tbuckley/cabot-search huggingface dataset:
Management of hand-foot skin reaction (HFSR)/hand-foot syndrome (HFS) in SOLTI-0701: A double-blind, randomized phase IIb study comparing sorafenib (SOR) versus placebo (PL) in combination with capecitabine (CAP) in patients (pts) with advanced breast cancer (BC).
Authors: P. Gomez, H. H. Roche, F. Costa, J. Segalla, H. Pinczowski, S. Cabral Filho, E. Ciruelos, B. M. Van Eyll, J. Baselga
Journal: Journal of Clinical Oncology (2010)

1083 Background: We reported data from SOLTI-0701 demonstrating a clinical benefit with the oral regimen of SOR+CAP vs. PL+CAP in pts with advanced BC for progression-free survival (median, 6.4 vs. 4.1 mo; hazard ratio 0.58; 1-sided p=0.0006). Toxicities were comparable between treatment arms except for HFSR/HFS, which was not unexpected as HFSR and HFS are associated with SOR and CAP, respectively. Here we describe HFSR/HFS toxicity during this study. Methods: SOLTI-0701 is a multinational (Brazil, France, Spain) phase 2b study in HER2-negative pts with locally advanced or metastatic BC and ≤1 prior chemo regimen for advanced BC (n=229). Pts were randomized (1:1) to receive CAP (1,000 mg/m2 po, twice daily [BID], 14 of every 21 days) with PL or SOR (400 mg po, BID). The protocol recommended managing HFSR/HFS with symptomatic therapy, study drug (SOR, PL, CAP) interruption for grade (G) 2 toxicity, study drug interruption and dose reduction for recurrent G2 or G3 toxicity, and discontinuation for persistent G2/G3 toxicity. Results: Incidence of HFSR/HFS for SOR+CAP vs. PL+CAP was 89% vs. 63% for any grade and 45% vs. 13% for G3; Kaplan-Meier estimate of median time to onset for first incidence of any grade was 14 and 64 days, respectively. In the SOR+CAP arm, 48% and 78% of pts required SOR and CAP dose reductions, resulting in mean daily doses of 603 mg and 1485 mg/m2, respectively; mean number of cycles was 7.7 and 7.5, respectively. In the PL+CAP arm, 11% and 32% of pts required PL and CAP dose reductions, resulting in mean daily doses of 749 mg and 1,850 mg/m2, respectively; mean number of cycles was 6.5 and 6.6, respectively. HFSR/HFS led to treatment discontinuation in 8 pts (7.0%) for SOR+CAP and 2 pts (1.8%) for PL+CAP. Conclusions: Despite high incidence of HFSR/HFS, few pts discontinued treatment due to HFSR/HFS. Dose attenuation for both treatment agents was effective. More proactive management may reduce event duration and severity. In view of the PFS benefit, a phase 3 registration trial will commence in 2010 evaluating the combination of SOR+ CAP for advanced BC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Pharmaceuticals
Guidelines can require me to recommend care that I think is wrong
Authors: Andrew Spooner
Journal: BMJ (2015)

Rigid adherence to rules diminishes doctors’ and patients’ autonomy

The King’s Fund said in 2012, “Many doctors aspire to excellence in diagnosing disease. Far fewer, unfortunately, aspire to the same standards of excellence in diagnosing patients’ preferences for their care.”1

I am a GP in a small town. I am besieged by process based rules in the form of guidance from the National Institute for Health and Care Excellence (NICE), professional bodies, specialist colleagues, pharmacy advisers, and many others.

I went into medicine as a successful person. During my career I’ve aspired to improve the care I provide and also the healthcare system. I have felt successful at this: I see myself as doing a good job for the patient, and clinical interactions with “my” patients are an important part of how I feel about myself.

Reports of litigation, communications from medical defence societies, and stories of missed cancer diagnoses lead to the fear that …
Phase II study of reovirus with paclitaxel (P) and carboplatin (C) in patients with metastatic non-small cell lung cancer (NSCLC) who have Kras or EGFR-activated tumors.
Authors: E. T. Lam, G. A. Otterson, K. R. Donthireddy, J. Thurmond, E. Hade, M. C. Coffey, M. A. Villalona-Calero
Journal: Journal of Clinical Oncology (2010)

TPS292 Background: Epidermal growth factor receptor (EGFR) dysregulation and Kras mutations occur commonly in NSCLC, both leading to downstream activation of Ras-dependent pathways. Kras mutations are associated with a worse prognosis, poorer benefits to chemotherapy, and resistance to EGFR tyrosine kinase inhibitor therapy. Targeting the Ras-dependent pathways is a major area of unmet therapeutic need in NSCLC. Reovirus is a naturally occurring virus with few pathogenic effects in humans which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. Cells that express high levels of EGFR are also susceptible to reovirus infection. In preclinical studies, reovirus has been shown to induce host immunity and cell cycle arrest, acting synergistically with standard cytotoxic agents. Encouraging results have come from 18 completed or ongoing phase I and II studies with ≥ 200 patients with advanced solid malignancies treated with reovirus, alone or in combination with chemotherapy. The adverse effects of reovirus have been predominantly mild to moderate flu-like symptoms. We have hypothesized those patients with EGFR-mutated, EGFR-amplified, or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and will exhibit response to treatment with reovirus. Methods: This is a Fleming single stage, single-arm, phase II study to evaluate the objective response rate and 6-month progression-free survival of reovirus in combination with P and C as first-line therapy in patients with metastatic NSCLC. Eligible patients are those with ECOG PS 0-2, adequate organ function, no prior systemic chemotherapy, and tumors with the specified genotype. Reovirus (3 × 1010 TCID50) will be administered intravenously daily on days 1-5, C (AUC 6) on day 1, and P (200 mg/m2) on day 1 of each 21-day cycle. Correlative studies testing for mitogen-activated protein kinase (MAPK) phosphorylation in tumor specimens will be performed to confirm the presence of an activated Ras/MAPK pathway. Thirty-six response-evaluable patients will be recruited. To date, we have enrolled and treated 7 patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncolytics Biotech Oncolytics Biotech
Study of the prognostic value and chemosensitivity according to the type of translocation in synovial sarcoma
Authors: G. Des Guetz, O. Delattre, M. Peters, D. Ranchere-Vince, P. Terrier, M. O. Vilain, E. Blot, A. Savignoni, P. Pouillart
Journal: Journal of Clinical Oncology (2004)

9016 Background Synovial sarcomas, which represent 5% to 10% of all sarcomas, are characterized by the X-18 chromosomal translocation. Two fusion genes are created by the translocation: X-SSX1 and X-SSX2. A large-scale multicenter study published in 2002 revealed that the SYT-SSX1 translocation was associated with a poorer prognosis (Ladanyi, Cancer Res 62, 135–140). However, the chemosensitivity according to this translocation is not known. Methods The prognostic value of the type of translocation X-SSX1 or X-SSX2 was investigated in a series of 38 patients with synovial sarcoma (28 localized and 10 initially metastatic), treated by surgery, chemotherapy and radiotherapy in 3 major cancer centers (IGR, Centre L. Bérard, Centre O. Lambret). Chemotherapy was evaluated for 14 patients (neoadjuvant treatment or treatment for metastatic disease) The type of transcript was determined on the initial biopsies of the tumor by RT-PCR. The median follow-up was 47 months (7–256) Results For patients with a non-metastatic tumor (28 patients), a recurrence-free survival benefit was demonstrated in the X-SSX2 group (23 versus 10 months p<0,05) . For the 10 patients with metastatic disease initially, the X-SSX2 translocation is associated with a better prognosis (overall survival : 31 versus 9 months p=0,01). The X-SSX2 group appeared to present a better chemosensitivity (objective response 4/7 versus 1/7 in the X-SSX1 group) p=0,09. Conclusion Synovial sarcomas are rare but it seems important to determine prognostic factors. The type of transcript is an element which could guide the prognosis and determine treatment, and, more importantly, can constitute a useful line of research. No significant financial relationships to disclose.
The Transcription Factor BATF Controls CD8+ T Cell Effector Differentiation
Authors: R. Anthony Barnitz, Makoto Kurachi, Madeleine E. Lemieux, Nir Yosef, Michael A. DiIorio, Kathleen B. Yates, Jernej Godec, Pamela Odorizzi, Aviv Regev, E. John Wherry, W. Nicholas Haining
Journal: Blood (2013)
Do all germ cell tumor patients with residual masses in multiple sites require postchemotherapy resections?
Authors: L H Einhorn
Journal: Journal of Clinical Oncology (1997)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1997.15.1.409 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8996171 Do all germ cell tumor patients with residual masses in multiple sites require postchemotherapy resections? L H EinhornxL H EinhornSearch for articles by this author https://doi.org/10.1200/JCO.1997.15.1.409 PDF "Do all germ cell tumor patients with residual masses in multiple sites require postchemotherapy resections?." Journal of Clinical Oncology, 15(1), pp. 409–410© 1997 by American Society of Clinical Oncology
Multimodal SHG-2PF Imaging of Microdomain Ca <sup>2+</sup> -Contraction Coupling in Live Cardiac Myocytes
Authors: Samir Awasthi, Leighton T. Izu, Ziliang Mao, Zhong Jian, Trevor Landas, Aaron Lerner, Rafael Shimkunas, Rahwa Woldeyesus, Julie Bossuyt, Brent M. Wood, Yi-Je Chen, Dennis L. Matthews, Deborah K. Lieu, Nipavan Chiamvimonvat, Kit S. Lam, Ye Chen-Izu, James W. Chan
Journal: Circulation Research (2015)

Cardiac myocyte contraction is caused by Ca(2+) binding to troponin C, which triggers the cross-bridge power stroke and myofilament sliding in sarcomeres. Synchronized Ca(2+) release causes whole cell contraction and is readily observable with current microscopy techniques. However, it is unknown whether localized Ca(2+) release, such as Ca(2+) sparks and waves, can cause local sarcomere contraction. Contemporary imaging methods fall short of measuring microdomain Ca(2+)-contraction coupling in live cardiac myocytes.To develop a method for imaging sarcomere level Ca(2+)-contraction coupling in healthy and disease model cardiac myocytes.Freshly isolated cardiac myocytes were loaded with the Ca(2+)-indicator fluo-4. A confocal microscope equipped with a femtosecond-pulsed near-infrared laser was used to simultaneously excite second harmonic generation from A-bands of myofibrils and 2-photon fluorescence from fluo-4. Ca(2+) signals and sarcomere strain correlated in space and time with short delays. Furthermore, Ca(2+) sparks and waves caused contractions in subcellular microdomains, revealing a previously underappreciated role for these events in generating subcellular strain during diastole. Ca(2+) activity and sarcomere strain were also imaged in paced cardiac myocytes under mechanical load, revealing spontaneous Ca(2+) waves and correlated local contraction in pressure-overload-induced cardiomyopathy.Multimodal second harmonic generation 2-photon fluorescence microscopy enables the simultaneous observation of Ca(2+) release and mechanical strain at the subsarcomere level in living cardiac myocytes. The method benefits from the label-free nature of second harmonic generation, which allows A-bands to be imaged independently of T-tubule morphology and simultaneously with Ca(2+) indicators. Second harmonic generation 2-photon fluorescence imaging is widely applicable to the study of Ca(2+)-contraction coupling and mechanochemotransduction in both health and disease.
Loss of <i>Tifab</i>, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor–TRAF6 signaling
Authors: Melinda E. Varney, Madeline Niederkorn, Hiroyasu Konno, Takayuki Matsumura, Jin Gohda, Nobuaki Yoshida, Taishin Akiyama, Susanne Christie, Jing Fang, David Miller, Andres Jerez, Aly Karsan, Jaroslaw P. Maciejewski, Ruhikanta A. Meetei, Jun-ichiro Inoue, Daniel T. Starczynowski
Journal: The Journal of Experimental Medicine (2015)

TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.
Metastatic breast cancer (MBC): FDA approval overview
Authors: P. Cortazar, J. R. Johnson, R. Justice, R. Pazdur
Journal: Journal of Clinical Oncology (2008)

1013 Background: Improved survival in a randomized controlled trial is the gold standard for drug approval in 1st line MBC. Time to progression (TTP) and progression-free survival (PFS) have been used for drug approvals in 2nd-3rd-line MBC. Methods: Review of clinical trials leading to new drug approvals for MBC. Results: 1st-line MBC: trastuzumab + paclitaxel was approved based on superior TTP supported by a statistically significant improvement in 12-month survival rates in the trastuzumab group, since overall survival (OS) data were immature. An OS improvement was confirmed after approval in spite of 65% crossover to the trastuzumab group. Gemcitabine + paclitaxel was approved based on superior TTP supported by a strong trend toward improved survival in an interim analysis (18.6 vs. 15.8 mo, p=0.0489). 2nd-3rd-line MBC: Paclitaxel was approved based on superior TTP (4.2 vs. 3.0 mo, p=0.027). The docetaxel approval was based on a statistically significant survival advantage (11.4 vs. 8.7 mo, p=0.01) for docetaxel compared to mitomycin + vinblastine. Capecitabine was approved in combination with docetaxel for patients with failure of prior anthracycline chemotherapy. Approval was based on a statistically significant survival advantage (442 vs. 352 days, p=0.01) with the capecitabine + docetaxel combination compared to docetaxel monotherapy. Lapatinib was approved for patients with MBC whose tumors over-express HER2 and with failure of prior chemotherapy. Approval was based on a TTP improvement (median TTP 27.1 weeks vs. 18.6 weeks p=0.0001) with lapatinib + capecitabine compared to capecitabine alone. The ixabepilone approval for patients with MBC resistant to taxanes and anthracyclines was based on a statistically significant improvement in PFS (5.7 vs. 4.1 mo, p<0.0001) with the ixabepilone + capecitabine combination compared to capecitabine monotherapy. Conclusions: Survival was the basis for approval in the 1st-line setting and TTP and PFS have served as the basis for approval in the 2nd-3rd line setting. TTP and PFS have not been the basis for FDA approvals for 1st-line MBC. No significant financial relationships to disclose.
Long term outcomes in malignant hemangiopericytoma
Authors: S. K. Yadav, K. Haider, A. S. Yadav, A. Sami, D. Mirchandani, I. Ahmad, R. Alvi, S. Ahmed
Journal: Journal of Clinical Oncology (2005)

9072 Background: Malignant hemangiopericytoma (MH) is a rare entity, arising from the capillary pericyte. Limited data is available regarding its clinical behavior and outcome. We present a series of patients with long term follow up period. Methods: Clinical characteristics, pathologic data and treatment of 14 patients diagnosed with MH between 1972 and 1992, at our centre, were reviewed retrospectively. All cases were biopsy proven. Survival was determined by using Kaplan-Meier curve. Results: The median age was 49 yrs. (range 34 - 74) and male: female ratio was 1:6. The primary disease sites were as follows: intracranial meningeal 5 (35.7%), extremities 3 (21.4%), uterus 3 (21.4%), metastatic 2 (14.3%), sinonasal 1 (7.1%). Thirteen patients had complete surgical resection of tumor at initial presentation. Two patients got post operative RT. No patient got adjuvant chemotherapy. Two patients got chemotherapy on disease recurrence. Median survival was 14 years. Out of 12 patients with localized disease, 3 had recurrence. 2 patients with intracranial meningeal disease at diagnosis recurred 6.7 and 3.3 years after initial surgery while 1 patient with extremity disease at initial diagnosis recurred after 10.5 years. None of the recurred patients had initial post operative RT. All the patients who recurred and those with metastatic disease at diagnosis died. One patient died without recurrence. Recurrence free survival was 6.5 years. Median survival after recurrence was 3.5 years. Fourteen year cause specific survival was 54%. Conclusions: Hemangiopericytoma is a disease of middle age with female preponderance. Surgical resection is still the main treatment with about 54% of patients surviving 14 years in our series (median is not reached). Patients with localized disease can recur several years after initial treatment. In our series median survival after recurrence was 3.5 years, which is longer than reported in other studies. Role of radiation and systemic therapy needs to be defined in this disease. No significant financial relationships to disclose.
Hepatitis B reactivation during combination chemotherapy for AIDS-related lymphoma is uncommon and does not adversely affect outcome
Authors: J. Stebbing, M. Atkins, T. Newsom-Davis, B. Gazzard, M. Bower
Journal: Journal of Clinical Oncology (2004)

6673 Background: Hepatitis B (HBV) re-activation and susequent liver damage during anti-cancer chemotherapy has been reported in a number of studies. As co-infection with HBV and the immunodeficiency virus-1 (HIV-1) is common, we examined the incidence and degree of HBV re-activation in a cohort of individuals with AIDS-related lymphoma (ARL). Methods: HBV viral load and surface antigen testing before, during and following cytotoxic chemotherapy with CDE or BEMOP/CA for ARL. Results: Out of 61 individuals tested, 30 were positive for hepatitis B core antibody. All were hepatitis B surface antigen negative and HBV DNA was undetectable prior to chemotherapy. During chemotherapy, re-activation as defined by a detectable HBV DNA was observed in only 5 out these 30 patients (17%) and only 2 demonstrated subsequent surface positive antigenemia. Conclusions: HBV re-activation during chemotherapy for AIDS-related lymphoma appears uncommon. In HBV surface antigen negative HIV-1 infected individuals with ARL, the risk of HBV related hepatitis during chemotherapy appears insignificant. No significant financial relationships to disclose.
Abstract 13701: Impact of Stent Platform on Longitudinal Stent Deformation: an in vivo 3-dimensional Optical Coherence Tomography Study
Authors: Ryotaro Yamada, Teruyoshi Kume, Kenzo Fukuhara, Terumasa Koyama, Tomitaka Higa, Yoji Neishi, Hiroyuki Okura
Journal: Circulation (2014)

Introduction: Recently, longitudinal coronary stent deformation has been highlighted as a possible cause of drug-eluting stent failure. Although bench tests and in-vivo studies have demonstrated difference in longitudinal stent strength among the stents with different platforms, its clinical impact is still unknown. The aim of this study was to investigate the longitudinal deformation of the everolimus-eluting stents (EES) with different stent platforms by using 3-dimensional frequency domain optical coherence tomography (3D FD-OCT). Methods: Fifty-nine lesions treated with EES (Xience Prime (CoCr-EES): n=28, Promus element (PtCr-EES): n=31) were studied. Stent length was measured by 3D FD-OCT. Percent longitudinal stent shortening (%SS) was defined as the longitudinally shortened stent length standardized by nominal stent length. Longitudinal stent deformation was defined as %SS &gt;10%. Results: Patients’ and procedural characteristics were similar between CoCr- and PtCr-EES. There was no difference in mean %SS between PtCr-EES and CoCr-EES (3.1±6.5 vs. 0.9±5.6%, p=0.197). However, incidence of longitudinal stent deformation was significantly higher in PtCr-EES than in CoCr-EES (16.1% vs 0%, p=0.026) (Figure). Conclusions: Incidence of longitudinal stent deformation was different between EESs with different stent platforms. Stent material, stent design and/or stent delivery balloon may affect longitudinal stent deformation.
Cell context of BCRP (ABCG2) affects clofarabine cytotoxicity
Authors: Shinjiro Nagai, Kazumasa Takenaka, Kali Domoney, Isabelle Letourneau, Sharyn Baker, John Schuetz
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3248 

Breast cancer resistance protein (BCRP) is a member of ATP-binding cassette transporters, also known as ABCG2, and is involved in resistance to multiple structurally diverse compounds. We have recently demonstrated that BCRP reduces the intracellular accumulation of purine analogues (Cancer Res 67: 6965, 2007). Among these is cladribine. Based upon these findings we speculated that a structural analog, clofarabine, a promising agent in the treatment of patients with hematological malignancies, might also be a BCRP substrate. To address this issue we used cell lines engineered to overexpress BCRP. One cell line was the human osteosarcoma cell line, Saos-2, and the other cell line was an acute myeloid leukemia cell line, OCI-AML3. Immunoblot analysis indicated that both cell lines expressed similar levels of BCRP. Both cell lines showed that BCRP reduced intracellular accumulation of clofarabine and that a specific BCRP inhibitor, fumitremorgin C (FTC) increased intracellular retention. Further studies showed that in the BCRP overexpressing Saos-2 cell line addition of FTC sensitized these cells to clofarabine thus demonstrating that intracellular concentration of clofarabine was limiting to its cytotoxicity. Unexpectedly, OCI-AML3 cells overexpressing BCRP did not exhibit reduced sensitivity to clofarabine. These studies suggest that cell context plays a fundamental role in determining how BCRP impacts a cell’s cytotoxic response to a chemotherapeutic agent.