tbuckley/cabot-search huggingface dataset:
Larotaxel (L) in combination with trastuzumab in patients with HER2 + metastatic breast cancer (MBC): Interim analysis of an open phase II label study
Authors: V. Dieras, P. Viens, C. Veyret, G. Romieu, A. Awada, E. Lidbrink, H. Bonnefoi, D. Mery-Mignard, F. Dalenc, H. Roché
Journal: Journal of Clinical Oncology (2008)

1070 Background: Larotaxel (L), a semi-synthetic taxoid, has shown preclinical and clinical activity against taxane-resistant BC, and it presents the ability to cross the blood brain barrier. In HER2 + BC, trastuzumab (H) combined with taxanes is highly active, particularly in early stage BC. However, there is a need to develop new combinations for HER2+ pts who develop metastatis (mets), especially brain mets. Methods: MBC pts, < 1 prior chemotherapy (Ct) for metastatic disease, measurable disease, HER2 + (IHC ≥ 3+ and/or FISH +), baseline LVEF≥ 50%, were eligible to receive 90 mg/m2 L, 1-hour infusion and 6 mg/kg (8 mg/kg loading dose) H, every 3 weeks(w). Inclusion of patients with asymptomatic brain mets (mandatory baseline CTscan ) was allowed. Main objectives: activity of LH combination (ORR as per RECIST), progression free-survival, CNS outcome or occurrence, overall survival, safety and pharmacokinetic (PK) profiles. Tumor assessments and LVEF were done every 2 cycles(cy). Results: As of Dec. 2007, 41/50 pts were treated. The first 26 evaluable pts are presented in this per-protocol interim analysis: median age of 55.5 y (30–78), 19 pts (73%) with > 2 organs involved (including 4 with brain mets), 17pts with prior Ct for metastatic disease (prior taxane: 13 and prior H:15). The median number of cy was 6 (1–12). Most common gr 3–4 adverse events: febrile neutropenia/neutropenic infection (4), diarrhea (2), asthenia (6). Eleven (42.3%) confirmed partial responses (PR) were reported in 1st or in 2nd line with 1 PR and 3 stable disease (SD) lasting ≥18 w in pts with brain mets. Preliminary PK results: clearance of L at cy1 and 6 are similar to those observed in monotherapy. Conclusions: L and H at full doses can be combined with a manageable toxicity. Preliminary data suggest good activity in pretreated pts with high tumor burden, including pts with brain mets. PK analysis will be presented on the whole population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis
Outcomes of inflammatory versus noninflammatory T4 breast cancers in the age of taxanes and trastuzumab.
Authors: S. Rehman, R. D. Tendulkar, C. A. Reddy, R. M. Macklis
Journal: Journal of Clinical Oncology (2011)

e11584 Background: Modern outcomes for inflammatory breast cancer (IBC) and non-inflammatory (non-IBC) stage T4 breast cancers are unknown. Our objective was to determine the rates of overall survival (OS), locoregional control (LRC), and distant metastases free survival (DMFS) in patients with T4 breast cancer in the modern treatment era of taxanes and trastuzumab. Methods: We retrospectively reviewed the charts of all 169 patients diagnosed with non-metastatic T4 breast cancers from 2000-2009 at the Cleveland Clinic. Kaplan-Meier curves were created to determine OS, LRC, and DMFS. Results: Overall, 104 (62%) patients had IBC and 65 (38%) patients had non-IBC T4 cancers. Comparing IBC and non-IBC patients, respectively, 57 (55%) and 17 (26%) were ER/PR negative, 34 (33%) and 8 (12%) were Her2/neu amplified, 75 (72%) and 31 (48%) were clinically node positive, and 62 (60%) and 38 (59%) were pathologically node positive. For the entire cohort, 129 (76%) patients completed all planned therapies (chemotherapy, surgery, and radiation, when indicated), 128 (76%) patients received a taxane, and 28 of 42 (67%) patients with Her2/neu amplified tumors received trastuzumab. In the IBC and non-IBC groups, 100 (96%) and 26 (40%) patients received upfront chemotherapy, and 23% (23/100) and 12% (3/26) achieved a pathologic complete response, respectively. Comparing outcomes of IBC to non-IBC, the five-year OS, LRC, and DMFS were 46% vs. 61% (p=0.15), 83% vs. 97% (p=0.01), and 44% vs. 59% (p=0.04), respectively. On multivariate analysis using Cox proportional hazards regression, significant predictors of distant metastases included inability to complete all planned therapies, ER/PR negative, and clinical lymph node positivity, while significant predictors of complete response to chemotherapy were IBC and use of a taxane. Conclusions: Outcomes for IBC were worse than those for non-IBC T4 breast cancers. Despite taxane-based chemotherapy and trastuzumab, overall outcomes for IBC remain poor and more aggressive strategies are needed.
Gastric cancer in Turkey: A single center experience of 683 cases
Authors: G. Demir, E. Buyukunal, E. Kizilkilic, M. Ozguroglu, N. Mandel, F. Demirelli, S. Serdengecti
Journal: Journal of Clinical Oncology (2004)

4254 Background: Gastric cancer is one of the most frequent cancers of the gastrointestinal tract in the Middle East region. Remarkable differences in clinical and pathological features, and the outcome of the disease are observed between countries which lead to define the cases as western and eastern types of gastric cancer. However, the place of the Turkish patients in this spectrum is not well defined. Methods: In this retrospective single center study we aimed to analyze the characteristics and outcomes of Turkish patients with stomach cancer. Results: 683 patients (409 males, 274 females; m/f :1.49) were included. Mean age of diagnosis was 57.4 ± 12 years. Anatomical localization of the tumors were as follows; antrum 44.1%; corpus 26.9%; cardia 12.7%; diffuse 15.7%; pylorus 0.6%. At the initial diagnosis only 2.6% of the patients had stage I disease, 8% had stage II, 37. 4% had stage III, and 50.2% had stage IV disease. All the patients had histologically proven adenocarcinoma, 41% were poorly differantiated, 41.6% were moderately differantiated, 12.7% were well differantiated, and 4.7% were neuroendocrine tumors. Median survival times of the patients were in stage I 52 months, in stage II 42.4 months, in stage III 33.9 and in stage IV 9.8 months. Conclusion:. The mean age of Turkish patients are younger and the incidence of antral tumors are still much more higher than cardia tumors like the other middle-east countries. But the survival rates according the stage of the disease is different from other middle-east countries with poor survival rates and worse prognosis. High incidence of advanced stages of the disease suggests that screening programs are needed especially in east Anatolian regions of Turkey for early detection. In conclusion Turkish patients do not belong either to the easten type or the western type gastric cancer and show some features of both forms of the disease. No significant financial relationships to disclose.
Abstract 191: Phosphodiesterase 9a Modulates Cardiomyocyte Natriuretic Peptide-Stimulated cGMP Pool and Cardiac Hypertrophy
Authors: Dong I Lee, Takashi Sasaki, Guangshuo Zhu, Peter R Rainer, Manling Zhang, Thomas Danner, Su-huyn Jo, Djahida Bedja, Eiki Takimoto, David A Kass
Journal: Circulation Research (2013)

Cardiac hypertrophy in response to pathologic stress is a major contributor to heart disease. Many studies have revealed that compartmentalized cyclic guanosine monophosphate (cGMP) regulation by phosphodiesterases (PDEs) can potently modify acute and chronic cardiac stress responses. PDE5a normally regulates cGMP generated from nitric oxide (NO)-stimulated soluble guanylate cyclase (sGC) but not natriuretic peptide (NP)-stimulated cGMP. Its inhibition blunts maladaptive hypertrophy and remodeling. Regulators of NP-cGMP remain uncertain. Here we reveal that PDE9a, a highly cGMP-specific PDE (×100 affinity vs PDE5a) that is expressed predominantly in the brain modulates myocyte cGMP as well, targeting NP-stimulated pools. PDE9a gene expression is observed in rat neonatal cardiac myocytes (RNCM) and adult mouse myocytes. Protein expression was identified in myocytes by immunohistochemistry, using gene silencing models as a negative control. PDE9a expression is upregulated by various hypertrophic stimuli (phenylephrine (PE) or endothelin-1 (ET-1), and observed in myocytes from pressure-overloaded whole myocardium. PDE9a inhibition with a selective antagonist (PF-9613) or gene silencing significantly abrogated PE- or ET-1-dependent upregulation of pathological-hypertrophy fetal genes and NFAT activity in RNCM, and PDE9a inhibition attenuated ET-1-induced hypertrophy in adult mouse myocytes. PF-9613 had no impact in cells lacking PDE9a (from knockout mice) or after gene silencing. Biochemical and cGMP-sensitive fluorescent probe studies shows PDE9a inhibition augments ANP- but not NO-dependent cGMP stimuli in RNCM and adult myocytes. PDE9a knockout (KO) mice were protected against hypertrophy/remodeling after pressure-overload, accompanied by a rise in myocardial cGMP. In PDE9a KO mice also exhibited less fibrosis and reduced expression of fibrotsis-related genes over wild-type mice. Together, these data identify PDE9a as a novel regulator of myocyte cGMP and hypertrophy that impacts a different compartmentalized cGMP pool to that by PDE5a. Our observations may provide a novel therapeutic approach in the treatment of heart failure.
Cutaneous manifestations of<i>Helicobacter cinaedi</i>: a review
Authors: S. Shimizu, H. Shimizu
Journal: British Journal of Dermatology (2015)

Helicobacter cinaedi is an emerging Gram‐negative spiral bacillus that was first reported in 1984. It has been implicated as a cause of gastroenteritis and bacteraemia in immunocompromised individuals. Helicobacter cinaedi‐associated bacteraemia is sometimes accompanied by skin lesions; however, the cutaneous manifestations of this pathogen are not widely known. To our knowledge, a comprehensive review with detailed analysis of skin lesions associated with H. cinaedi has not been conducted. This article summarizes the clinical appearance of H. cinaedi cellulitis and its management. In addition, we conducted a retrospective review of 73 patients with H. cinaedi bacteraemia at a single institution, to further clarify the characteristic cutaneous features. It was found that 30% (22/73) of the cases of H. cinaedi bacteraemia had sudden‐onset erythema accompanied by high fever. The most common cutaneous symptom of H. cinaedi bacteraemia was found to be mild cellulitis, appearing as multiple painful infiltrated erythemas on the extremities. As H. cinaedi is not always detectable in routine blood culture techniques, evaluation of these characteristic cutaneous manifestations seems important in diagnosis. Helicobacter cinaedi infection should be added to the diagnostic list of unspecified fever with painful infiltrated erythemas.
Comparable 3-year outcome following ABVD or BEACOPP first-line chemotherapy, plus pre-planned high-dose salvage, in advanced Hodgkin lymphoma (HL): A randomized trial of the Michelangelo, GITIL and IIL cooperative groups
Authors: A. M. Gianni, A. Rambaldi, P. Zinzani, A. Levis, E. Brusamolino, A. Pulsoni, M. Liberati, E. Pogliani, S. Cortelazzo, P. Valagussa
Journal: Journal of Clinical Oncology (2008)

8506 Background: The availability of successful and tolerated salvage programs challenges the choice of more effective but more toxic regimens as preferred first-line treatments of chemosensitive tumors. In fact, a less toxic and more applicable initial therapy that can be effectively salvaged, might be a preferable strategy to a moderately more effective regime with a higher rate of toxic events and a lower rescue rate. We thus compared the rate of freedom-from-progression (FFP), freedom-from-second-progression (FF2P) and overall survival (OS) of patients with advanced HL treated according to two opposite strategies: ABVD first, versus BEACOPP first, plus high-dose salvage as pre- planned intended treatment for both arms. Methods: From March 2000 to March 2007, a total of 321 eligible patients with stage IIB/IV and/or ≥3 IPS (international-prognostic-score) HL were stratified and randomized; 166 patients received 6–8 cycles of ABVD, and 155 patients were treated with 4 cycles of BEACOPP escalated plus 4 cycles of BEACOPP standard. Responding patients received 30 Gy of radiotherapy to sites of initial bulky disease or of residual mass. For treatment failures the intent was to deliver re-induction chemotherapy followed by stem-cell supported BEAM, and up to 25 Gy of radiotherapy, as required. Results: Main patient characteristics and 3- year results (median observation 30 months, lead 85 months) are summarized in the table: Conclusions: A longer follow-up is necessary to account for late relapses and secondary tumors. Within these limits, the present study, by taking into account both first-line and second-line chemotherapy, helps defining a preferred therapeutic plan for advanced HL. In fact, BEACOPP-first scored a superior FFP in 16% of the patients, but showed a comparable FF2P and an identical OS rate, and was thus an overtreatment for the 71% already cured by ABVD-first. No. IPS <3 IPS ≥3 Toxic deaths 3-yr FFP * 3-yr FF2P ° 3-yr OS ° ABVD 166 77 89 1^ 71±4% 87±4% 91±3% BEACOPP 155 69 86 6^^ 87±3% 92±4% 90±3% * P=0.01; ° P=NS; ^ during ABVD; ^^ 4 during BEACOPP, 2 during salvage No significant financial relationships to disclose.
Phase II trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIb/IV non-small cell lung cancer (NSCLC).
Authors: T. J. Lynch, I. N. Bondarenko, A. Luft, P. Serwatowski, F. Barlesi, R. T. Chacko, M. Sebastian, J. Siegel, J. Cuillerot, M. Reck
Journal: Journal of Clinical Oncology (2010)

7531 Background: IPI is a fully human monoclonal antibody that potentiates immune response by selectively inhibiting CTLA-4. CA184- 041 is a randomized, double-blind phase II study of first-line IPI in recurrent/metastatic lung cancer in combination with P (175 mg/m2)/C (AUC=6). Methods: 203 pts with chemotherapy-naive, recurrent or stage IIIb/IV NSCLC were randomized 1:1:1 to receive either: IPI (10 mg/kg IV q3wks) + concurrent (CON) IV P/C (175 mg/m2 and AUC=6, q3wks); or IPI + sequential (SEQ) P/C, or P/C alone (PBO). After P/C, IPI was administered as continuation maintenance therapy q12 wks until toxicity or disease progression. Efficacy was assessed by mWHO and novel immune- related response criteria (irRC), providing a more comprehensive evaluation of immunotherapeutics (Clin Canc Res 2009;15:7412). The primary objective compared immune-related progression-free survival (irPFS) between CON and PBO and SEQ and PBO using a log-rank test with one-sided alpha of 0.1. Results: Baseline characteristics were generally balanced between the arms. The Table presents PFS and immature OS using the irRC and mWHO. IPI plus P/C was generally well tolerated. Grade (Gr) 3/4 AEs were 58%, 52% and 42% for CON, SEQ and PBO, respectively. Generally reversible and manageableGr 3/4 immune-related AEs (pre-selected to reflect IPI mechanism of action) were 20% and 15% for CON and SEQ, respectively. Conclusions: Ipilimumab addition to P/C, in concurrent and sequential regimens, extended irPFS in NSCLC pts compared with P/C alone. Safety results suggest a moderate added toxicity to the P/C regimen due to ipilimumab with no novel toxicities and rare and comparable drug-related death rates across all arms. These results support further investigation of ipilimumab in NSCLC. IPI + P/C P/C CON (n = 70) SEQ (n = 68) PBO (n = 66) irPFS Median mo 5.52 5.68 4.63 95% CI 4.17, 6.74 4.76, 7.79 4.14, 5.52 p value 0.094 0.026 HR 0.775 0.686 95% CI 0.53, 1.13 0.47, 1.01 PFS Median mo 4.11 5.13 4.21 95% CI 2.76, 5.32 4.17, 5.72 2.76, 5.32 p value 0.250 0.024 HR 0.882 0.691 95% CI 0.61,1.27 0.48, 1.00 OS Median mo 11.01 11.56 9.99 95% CI 8.38, 12.75 9.26, 14.39 6.97, 13.63 p value 0.429 0.104 HR 0.962 0.748 95% CI 0.63, 1.48 0.48, 1.18 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Infinity Pharmaceuticals AstraZeneca, Boehringer Ingelheim, Genentech, Lilly, Merck, Roche Bristol-Myers Squibb, Infinity Pharmaceuticals AstraZeneca, Lilly, Merck, Roche Bristol-Myers Squibb
A phase I trial of vorinostat in combination with bevacizumab and irinotecan in recurrent glioblastoma.
Authors: P. Chinnaiyan, S. Chowdhary, S. Brem, M. Yu, R. Murtagh, A. Rojiani, Y. Tsai, E. Pan
Journal: Journal of Clinical Oncology (2010)

TPS150 Background: Combination therapy consisting of bevacizumab and irinotecan represents a commonly applied regimen in the treatment of recurrent glioblastoma. Based on preclinical data demonstrating the capacity of the histone deacetylase (HDAC) inhibitor vorinostat to enhance the effects of these agents, along with demonstrating independent activity in glioblastoma, we conducted a phase I study to determine the safety and toxicity when combining vorinostat with bevacizumab and irinotecan in recurrent glioblastoma. Methods: Eligibility criteria include histologically proven glioblastoma with documented radiographic progression, >18 years old, KPS≥60, and adequate bone marrow reserve and organ function. Three dose levels of vorinostat will be tested: 200 mg, 300 mg and 400 mg administered on days 1-7 and 15-21 every 28 days. Dose-finding will use a standard 3+3 design with the MTD being defined as the dose with DLTs in 1/6 or fewer patients, up to the previously established dose of single-agent vorinostat (400 mg). Bevacizumab (10 mg/kg IV) and irinotecan (125 mg/m2 IV) will be administered on days 1 and 15 every 28 days. MTD will be defined after cycle 1 using NCI CTCAE v3. A total of 13 patients have been accrued to date, and this trial is currently enrolling at the final vorinostat dose level (Dose Level 3). A follow-up phase II clinical trial to evaluate the efficacy of this regimen is planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Research Laboratories
Combined DNA repair gene single nucleotide polymorphisms (SNPs) in gemcitabine (gem)/cisplatin (cis)-treated non-small-cell lung cancer (NSCLC) patients (p)
Authors: C. Sarries, V. Alberola, R. De Las Penas, C. Camps, B. Massuti, R. Garcia-Gomez, A. Insa, M. Sanchez-Ronco, M. Taron, R. Rosell
Journal: Journal of Clinical Oncology (2004)

7031 Background: We assessed SNPs in five DNA repair genes belonging to three of the major DNA repair pathways: XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD Asp312Asn, XPD Lys751Gln, ERCC1 C118T, and RRM1 -37C/A and correlated the results with outcome in gem/cis-treated NSCLC p. Methods: 135 stage IV NSCLC p were included from August 2001 to July 2002. TaqMan 5' nuclease assay was used to examine SNPs from baseline peripheral blood lymphocytes. Results: p characteristics: median age: 61; 92% male; PS 0: 28.1%, 1: 71.9%; adenocarcinoma: 46.7%. Overall outcome: response rate (RR) 43%; time to progression (TTP) 6.78 months (m); median survival (MS) 10.9 m. See table for distribution of genotypes. TTP was 6.78 m for p with XPD Lys751Lys, 7.57m for Lys751Gln, and 5.3 m for Gln751Gln (P=0.03). In 41 p with lung metastases, TTP was 6 m for p with RRM1 C/C, 8.4 m for C/A, and 5.3 for A/A (P=0.03). TTP was 11.3 m for 23 p with both XPD Lys751Gln and RRM1 C/A, as compared to 6.6 m for 112 remaining p (P=0.006). A similar tendency was observed for MS (P=ns). No other significant differences according to genotype were observed. Conclusions: Heterozygosity for both XPD 751 and RRM1 may be a predictive marker of chemosensitivity. No significant financial relationships to disclose.
Sustained Response After Short-Medium-Term Treatment With Eltrombopag In Patients With ITP
Authors: Tomás José González-López, José Ramón González-Porras, Maryam Arefi, Erik De Cabo, Blanca Sanchez Gonzalez, Arancha Alonso, Mónica Martin, Reyes Jimenez, Maria Calbacho, Abelardo Bárez, Jesus F San Miguel
Journal: Blood (2013)
Prediction research and the emergency commitment of dangerous mentally ill persons: a reconsideration
Authors: J Monahan
Journal: American Journal of Psychiatry (1978)

The author suggests that research on the prediction of violent behavior does not support the unqualified conclusion that the accurate predictions of violence is impossible under all circumstances or that psychiatrists, psychologists, and others will invariably overpredict its occurrence by several orders of magnitude. Further, he suggests that there are theoretical reasons why one could expect that one set of circumstances--those which typically apply in the short-term emergency commitment of mentally ill persons predicted to be imminently violent--may be exempt from the systematic inaccuracy found in the current research.
Antitumor Immunity in the Shope Papilloma-Carcinoma Complex of Rabbits. Ill. Response to Reinfection With Viral Nucleic Acid&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Charles A. Evans, Yohei Ito
Journal: JNCI Journal of the National Cancer Institute (1966)

Challenge inoculation with infectious viral nucleic acid was used to assess the antitumor immunity of rabbits previously infected with Shope papilloma virus. Each animal was inoculated at 5 sites. Papillomas developed on all 6 carcinomatous animals and on 9 of 10 animals with persistent papillomas. Primary papillomas on 2 rabbits regressed soon after nucleic acid inoculation and no tumors developed at challenge sites on them. No papillomas appeared on 15 regressor animals, although the interval from regression of the primary papilloma to challenge was as long as 5 months. Results were the same whether the regression of the primary tumor had occurred as early as 5 weeks or as late as 6 months after the initial virus inoculation. In round numbers, the proportion of inoculated sites at which tumors developed was: normal rabbits—90 percent, carcinomatous rabbits—90 percent, rabbits with persistent papillomas—75 percent, and regressor rabbits—0 percent. In 10 normal animals inoculated with nucleic acid, all tumors regressed in 4 within 7 weeks after inoculation and all tumors regressed in one by the 10th week. No nucleic acid-induced tumors regressed on any animal with persistent papillomas or carcinomas during an observation period of 16 weeks. It is concluded thatviral nucleic acid induces infection and tumor development in animals bearing persistent papillomas or carcinomas with a frequency close to the infection rate in normal animals, in spite of the known presence of neutralizing antibody in previously infected rabbits. Substantial resistance to tumor development persists for many months after regression of a papilloma.
Species adaptation in a protein molecule.
Authors: M F Perutz
Journal: Molecular Biology and Evolution (1984)

The allosteric properties of hemoglobins, especially their responses to ligands other than oxygen, vary widely in different classes of vertebrates. Knowing the stereochemistry of the cooperative effects in human hemoglobin, one can infer the stereochemical basis of these variations from the changes in amino acid sequence. The results indicate that the tertiary and quaternary structures of deoxy- and oxyhemoglobin have remained almost invariant during vertebrate evolution and that most of the amino acid replacements between species are functionally neutral. Adaptations leading to responses to new chemical stimuli have evolved by only a few (one to five) amino acid substitutions in key positions. Once such a response has become superfluous, it may be inactivated, not necessarily by a reversal of one of the original substitutions but by any other that happens to inhibit it.