-TCP/Matrigel combinations robustly maintained proliferation, osteogenic differentiation, and matrix remodeling capacities of MSCs and maintenance of HSPCs function over time. In vivo, scaffolds promoted strong and robust recruitment of hematopoietic cells to sites of ectopic transplantation, vascularization, and soft tissue formation. Our tissue-engineered BM system is a powerful tool to explore the regulatory mechanisms of hematopoietic stem and progenitor cells for a better understanding of hematopoiesis in health and disease.
Phase l study of the oral CDK-TRKA inhibitor PHA-848125 administered with prolonged schedules of administration.
Authors: S. Cresta, C. Sessa, G. Del Conte, A. Locatelli, E. Gallerani, F. Fiorentini, A. Scaburri, M. A. Pacciarini, R. Alzani, L. Gianni
Journal: Journal of Clinical Oncology (2010)

3065 Background: PHA-848125 (PHA) is a dual CDK/TRKA oral inhibitor showing single agent antitumor activity in several tumor models including pancreas, prostate and glioma. PHA exhibited more than additive activity in combination with docetaxel, topotecan, temozolomide, bevacizumab, irinotecan, 5-FU, and gemcitabine. Methods: Phase I study to determine safety, pharmacokinetics (PK), pharmacodynamics (PD), and recommended dose for phase II (RP2D) of PHA administered once daily 21 days on/ 7 days off in 4-week cycles (cy) (schedule 1) or 14 days on/ 7 days off in 3-week cys (schedule 2) to advanced solid tumor patients (pts). Cohorts of 3-6 pts were enrolled in schedule 1 at doses of 16 (7 pts) and 24 (6 pts) mg/m2/day and in schedule 2 at doses of 24 (3 pts), 48 (4 pts), 72 (4 pts), and 54 (4 pts) mg/m2/day. Results: Schedule 1 was not tolerated: 2 pts experienced first cycle DLTs at 24 mg/m2: grade (gr) 3 dizziness and asymptomatic worsening of electroretinography (ERG). In schedule 2, 15 pts received a total of 53+ cys (median 3, range 1-12). 2 DLTs occurred at 72 mg/m2 (maximum tolerated dose, MTD): increased paresthesia and asymptomatic worsening of ERG. Cohort expansion at 54 mg/m2 is ongoing. Drug-related side effects were mainly asthenia (max gr 2), nausea (max gr 2) and tremors (max gr 1). Hematological toxicity was mostly mild/moderate. One patient with parotid gland carcinoma remained on study for 12 months. The exposure increased with dose, with Cmax at 2.0 h (median) and half-life of 18-51 h. Day 14/day 1 AUC (0-24h) ratio was around 3. At 48 mg/m2, day 14 AUC (0-24h) was 12.9 μ M·h (CV: 13%) and Cmax 0.73 μ M. Interesting data on PD biomarkers in skin biopsies by IHC and PCR indicated modulation consistent with the given doses. Conclusions: Overall PHA is well tolerated with the 14-day treatment schedule. The RP2D is expected to be 54 mg/m2. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Accelera, Nerviano Medical Sciences
Predictive and prognostic nomograms for breast cancer treated with primary chemotherapy (PC)
Authors: S. Delaloge, R. Rouzier, L. Pusztai, F. Andre, J.-R. Garbay, M. Spielmann, M.-C. Mathieu, V. Valero, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2005)

599 Background: Nomograms are mathematical tools that provide overall probability of a specific outcome for an individual patient by combining prognostic factors. There is no available calibrated and validated nomogram for breast cancer patients to predict outcome after PC. The aim of this study was to develop and validate nomograms for predicting pathologic complete response (pCR), breast conservation and survival for patients treated with PC. Methods: Using the databases from 2 institutions: the Institut Gustave Roussy (IGR) and the M. D. Anderson Cancer Center (MDACC), we identified 1155 women diagnosed with breast cancer and treated with an anthracycline-based PC. We constructed logistic regression models for pCR, residual tumor size and breast conservation after PC with IGR data. Cox proportional hazards regression was used for the multivariate model of survival. Results from these models were used to generate the nomograms. The nomograms were validated internally using bootstrap resampling and externally using the MDACC series. Results: Estrogen receptor status, histologic grade, initial tumor size, age and multicentricity were included in the logistic regression models for pCR, residual tumor size and breast conservation. The areas under the ROC curves (AUC) of the models ranged from 0.70 to 0.75 in the training set. The accuracy of the nomograms was high in the independent validation set for pCR and residual tumor size (AUC=0.69 and 0.79). The accuracy of the nomogram for the probability of breast conservation was limited by the difference of practice between the two institutions.Two survival nomograms were constructed. The first model included baseline characteristics before PC. The second model also included pathological results from surgical specimens to account for PC efficacy. Including pCR and extent of nodal disease at surgery independently improved the AUC of the survival model (0.65 and 0.70 for the first and the second model). Five-year survival nomogram calibration was good. Conclusions: We developed several predictive and pronostic nomograms for breast cancer patients candidate for PC. These tools could be useful in counseling patients for treatment options. They will be available on-line. No significant financial relationships to disclose.
Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.
Authors: D M Burstein, R A Rodby
Journal: Journal of the American Society of Nephrology (1993)

The hepatitis C virus genome has been recently sequenced and cloned, allowing the identification of patients exposed to this virus, which is now felt to be the principal cause of "non-A, non-B" hepatitis. The hepatitis B virus has long been implicated in the pathogenesis of several glomerulopathies including membranoproliferative glomerulonephritis, mixed cryoglobulinemia, and membranous glomerulonephritis. Several authors have recently reported an association between hepatitis C virus infection and glomerular disease. The case of a patient with chronic hepatitis C virus infection who developed the nephrotic syndrome 3 months after liver transplantation is described. Serologic testing was significant for an elevated rheumatoid factor, circulating cryoglobulins, and a mildly depressed C4 level. Hepatitis C virus antibody and viral RNA (by polymerase chain reaction) were present in both the serum and cryoglobulin fraction. A renal biopsy demonstrated membranoproliferative glomerulonephritis. It is believed that persistent infection with the hepatitis C virus is responsible for an immune complex-mediated glomerulonephritis in this patient. Because hepatitis C has now been pathogenetically linked to several glomerulopathies, testing for this virus should be considered in the serologic work-up of the patient with glomerulonephritis.
The prognostic significance of hypoxia inducible factor-2α in primary breast cancer
Authors: K. Jirström, K. Helczynska, A. Larsson, L. Holmquist Mengelbier, E. Fredlund, S. Borgquist, G. Landberg, S. Påhlman
Journal: Journal of Clinical Oncology (2008)

22081 Background: We investigated the relationship between the two hypoxia-inducible-factor-α (HIF-α) subunits in invasive breast cancer in vivo and their specific correlations to clinicopathological parameters, survival, and VEGF expression. Methods: We first conducted immunohistochemical analyses of HIF-1α, HIF-2α, and VEGF expression in tissue microarrays with tumours from 512 consecutive breast cancer patients with long-term follow-up. HIF-1α and HIF-2α and their impact on survival were then verified in another cohort of 179 patients. HIF-α protein andHIF-αand VEGFmRNA levels after hypoxic induction and knock-down experiments in cultured breast cancer cell lines were studied by Western blot and Q-PCR techniques. Results: We found no correlation between HIF-1α and HIF-2α expression and HIF-α subtype specific correlations to clinicopathological parameters and VEGF. HIF-2α was an independent prognostic factor whereas HIF-1α exhibited variable, non-significant correlation to survival. Culture for 4 or 24 hours at 21%, 5%, and 1% oxygen levels resulted in varying HIF- α protein levels, thereby verifying hypoxia level and time dependent induction of HIF-1α and HIF-2α. Knock-down experiments showed a subtype specific, time dependent utilization of the two transcription factors in hypoxia induced VEGF expression. Conclusions: Our in vitro and in vivo results show evidence for differential regulation and utilization of the two HIF- α subunits and that high protein expression associates to adverse outcome and distant metastasis in breast cancer. No significant financial relationships to disclose.