tbuckley/cabot-search huggingface dataset:
A phase II evaluation of pemetrexed (LY231514, IND #40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: A study of the gynecologic oncology group
Authors: D. S. Miller, J. A. Blessing, C. N. Krasner, R. J. Mannel
Journal: Journal of Clinical Oncology (2008)

5524 Objective: To estimate the anti-tumor activity of pemetrexed (LY231514) in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer who have failed on higher priority treatment protocols and to determine the nature and degree of toxicity of pemetrexed in this cohort of patients. Methods: A multicenter cooperative group Phase II Trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had recurrent or persistent epithelial ovarian or primary peritoneal cancer and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m2 was to be administered as an IV infusion over 10 minutes every 21 days. Response was assessed by RECIST criteria. Dose adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. Results: From July 6, 2004 to August 23, 2006, 51 patients were entered by 15 member institutions of the GOG. Two patients were ineligible (wrong primary, low creatinine clearance) and one did not receive treatment. A total of 259 cycles (median: 4; range 1 to 19) of pemetrexed were administered with 40% of patients receiving 6 or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15%. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses with a median duration response of 6.8 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were inevaluable. Median progression-free survival (PFS) was 3.0+ months and overall survival (OS) was 11.4+ months. Conclusion: Pemetrexed has demonstrated activity in the treatment of recurrent platinum resistant ovarian carcinoma at the dose and schedule tested. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology Lilly Oncology
Quality of Repopulation in Nonobese Diabetic Severe Combined Immunodeficient Mice Engrafted With Expanded Cord Blood CD34+ Cells
Authors: Michael P. Blundell, Christophe Demaison, Gaby Brouns, Jacki P. Goldman, Hubert B. Gaspar, Christine Kinnon, Adrian J. Thrasher, Lorenza Lazzari, Girolamo Sirchia
Journal: Blood (1999)
Markers of angiogenesis in cervical cancer: A Gynecologic Oncology Group study
Authors: L. Randall-Whitis, B. J. Monk, E. S. Han, K. Darcy, R. A. Burger, S. Liao, W. A. Peters, R. J. Stock, J. P. Fruehauf
Journal: Journal of Clinical Oncology (2007)

5536 Background: Extensive tumor angiogenesis has correlated with poorer progression-free and overall survival in cervical cancer; however, specific markers of angiogenesis have not been studied prospectively. Methods: Cervical cancer patients with high-risk features on radical hysterectomy were eligible for randomization to adjuvant pelvic irradiation ± radiosensitizing platinum. Following central pathology review, formalin-fixed, paraffin-embedded tumors were sectioned into 4-micron specimens. Semi-quantitative immunohistochemisty (IHC) was performed using previously validated antibodies against mutant p53 (mp53), vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP-1), and endothelial markers CD 31 and CD 105. Tumoral histoscores (HS) were calculated for mp53 and VEGF using the formula: [% cells positive × (intensity +1)], with a 5% threshold for positivity and intensity ranging 1–4+ (3+ = intensity of positive control). Intensity scores (0–4+) were assigned to TSP-1 specimens referencing the positive control (3+). MVD “hotspots” were counted in a 20X high-power field. HS and MVD counts were considered as continuous variables and TSP-1 intensity as an ordinal variable. Associations between markers were determined by Pearson’s and Spearman’s correlation tests, between markers and clinico-pathologic variables by Wilcoxon rank test, and between markers and survival by Cox regression modeling. Results: One hundred seventy-six specimens were analyzed. Acquisition of mp53 and increased VEGF expression were associated with increased MVD assessed by both CD31 (p=0.08 and p=0.002, respectively) and CD105 (p=0.02 and p=0.012, respectively). Statistically significant associations between markers and high-risk pathologic factors included: low-level TSP-1 and high CD-105 counts with lymph node metastases; high VEGF scores with advanced stage, non-squamous histologic subtype, and depth of tumor invasion; and high CD 31 counts with parametrial metastases. Survival analysis is currently being performed. Conclusions: Angiogenesis occurs early in cervical carcinogenesis, and may be a rational target for biologic therapy in cervical cancer. No significant financial relationships to disclose.
Induction of Pancreatic Duct Carcinomas in the Syrian Hamster With 2,6-Dimethylnitrosomorpholine 2
Authors: Ulrich Mohr, Gerd Reznik, Eberhard Emminger, William Lijinsky
Journal: JNCI Journal of the National Cancer Institute (1977)

Pancreatic duct carcinomas were induced in Syrian hamsters by intragastric administration of 2,6-dimethylnitroso-morpholine. As early as 30 weeks after treatment began, tumors were macroscopically visible in the pancreas; the maximum incidence of such tumors reached 71% by the end of the experiment. They were ductal in origin, and some metastasized to the lung. They were identified histologically as adenomas and carcinomas and developed in different parts of the organ without demonstrating any preferred localization.
Breast surgeon faces 21 charges of unlawfully wounding 11 patients
Authors: Clare Dyer
Journal: BMJ (2016)

Ian Paterson, the English breast surgeon accused of carrying out unnecessary or inappropriate operations on hundreds of women, now faces rare criminal charges of unlawfully wounding 11 of his patients.

Paterson, 58, appeared at Birmingham Magistrates’ Court on 18 January charged with wounding with intent to do grievous bodily harm, contrary to section 18 of the Offences against the Person Act 1861. The …
Modulation of circulating biomarkers in NSCLC patients correlate with stage.
Authors: S. P. Bradley, P. Hamer, L. W. Miller, W. P. Carney
Journal: Journal of Clinical Oncology (2010)

e21093 Background: NSCLC accounts for ∼80% of all lung cancer cases. Five-year survival rates for stage IV disease are very poor compared with stage I (2% vs. 56%). Therefore, tools are needed to assist with early diagnosis for lung cancer patients and guide targeted therapies that might benefit them. We measured the modulation of specific biomarkers across lung cancer stages in NSCLC patients that are relevant to targeted therapies currently available or in development. Methods: 17 stage I, 24 stage II, 47 stage III, and 48 stage IV lung cancer patient serum samples were assayed for the following circulating biomarkers by ELISA: EphA2, HER-2/neu, VEGF165, and sVEGFR-2. We have developed a test for circulating EphA2 which may be useful for EphA2 targeted therapies. Results: We found significant differences between stages for the following biomarkers using the Kruskal-Wallis test: EphA2 (p < 0.0001), HER2/neu (p < 0.0001), VEGF165 (p < 0.0001), and sVEGFR-2 (p < 0.0001). Post-hoc analysis (Tukey's method) was performed to compare individual stages. VEGF165 levels were lowest in stage I and trended upwards at stage II, then downwards in later stages. Soluble-VEGFR-2 exhibited a similar pattern with lowest levels in stage I and highest levels in stage II (p = 0.001), while finally trending downwards in later stages. While not significant, soluble-EphA2 expression trended upwards from stage I to stage IV. In addition, soluble-HER2/neu expression was low in stages I-III and then significantly increased in stage IV (p < 0.0001). Conclusions: Based upon the high levels of VEGF165 and sVEGFR-2 found in stage II, intervention with anti-angiogenesis therapies may benefit early stage NSCLC patients. The significant increase of soluble HER2/neu in stage IV indicates that intervention with ErbB therapies may benefit late stage NSCLC patients. A panel composed of these particular biomarkers may help to guide therapy decisions for NSCLC patients in whom these target therapies hold promise. This preliminary biomarker study in NSCLC highlights the need for further investigation of this panel correlated to survival outcomes and therapy prediction. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Siemens Healthcare Diagnostics
Abstract 2537: CDK4/6 inhibition synergizes with KRAS-MAPK pathway targeting in pancreatic cancer
Authors: Jason A. Castellanos, Nagaraj Nagathihalli, Michael N. Van Saun, Cameron Kasmai, Yanhua Xiong, Nipun Merchant
Journal: Cancer Research (2015)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult human malignancies to treat due to its innate and acquired therapeutic resistance. Our hypothesis is that cyclin-dependent kinase 4 (CDK4) mediates therapeutic resistance to targeting of the KRAS-MAPK pathway in PDAC. Experimental Procedure: We characterized the expression of total and phosphorylated Retinoblastoma (Rb) and MEK protein levels in KRAS wild-type (BxPC3) and KRAS mutant (PANC1, MiaPaca2) human PDAC cell lines at baseline and with MEK and CDK4 inhibition alone or in combination. We then assessed the effects of combined therapy on cell-cycle progression and tumorigenicity (in vitro and in vivo). Finally, using the Ptf1a cre/+;LSL-Kras G12D/+;Tgfbr2 flox/flox (PKT) mouse model of PDAC, we assessed the in vivo overall tumor growth and survival after combined treatment with CDK4/6 and MEK inhibitors. Results: Rb functions as a tumor suppressor, and it is inactivated when phosphorylated by CDK4-Cyclin-D1. The CDK4/6 inhibitor (LEE011) effectively inhibits phosphorylation of Rb in cell lines regardless of KRAS mutational status. Combined inhibition of CDK4/6 and MEK (MEK162) decreased phosphorylation of RB and MAPK expression synergistically in the KRAS mutant cell lines, but not the KRAS wild-type BxPC3 cell line. Cell cycle progression was delayed effectively with MEK inhibition alone in the KRAS wild-type cell line, yet only combined CDK4/6 and MEK inhibition effectively delayed cell cycle progression in the KRAS mutant cell lines. Colony formation and invasion were also significantly decreased when Kras mutant cells were treated with combined CDK4/6 and MEK inhibition compared to all monotherapy and control groups. Finally, treatment of PKT mice resulted in a modest increase in OS with MEK inhibition alone, but mice receiving combined CDK4/6 and MEK inhibition exhibited a four-fold increase in OS. Conclusions: Combined inhibition of CDK4/6 and MEK results in significantly enhanced therapeutic efficacy and prolonged survival in the aggressive PKT mouse model of PDAC. This study suggests that concurrent inhibition of CDK4/6 and MEK may be an effective treatment for PDAC. Citation Format: Jason A. Castellanos, Nagaraj Nagathihalli, Michael N. Van Saun, Cameron Kasmai, Yanhua Xiong, Nipun Merchant. CDK4/6 inhibition synergizes with KRAS-MAPK pathway targeting in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2537. doi:10.1158/1538-7445.AM2015-2537
Phase I study of temozolomide in conjunction with gemcitabine
Authors: R. Goel, S. Gertler, D. J. Stewart, S. Laurie, G. Goss, N. Reaume, C. Cripps, D. Bedard, A. Rodgers, D. Cutler
Journal: Journal of Clinical Oncology (2004)

2127 Background: Temozolomide (TZ) is an oral alkylating agent used in the treatment of brain tumours, and malignant melanoma. Gemcitabine (GC) is a nucleoside analogue clinically active versus several human tumors, including pancreatic cancer, breast cancer, non-small cell lung cancer, bladder cancer etc. In vitro, these 2 drugs exhibit additive cytotoxic effects against the astrocytoma U373MG cell line. Methods: A phase I clinical study of these 2 drugs in combination was initiated. Dose Level (DL) 1 received: TZ 100 mg/m2, days 1–7 and 15–21; GC 750 mg/m2 days 1, 8, and 15; every 28 days. DL 2 received TZ 125 mg/m2 and GC 750 mg/m2. DL 3 received TZ 125 mg/m2 and GC 1000 mg/m2. DL 4 received TZ 150 mg/m2 and GC 1000 mg/m2. Two Dose-Limiting Toxicities (DLTs) occurred at DL 4; therefore, DL 3 was considered the maximally tolerated dose. As per study, 6 more patients were treated at DL 3 (termed DL 3'). Three prior chemotherapy regimens were allowed . Results: Patient characteristics: male 11/female 13; median age 55 (range 26–77); performance status 0 (n=3), 1 (n=14), and 2 (n=7); prior therapy: chemotherapy 21, radiotherapy 10, no prior anticancer therapy 2; tumour types: non-small cell lung 8, primary brain tumour 2, miscellaneous 14. To date, 6 patients were treated at DL 1, 4 at DL 2, 4 at DL 3, 4 at DL 4, and 6 patients at DL 3'. To date, data analysis has been completed on patients treated on DLs 1–4. The number of cycles (at these DLs) given: <1 (n=4), 1 (n=3), 2 (n=4), 3 (n=5), 4 (n=2). The nadir counts (x109/L) after cycle 1: DL 1-white blood cell (wbc) 3.2 (range 2.5–6.5), neutrophil (PMN) 1.7 (range 1.0–3.5), platelets 154 (range 56–228), DL 2-wbc 3.8 (range 2.2–4.2), PMN 1.3 (0.8–1.8), platelets 154 (88–173), DL 3-wbc 2.2 (range 1.3–3.0), PMN 1.5 (0.7–1.7), platelets 104 (64–373), DL 4-wbc 2.6 (0.5–2.6), PMN 1.5 (0.2–2.6), platelet 95 (55–165). No significant non-hematologic toxicity has been observed. Conclusions: This chemotherapy regimen is well-tolerated. Encouraging activity of the regimen is suggested in this group of heavily pre-treated patients with resistant tumours; 8 patients received more than 2 courses of therapy. Supported by Schering-Plough Research Institute. No significant financial relationships to disclose.
Expression of epidermal stem cell markers in skin and adnexal malignancies
Authors: S.R. Quist, M. Eckardt, A. Kriesche, H.P. Gollnick
Journal: British Journal of Dermatology (2016)

Epidermal stem cells are multipotent cells that maintain the skin epidermis. Potential markers for stem cells have been identified in mammalian skin from mouse experiments; however, it is unclear if stem cells also contribute to tumour formation in human skin. To investigate the expression of potential stem cell markers, such as leucine‐rich repeat‐containing G protein‐coupled receptor (Lgr) 5, Lgr6, leucine‐rich repeats and immunoglobulin‐like domain protein 1 (Lrig1) and cytokeratin 15 (CK15) in basal cell carcinomas and tumours of the skin appendages. We tested 45 human basal cell carcinomas (BCCs), including superficial, nodular, adenoid, infiltrating and sclerosing types, and 38 human tumours of skin appendages, including 13 sebaceous adenomas and carcinomas, 20 eccrine sweat gland tumours and five pilomatricomas, for the expression of hair follicle stem cell markers such as Lgr5, Lrig1, CK15, β‐catenin and SRY (sex determining region Y)‐box 9 (SOX9), and compared these findings with those of healthy age‐matched human epidermis. We detected the expression of stem cell markers in all tumours tested. Regarding Lgr5, Lrig1, CK15 and SOX9, expression seemed to be lower in more aggressive tumour types, such as in the most advanced parts of infiltrating BCC, in sebaceous carcinoma and late‐stage porocarcinoma, compared with less aggressive superficial or nodular BCC or early‐stage porocarcinoma and sebaceous gland tumours. In aggressive, sclerosing BCC, Lrig1 and Lgr5 were downregulated but CK15, SOX9 and nuclear β‐catenin were upregulated. Expression of potential stem cell markers of the epidermis and hair follicles was observed in skin tumours of appendages and BCCs. However, during tumour progression, many of these markers seemed to be downregulated.
Prognostic factor analyses of myeloma (MM) survival outcomes on intergroup trial S9321 (int 0141): Examining whether different variables govern different time segments of survival
Authors: J. Crowley, V. Bolejack, K. Robert, K. Anderson, B. Barlogie
Journal: Journal of Clinical Oncology (2009)

8599 Background: MM survival varies enormously from few months to more than a decade. Baseline prognostic factors (PF) have been identified that are linked to survival outcomes, especially B2M and albumin. MM survival plots are typically characterized by 3 segments of slopes with decreasing steepness, suggesting that different PF may govern these time segments. Methods: We therefore examined, in S9321, PF that were associated with overall survival (OS) from baseline (BL) and from 3 subsequent landmarks 3, 5, and 7 years later (LM3, LM5, LM7). With a median follow-up of 9 years, OS and EFS were virtually identical in transplant and standard therapy arms so that the data were pooled. Results: Median OS and EFS for 817 eligible patients are 48 and 22 months. The BL model identified age (&gt;60yr), hemoglobin (&lt;10g/gL), platelet count (&lt;130,000/uL), albumin (&lt;3.5g/dL), B2M (&gt;3.5g/dL), calcium (&gt;10mg/dL), creatinine (&gt;2mg/dL), LDH (&gt;190U/L), performance status (PS, &gt;1), IL-6 level (&gt;140mg/L) and plasma cell labeling index (PCLI, &gt;1%) as being univariately associated with short OS, while age (p=0.002), platelet count (p=0.04), calcium (p&lt;0.001), B2M (p=0.002), LDH (p=0.010) and PCLI (p&lt;0.001) retained significance in multivariate analysis. For the LM3 analyses, age (p=0.006) and B2M (p=0.009) were independently associated with poor OS, whereas PCLI was the only PF associated with LM5 (p=0.026) and age with LM7 (p&lt;0.001). While associated univariately with OS from BL, CRP, platelet count, hemoglobin, albumin, calcium, creatinine, LDH, IL6 and PS all failed to affect OS from later LM times. Conclusions: Whereas the initial 3 years of OS are governed by a combination of features related to disease aggressiveness (LDH, calcium, albumin, CRP), tumor burden (hemoglobin, platelet count) and host tolerance (PS, creatinine), B2M and PCLI as reflectors of tumor burden and proliferation have sustained long-term OS implications. The age factor figures in partly due to death from other causes. In an era of ever-improving survival outcomes, such LM-based PF analysis may reveal trial-specific differences and thus provide guidance toward individualizing therapy. [Table: see text]
Sickle-cell Anaemia in the Accra District of the Gold Coast
Authors: G. M. Edington
Journal: BMJ (1953)

FAILED FORCEPS" BRr=9Jou incision or manual stretching of the cervix has been recom- mended (Browne, 1949).These procedures, however, have a limited application and are fraught with hazard.In such cases, therefore, it is probably wiser to transfer the patient to hospital.Malpositions of the Foetal Head.-Since, as has been pointed out by Freeth (1950), it is unwise to assume that the occiput is necessarily anterior, it is essential to determine the position of the foetal head before applying the forceps.For this it is usually recommended that an ear be sought or, failing this, that the nape of the neck be identified (Browne, 1949).These measures, although possessing a high degree of accuracy, have the disadvantage that full anaesthesia is necessary for their proper applica.ion.This objection no longer obtains if use is made of the suture lines to determine the position of the occiput.These land- marks can easily be reached in most patients, and with practice a high degree of accuracy in their identification may be obtained.Late in labour caput formation may obscure these features to some extent, though in all but exceptional cases they can usually be made out with time and patience.If doubt still exists a good case can be made for examination under anaesthesia, the whole hand being passed into the vagina.Such a measure should, however, in no way commit the obstetrician to immediate delivery if the position of the head or the state of the cervix implies that this course would be unsafe.
Phase II study of the histone deacetylase (HDAC) inhibitor belinostat for the treatment of myelodysplastic syndrome (MDS).
Authors: A. F. Cashen, M. Juckett, A. Jumonville, M. R. Litzow, P. J. Flynn, J. R. Eckardt, B. LaPlant, K. M. Laumann, C. Erlichman, J. F. DiPersio
Journal: Journal of Clinical Oncology (2010)

6607 Background: Inhibition of HDAC can induce differentiation, growth arrest, and apoptosis in cancer cells. Belinostat (PXD101) is a potent inhibitor of both class I and class II HDAC enzymes. This phase II study was undertaken to estimate the efficacy of belinostat for the treatment of MDS. Methods: Adults with MDS (any WHO classification, plus at least 1 significant cytopenia if < 5% bone marrow blasts) were eligible if they had ≤ 2 prior therapies for MDS, adequate renal and hepatic function, and ECOG 0-2. The primary endpoint was proportion of confirmed responses (CR, PR, and hematologic improvement [HI]) during the first 12 wks of treatment. Patients were treated with belinostat 1,000 mg/m2 as a 30 min IV infusion on days 1-5 of a 21 day cycle for 4 cycles. Responding pts could receive additional cycles until disease progression or unacceptable toxicity. 21 pts were to be enrolled in the first stage, and if 3 or more responses were observed, an additional 29 would be enrolled in stage 2. Results: 21 pts (median age, 67 years) were enrolled, and all are evaluable. Patients were a median 13.4 mo. from diagnosis (range, 0.3-210) and had bone marrow blasts of < 5% (n = 14), 5%-9% (n = 6), and 10%-19% (n = 1). 13 pts (62%) had good-risk cytogenetics, and 7 (33%) had poor risk. 17 pts (81%) were transfusion dependent. Prior therapy included azacitidine (N=7) and chemotherapy (n = 8). Patients were treated with a median 2.5 cycles (range, 1-8) of belinostat. There was one confirmed response–HI in neutrophils–that lasted 2.1 mo., for an ORR of 5% (95% CI, 0.2-23). Median OS was 14.5 mo. Median time to progression was 15.5 mo. Grade 3-4 toxicities considered at least possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), and headache (n = 1). 2 pts had grade 2 cytokine release syndrome during belinostat infusion, and 2 pts had QTc prolongation. Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual. Conclusions: Although well-tolerated, belinostat does not have sufficient efficacy to warrant further investigation as a single agent in MDS. Supported by NCI N01-CM62205. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Plexxikon