tbuckley/cabot-search huggingface dataset:
John William Laws Verdon Damms Henry Rea Patterson Raymond Hatfield Welch
Authors: H. Nunnerly, J. E Husband, P. Waller, J. Damms, S. Brandon, T. Welch
Journal: BMJ (1999)

# John William Laws {#article-title-2}

Former clinical director of radiology King's College Hospital ( b 1921; q Cambridge/Sheffield 1944; FRCP, FRCR; CBE), died from cancer on 20 March 1999. He was an outstanding radiologist, combining the qualities of a superb clinician with those of a meticulous scientist. At the Royal Postgraduate Hospital at Hammersmith he developed his clinical work, teaching and research, mainly in gastroenterology and lung disease. In 1967 he was appointed clinical director at King's where he rebuilt the x ray department and made it a centre of clinical activity. He developed a deep knowledge and interest in technology and was fascinated by the rapidly changing scene in radiology. The high standards which he set for himself and also expected from those working alongside him resulted in the department at King's becoming one of the best teaching centres for radiology in the United Kingdom. The close links which John established overseas still flourish and are at tribute to his international reputation. He was visiting professor and lecturer at many academic institutions and congresses outside Britain. He published …
Abstract 010: A Separable Upstream Promoter of the Slc8a1 (NCX1) Gene Efficiently Marks Cardiac Cell Populations Derived from Human Pluripotent Stem Cells
Authors: Alejandro Hidalgo-Gonzalez, Dmitry A Ovchinnikov, James Hudson, Justin Cooper-White, Wolvetang Ernst
Journal: Circulation Research (2013)

The sarcolemmal Na+/Ca2+ exchanger SLC8A1(NCX) regulates intracellular Ca+ in cardiomyocytes from early developmental stages. The upstream-most SLC8A1(NCX1) promoter is well conserved amongst the homoeothermic animals and contains putative binding sites for transcription factors of the NKX, GATA, STAT and CDX families. We hypothesized that functional cardiac cells with mature cardiac structural markers will express the sarcolemmal Na+/Ca2+ calcium antiporting channel, important for proper functional contractivity of in vitro differentiated human pluripotent stem cells. Pseudotyped lentiviral particles delivering NCX1cp-EGFP reporter cassette were used to confirm the efficiency and specificity of the reporter in rodent foetal cardiac cell isolates, and to establish stable human pluripotent stem cell lines. Cells were differentiated using a 2D induction protocol, and gene expression analysis and protein quantification carried at day 16. Initial NCX1cp-EGFP expression was observed from day 10-11 of cardiac differentiation. Beating foci were visualized 1-2 day after initial NCXCP-EGFP expression, reporter expression was confined to the grouped and individual beating cells, and highly correlated with the efficiency of spontaneously contractile cell production. At later stages, NCX1cp-EGFP expression correlated with clusters of formed spontaneously contractile units harbouring essentially all cardiomyocytes present in cultures, as evidenced by colocalization of high levels of cardiac troponin T (cTnT) and α-actinin proteins. The EGFP+ sorted fraction of differentiated cultures was found to be highly enriched in both early (ISL1, TBX5) and late (cTnT, MYH6) cardiomyocyte markers when compared to the EGFP- fraction. We conclude that a ~3 kb genomic fragment of the distal cardiac-specific promoter of the SLC8A1(NCX1) containing the upstream-most exon of the gene is sufficient to drive the expression of a lentiviral reporter in both rodent heart-derived primary and human (embryonic and induced) pluripotent stem cell-derived cardiac cells. Isolation of a homogenous and functional cardiomyogenic population represents one of the key objectives for cardiac tissue engineering, and in particular in vitro drug screening applications.
Longitudinal dynamic studies of porto-systemic shunting in portal hypertensive and cirrhotic mice by quantitative micro-SPECT imaging
Authors: Christophe Van Steenkiste, Steven Staelens, Steven Deleye, Filip De Vos, Stefaan Vandenberghe, Christophe Van De Wiele, Hans Van Vlierberghe, Martine De Vos, Isabelle Colle
Journal: Hepatology (2009)
Predicting time to metastatic progression from biochemical recurrence after radical prostatectomy
Authors: Z. A. Dotan, F. J. Bianco, P. T. Scardino, J. A. Eastham, P. Fearn, H. I. Scher, M. W. Kattan
Journal: Journal of Clinical Oncology (2004)

4642 Background: Many patients with a rising PSA (biochemical recurrence; BCR), after radical prostatectomy (RP) will eventually develop metastases, but our ability to predict the risk of progression over time is limited. We developed a model (nomogram) that incorporates all known prognostic factors to predict the probability of Mets 8 years after BCR. Methods: We queried our multidisciplinary prostate cancer database for patients who developed BCR after RP for clinically localized disease. We defined BCR as 3 subsequent peaks in PSA ≥0.1 ng/ml. After excluding 14 adjuvant radiation patients, we found 816 followed for 0.1 to 15.9 (median 4.3) years after BCR. We recorded times of secondary treatment (radiation or hormonal therapy), metastases and death. A Cox proportional hazards analysis incorporated preoperative PSA, use of neoadjuvant hormonal therapy (NHT), time from surgery to BCR, pathologic findings [surgical margin, presence of extracapsular extention, seminal vesicle invasion (SVI), lymph node metastases, and pathologic Gleason score (GS)], PSA doubling time (PSA DT) and PSA value at BCR into a predictive model. Results: Secondary treatment for BCR only was a frequent event: 216 patients (26.5%) had radiation therapy and 340 (41.7%) hormones; 157 developed metastases, 67 died of other causes and 244 (29.9%) were alive with out metastases or secondary treatment at last follow-up. In the multivariate model the following predicted metastatic progression: high preoperative PSA (P=0.01), use of NHT (P=0.02), presence of SVI (P=0.005), high pathologic GS (P<0.001), short PSA DT (P=0.01) and high PSA value at BCR (P<0.001). A nomogram for predicting risk of metastases at 8 years was constructed with a concordance index of 0.75. Conclusions: Multiple disease factors affect the risk of metastases after BCR. This new nomogram helps predict, at the time of BCR after RP, the 8-year probability of metastases for the individual patient and provides a useful tool to identify patients appropriate for intervention trials or surveillance. No significant financial relationships to disclose.
The feasibility and real-life effectiveness of the combination of chemotherapy (CT) and bevacizumab (Bev) in the treatment of high-grade gliomas (HGG) in a private community oncology center.
Authors: A. Calabrich, F. C. Azevedo, E. D. Saad, F. C. Maluf, A. C. Buzaid, R. J. Marques, R. Schmerling, F. Costa, P. M. Hoff, A. Katz
Journal: Journal of Clinical Oncology (2010)

e12552 Background: Phase II trials have shown the efficacy of Bev-based therapy in recurrent HGG. However, most of them were multicentric studies conducted in U.S. or European academic centers. Here, we describe a single private hospital experience in the use of this therapy in HGG. Methods: We performed a retrospective analysis of 39 patients (PTS) with HGG treated Bev and CT between 06/2006 and 12/2009 at the Oncology Center at the Sirio Libanes Hospital, in Sao Paulo, Brazil. PTS were evaluated for progression-free survival (PFS), overall survival (OS), and adverse events. Median age was 57 years (range 27-71), 59% were male, 27 had glioblastoma multiforme (GBM), and 12 had other HGG (7 anaplastic astrocitoma [AA], 2 brainstem gliomas, 2 anaplastic oligodendrogliomas, 1 grade 2 astrocitoma). Recurrent disease was present in 36/39 (92,3%). The median follow up was 9.8 months, and the median number of cycles was 12 (2-58). Bev (10 mg/kg q2w or 15 mg/kg q3w) was combined with irinotecan in 29 patients and with temozolomide in 11 (one patient switched from irinotecan to temozolomide due to drug-induced pneumonitis). Results: Median PFS was 9.4 months, and PFS at 6 months was 61%. In GBM, median PFS was 9.4 months, compared with 12.2 months in AA. Median OS was 18.7 months (11.8 months in GBM and 18.7 in AA). There were 4 venous thrombotic events, 3 pulmonary embolisms, 2 intracranial hemorrhages, and 1 patient had dehiscence of the surgical wound. Conclusions: To our knowledge, this is the largest community-based series reported to date using this treatment strategy. The fact that real-life experience reproduces the efficacy and safety results previously reported in recent phase II trials suggests that the combination of CT and Bev can be routinely used outside the context of clinical trials. No significant financial relationships to disclose.
Treatment of metastatic papillary renal cell carcinoma with immunochemotherapy with interleukin-2, interferon-alpha and 5- fluorouracil
Authors: E. Herrmann, O. A. Brinkmann, M. E. Bode, S. Bierer, T. Köpke, L. Hertle, C. Wülfing
Journal: Journal of Clinical Oncology (2007)

15644 Background: Combined immunochemotherapy with interleukin-2 (IL-2), interferon-alpha (IFN-a) and 5-fluorouracil (5-FU) is an established first-line therapy for metastatic renal cell carcinoma (RCC). However, data on histologic parameters predictive of clinical benefit are rare. Methods: Treatment courses of 164 patients consisted of IFN-a at 9 x 106 IU on day 1 of weeks 1 and 4 and days 1, 3, 5 of weeks 2 and 3; and at 18 x 106 IU on days 1, 3, 5 of weeks 5–8. Interleukin-2 was administrated at 18 x 106 IU twice daily on days 3–5 of weeks 1 and 4; and at 9 x 106 IU on days 1, 3, 5 of weeks 2 and 3. Additionally, patients received 5-FU at 750 mg m-2 on day 1 of weeks 5–8. In 153 patients, radical nephrectomy had revealed 22 cases of papillary RCC (pRCC, 13.4%) and 131 cases of clear cell RCC (ccRCC, 79.9%). In the remaining 11 (6.7%) their disease was inoperable. The overall response rates were evaluated according to WHO criteria. Results: For ccRCC and inoperable disease, responses of 34.4% and 27.3% after one cycle and 28.8% and 16.7% after two cycles, respectively, were noted. In contrast, no patient with pRCC showed any response after two cycles of combined immunochemotherapy. Conclusions: No objective response was seen in patients with pRCC. Hence, immunotherapeutic agents must be questioned in this histologic subtype. No significant financial relationships to disclose.
Phase I trial of the histone deacetylase inhibitor, valproic acid and the topoisomerase II inhibitor, epirubicin: A clinical and translational Study
Authors: P. N. Munster, D. C. Marchion, E. Bicaku, P. Sullivan, C. Beam, J. J. Mahany, R. Lush, D. M. Sullivan, A. Daud
Journal: Journal of Clinical Oncology (2005)

3084 Background: Pre-clinical data show that histone deacetylase inhibitors(HDACi) potentiate the DNA damage induced by topoisomerase II inhibitors (topo II). Exposure to HDACi results in histone hyperacetylation and chromatin decondensation thereby facilitating the access of topo II inhibitors to DNA. Valproic acid (VPA) is a well-tolerated, orally bio-available, anti-seizure drug that has recently been shown to inhibit HDAC. Epirubicin is a widely utilized topo II inhibitor with a favorable toxicity profile. Methods: A Phase I dose escalation study explored the toxicity, efficacy and the pharmacokinetics (PK) of VPA and epirubicin. Histone acetylation and topo II expression was evaluated in tumor samples and peripheral blood mononuclear cells (PBMC). VPA was administered as an IV loading dose followed by 5 doses of oral VPA given every 12 hours. Epirubicin was infused on day 3. Treatment cycles were repeated at 3 week intervals and tumor restaging was done every 2 cycles. Enrollment was opened to all metastatic solid tumors. Results: To date, 16 patients (pts) [8 females, median age 62 (44–78)] have been treated at 4 dose levels: VPA 15, 30, 45, and 60 mg/kg; with epirubicin at 75 mg/m2. The maximum tolerated dose has not been reached and dose escalation is continuing. Tumor types enrolled included: 8 melanoma (8), breast (5), cervical, lung, and adrenal carcinoma. The most common treatment related adverse events encountered included neutropenia (69%, G3/4), anemia (6% G1/3), nausea (31%, G1/2) and fatigue (25%, G1/2). Radiation recall was seen in all patients with prior radiation (6 pts). Major responses were observed in all tumor types including in anthracycline failures and in anthracycline-resistant cancers such as melanoma and cervical carcinoma (CR/PR 4/13; SD 3/13; PD 6/13). VPA PK data showed a linear increase with dose. Conclusions: A sequence-specific combination using the HDACi, VPA and epirubicin is feasible and with acceptable toxicity. VPA plasma levels exceeded concentrations needed for in-vitro synergy. The significant anti-tumor activity seen in this heavily pretreated patient population warrants further exploration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
A phase II study of fixed dose-rate gemcitabine in patients with relapsed Müllerian tumors
Authors: R. T. Penson, M. V. Seiden, S. M. Campos, C. N. Krasner, A. F. Fuller, A. Goodman, M. Roche, A. Willman, A. Muzikansky, U. A. Matulonis
Journal: Journal of Clinical Oncology (2004)

5151 Background: Gemcitabine (2',2'-difluorodeoxycytidine) is a novel purine analog with clinical activity against ovarian cancer. Accumulation of gemcitabine triphosphate (dFdCTP) increases in a linear fashion with prolonged infusions of gemcitabine and there is a strong relationship between intracellular accumulation of dFdCTP and DNA damage. Methods: Women with ovarian, fallopian tube or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. Patients could not have received more than 4 prior lines of chemotherapy and had to have measurable or evaluable disease. Gemcitabine 800 mg/m2 was administered by i.v. infusion at 10 mg/m2/min (Fixed dose-rate (FDR)) on days 1 and 8 of a 21 day schedule. Results: Twenty-eight patients with a median age 60 (range, 40–77) years were treated. Although 43% were ECOG 0, 50% had liver metastases. Eighty-eight cycles of therapy were delivered (Median 2(Range, 1–6)). Five of the first 10 patients treated at 800 mg/m2 could not receive day 8 FDR-gemcitabine because of neutropenia and the starting dose was reduced to 700 mg/m2. Even at this dose there was cumulative hematologic toxicity resulting in dose reductions. Vomiting, mucositis, diarrhea, allergy, rash, fever and alopecia were mild. In 28 patients there was only one partial response (4%, 95% CI 0 –18%) and median time to progression was 1.7 (Interquartile range, 1.2 –3.9) months. Conclusions: FDR-Gemcitabine 700 mg/m2 administered by i.v. infusion at a fixed dose-rate of 10 mg/m2/min had minimal activity against recurrent tumors of Müllerian origin. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Co. Eli Lilly Co.
Survival after surgery in patients with initially resectable metastasis receiving adjuvant/neoadjuvant FOLFOX therapy and in patients who had surgery after FOLFOX therapy
Authors: N. Perez-Staub, B. Chibaudel, F. Paye, J. Taieb, B. Gayet, O. Bourges, T. André, C. Tournigand, C. Louvet, A. de Gramont
Journal: Journal of Clinical Oncology (2009)

4118 Background: Surgery of metastases can cure approximately 20% of metastatic colorectal cancer (MCRC). About 15% of MCRC pts are resectable at presentation. Among the other pts, 10 to 30% can benefit from a salvage surgery after response to chemotherapy, improving their prognostic. We report here the results in pts resectable at presentation and in pts who underwent surgery after chemotherapy in phase 2 and 3 studies. Methods: We retrospectively analysed 167 pts who underwent R0/R1 surgery, 46 pts at presentation in a phase 2 study testing a combination of FOLFOX followed by FOLFIRI (MIROX, Taieb JCO 2005), and 121 pts who underwent a salvage surgery after FOLFOX treatment in OPTIMOX1 (Tournigand, JCO 2006) and OPTIMOX2 (Maindrault-Goebel, ASCO 2007) after updating the survival. Results: Patients’ baseline characteristics were (MIROX/OPTIMOX %): median age 56/62 yrs, PS 0 50/73, metachronous metastasis 41/21, ≥ 2 met sites 11/18, liver met 78/88, lung met 11/19, other met 17/10, two-stage surgery 9/10, second surgery after relapse 39/22, R0 resection 91/ 85. 114 among 142 evaluable patients had a response to FOLFOX (80%). Median time from randomisation to surgery was 8 mths in the OPTIMOX group. In the MIROX group, 46% had surgery of metastases before chemotherapy. Median disease-free survival from R0/R1 surgery was 18.6 months in MIROX group vs 9.4 months in OPTIMOX group (p=0.006).Median overall survival was 104.8 months in MIROX group vs 42.6 months in OPTIMOX group (p=0.02). Furthermore, initially resectable remained the strongest prognostic factor in this series. Conclusions: MCRC pts initially resectable at presentation have a better prognosis than pts who underwent a salvage surgery after FOLFOX chemotherapy. No significant financial relationships to disclose.
Safety analysis of FOLFOX as adjuvant chemotherapy for stage III colon cancer in phase II study (NORTH/HGCSG1003): Detailed analysis of peripheral sensory neuropathy.
Authors: Susumu Sogabe, Satoshi Yuki, Hiraku Fukushima, Norihiko Takahashi, Toshiaki Shichinohe, Takaya Kusumi, Fumitaka Nakamura, Ichiro Iwanaga, Kazuteru Hatanaka, Kencho Miyashita, Jun Konno, Kazuhito Uemura, Masaaki Nenohi, Masaya Kina, Naoya Sakamoto, Akinobu Taketomi, Satoshi Hirano, Toraji Amano, Yoichi M Ito, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2015)

701 Background: Oxaliplatin-containing regimen is a standard adjuvant chemotherapy for resected stage III colon cancer. Oxaliplatin-containing regimens were investigated for their efficacy in patients with resected stage III colon cancer in MOSAIC and XELOXA studies. Since these two international randomized studies were performed outside of Japan, we conducted a phase II study (NORTH/HGCSG1003) to assess the efficacy and safety of FOLFOX as adjuvant chemotherapy in Japanese patients (pts) with resected stage III colon cancer (UMIN ID: 000004590). Methods: This phase II study enrolled patients with resected stage III colon cancer. Patients received 12 biweekly cycles of FOLFOX4 or mFOLFOX6. Sample size was determined to be 243 pts. Primary endpoint was DFS. Secondary endpoints included overall survival (OS) and safety. Results: From September 2010 to March 2013, 273 pts were enrolled at 28 institutions. Safety analysis included 265 patients who received FOLFOX. Patients characteristics were as follows: median age, 65 (33-84); male/female: 131/134; PS 0/1:258/7; stage IIIA/IIIB/IIIC: 37/197/31; colon/rectosigmoid: 214/51. The most common grade 3-4 adverse events were neutrophil count decreased (48.1%), platelet count decreased (2.3%), and allergic reaction (1.5%). The incidence of peripheral sensory neuropathy (PSN) was 41.9% (grade 1), 38.1% (grade 2), and 6.4% (grade 3). PSN tended to be serious depending on the cumulative dose of oxaliplatin (table 1). Median cumulative dose of oxaliplatin at which PSN occurred were as follows: grade 1; 170 mg/m2, ≥ grade 2; 850 mg/m2, ≥ grade 3; (-). The median number of cycles of chemotherapy was 12, and the completion treatment rate was 80.4%. There was no treatment-related death. Conclusions: In Japanese patients with stage III colon cancer, FOLFOX is a well-tolerable regimen as adjuvant chemotherapy. Clinical trial information: 000004590. [Table: see text]
Preliminary results of a phase II randomized trial of two schedules of gemcitabine and carboplatin in platinum resistant ovarian or peritoneal carcinoma and a single institution experience with this combination
Authors: P. G. Rose, M. Smrekar, P. Haba, C. Visser, G. Peterson
Journal: Journal of Clinical Oncology (2005)

5148 Background: Gemcitabine inhibits the ERCC-1 mediated repair of platinum DNA adducts. Gemcitabine and carboplatin have demonstrated improved activity over carboplatin alone in platinum sensitive patients. Cisplatin and gemcitabine have demonstrated activity in platinum resistant ovarian carcinoma. Various schedules of carboplatin and gemcitabine have been studied with carboplatin either given on day 1 or day 8. Methods: We initiated a randomized trial comparing carboplatin at an AUC of 4 on day 1 with gemcitabine 800 mg/m2 on day 1 and 8 versus ½ the dose of carboplatin (an AUC of 2 on day 1 and 8) plus gemcitabine 800 mg/m2 on day 1 and 8. Results: Currently a total of 22 evaluable patients have been accrued to this protocol with a collective response rate of 50%. We have treated an additional 12 platinum resistant patients with the carboplatin Day 1 and Gemciabine Day 1 and 8 regimen with a response rate of 50% Conclusions: The combination of gemcitabine and carboplatin are active in platinum resistant ovarian and peritoneal carcinoma patients. Further accrual to this trial is necessary to assess the optimal shedule of these agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Oncology
Pharmacogenomic predictor of complete response to preoperative paclitaxel and 5-fluorouracil, doxorubicin, cyclophosphamide chemotherapy in breast cancer
Authors: L. Pusztai, K. R. Hess, K. Anderson, V. Valero, N. K. Ibrahim, J. A. Mejia, T. Vidaurre, H. L. Gomez, G. N. Hortobagyi, W. F. Symmans
Journal: Journal of Clinical Oncology (2006)

10000 Background: We developed a multi-gene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and 5-fluorouracil, doxorubicin, cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases. Methods: 133 patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with Affymetrix U133 A chips on fine needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. Results: Overall pCR rate was 26% in both cohorts. In the training set, 56 probes (49 genes) were identified as differentially expressed between pCR versus residual disease at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross validation. Many predictors performed equally well. A nominally best 30-probe set DLDA classifier was selected for independent validation. It showed substantially higher sensitivity (92% vs 61%), negative predictive value (96% vs 86%) and better AUC (0.877 vs 0.811) than a predictor including clinical variables (age, ER, grade). The combination of genomic and clinical information yielded the best model, AUC=0.883, sensitivity 92%, specificity 71%, PPV 52%, NPV 96%. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. Conclusion: A 30-probe set pharmacogenomic predictor alone or in combination with ER and grade predicts response to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12/13) and all but one of those who had residual cancer (27/28). No significant financial relationships to disclose.