tbuckley/cabot-search huggingface dataset:
Concomitant radiation therapy does not affect adjuvant CMF delivery in patients with operable breast cancer
Authors: F. Montemurro, M. Gatti, R. Faggiuolo, A. Durando, G. Choa, R. Piccinno, S. Redana, P. Sismondi, P. Gabriele, M. Aglietta
Journal: Journal of Clinical Oncology (2004)

793 Background: to evaluate if concomitant radiation therapy (C-RT) affects the dose intensity (DI) of adjuvant Cyclophosphamide (C), Methotrexate (M) and 5-Fluorouracil (5-FU) in patients (pts) with operable breast cancer. Methods: between Jan-2000 and Aug-2003, 152 pts, median age 56 yrs (26–74), received CMF (C 600 mg/m2, M 40 mg/m2, 5-FU 600 mg/m2, iv on days 1 and 8, every 4 wks). Planned treatment consisted of CMF alone (6 cycles) in 64 pts, 4 cycles of an anthracycline (A-CMF), either doxorubicin 75 mg/m2 or epirubicin 100 mg/m2 q3wks, followed by 4 cycles of CMF in 88 pts. One hundred-four pts underwent C-RT during CMF. This consisted of 50 Gy over a five week period (1.8/2 Gy for fraction), using two tangential megavoltage photon beams + additional dose of 10 to 16 Gy on the tumor bed. A supraclavicular field (45–50 Gy) was added in pts with >3 positive axillary lymph-nodes. The planned DI for C and 5-FU was 300 mg/m2/wk and that of M was 20 mg/m2/wk. The outcome of interest was the achievement of a relative DI ≥85% for the drugs in the CMF regimen. Results: the median relative DI was 94% for C and F (range 67–100%) and 93% for M (range 67–100%). One hundred twenty-one pts (80%) achieved a relative DI ≥85%. Of these, 48 had received A-CMF with C-RT, 18 A-CMF without C-RT, 35 CMF with C-RT, and 20 CMF without C-RT. Of the 31 pts achieving a relative DI <85%, 15 had received A-CMF with C-RT, 7 A-CMF without C-RT, 6 CMF with C-RT, and 3 CMF without C-RT. A multivariate logistic regression analysis showed that prior anthracyclines had a detrimental effect on DI, but this was not statistically significant at the 0.05 level (odds ratio [OR] 0.486, p = 0.10). Neither age, nor C-RT affected optimal CMF delivery (OR 0.981, p=033 and OR 1,150, p=0.75, respectively). The proportion of pts achieving a relative DI ≥85% was similar in pts submitted to A-CMF, with or without C-RT (76 % vs72%). Conclusions: concomitant RT did not affect the delivery of CMF in this series of pts, being sub-optimal dosing possibly related to prior anthracyclines in the sequential A-CMF regimen. Concomitant CMF and RT is a reasonable option to allow early initiation of adjuvant RT in patients with operable breast cancer. No significant financial relationships to disclose.
Abstract #5684: Amplification and over-expression of the miR-17-92 polycistron in the Sonic Hedgehog-driven subgroup of medulloblastoma
Authors: Paul Northcott, Africa Lopez, John Hagan, Wiesia Grajkowska, Yancey Gillespie, Richard Grundy, Timothy Van Meter, James Rutka, Carlo Croce, Anna Kenney, Michael Taylor
Journal: Cancer Research (2009)

Medulloblastoma is the most common malignant pediatric brain tumor and mechanisms underlying its development remain poorly understood. The important role played by microRNAs in cancer and cell cycle regulation is becoming increasingly recognized. We identified recurrent amplification of the miR-17/92 polycistron on chromosome 13q31.3 in 6% of pediatric medulloblastomas by high-resolution SNP genotyping arrays, and subsequent interphase FISH on a human medulloblastoma tissue microarray. MiR-17/92 has been previously shown to behave as an oncogene in lymphoma. Profiling the expression of 578 mature microRNAs in a series of 90 primary human medulloblastomas and 10 normal human cerebella revealed that components of the miR-17/92 polycistron are the most up-regulated microRNAs in medulloblastoma. Increased expression of miR-17/92 was present in three out of four molecular subgroups of medulloblastoma as determined by unsupervised hierarchical clustering of mRNA expression data from the same 90 tumors. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the Sonic Hedgehog (Shh) signaling pathway as compared to other subgroups of medulloblastoma. The tumors in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. The relationship between Shh signaling, N-myc expression, and miR-17/92 up-regulation was conserved in mice; we found that this microRNA cluster was highly expressed in medulloblastomas from Ptch+/- mice and NeuroD2SmoA1 mice, in which the Shh pathway is aberrantly activated. When we assayed primary cultures of Shh-treated post-natal day 5 cerebellar granule neuron precursors (CGNPs), we found that components of the miR-17/92 polycistron were the microRNAs whose expression was most strongly induced by Shh. Expression of miR-17/92 was driven by N-Myc, but not Gli1 or Gli2 in these cells. Exogenous miR-17/92 expression enabled the CGNPs to proliferate independent of Shh signaling, and synergized with Shh to further increase their proliferation. Our results are consistent with a model in which excessive Sonic Hedgehog signaling promotes the transformation of cerebellar neural precursor cells, driven at least in part by over-expression of the miR-17/92 polycistron. Moreover, in a subset of cases, excessive Sonic Hedgehog signaling is followed by oncogene addiction to miR-17/92, and genomic amplification of the miR-17/92 locus.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5684.
Patterns of failure in primary testicular non-Hodgkin's lymphoma.
Authors: J A Martenson, S J Buskirk, D M Ilstrup, P M Banks, R G Evans, J P Colgan, J D Earle
Journal: Journal of Clinical Oncology (1988)

Patterns of failure were analyzed in 30 patients with testicular non-Hodgkin's lymphoma: 16 had stage IE disease, ten had stage IIE, and four had stage IV. After orchiectomy, two of the 16 patients with stage IE disease received no additional therapy, one received multiagent chemotherapy, and 13 received pelvic and para-aortic radiation. Twelve patients with stage IE disease had progression, and the median time to progression was 12 months. Of the 14 patients with extratesticular involvement (stage IIE or IV), one (stage IV) received no treatment after orchiectomy, three (stage IIE) received para-aortic and pelvic radiation, and ten (seven stage IIE and three stage IV) received multiagent chemotherapy with or without radiation. Eight of the patients with stage IIE or IV disease had progression, and the median time to progression was 11 months. Widespread extranodal progression was observed in 17 of the 20 patients who had progression. The tendency of testicular lymphoma for early systemic progression suggests a need for multiagent chemotherapy in initial management.
MAPK activation predicts poor survival after pancreatico-duodenectomy
Authors: M. M. Javle, J. Yu, M. Chadha, T. Khoury, C. M. Levea, J. F. Gibbs, R. V. Iyer, D. Oleszek, M. G. Brattain, J. D. Black
Journal: Journal of Clinical Oncology (2005)

9578 Background: Fewer than 20% of patients (pts) with pancreatic cancer survive 5 years following pancreatico-duodenectomy. Limited data exist regarding downstream activation of EGFR signaling in pancreatic carcinoma. We investigated expression of EGFR, MAPK (ERK-MAPK), AKT, and their phosphoforms (p-) and correlated these with clinical outcome. Methods: Clinical data of forty-three consecutive cases of pancreatic carcinoma who underwent pancreatico-duodenectomy were obtained. Immunohistochemical staining of paraffin embedded blocks was performed using monoclonal antibodies against EGFR, MAPK, p-MAPK, AKT and p-AKT. Standard immunoperoxidase technique was used to detect the avidin- biotin peroxidase complex. Protein expression was visually scored using histoscore method, independently by two pathologists. Results: Forty-two pts underwent pancreatico-duodenectomy. Pts characteristics: sex-21 men, 22 women; median age- 66 years (range: 32 to 84); TNM Stage I-3 pts, Stage II/III-34 pts and Stage IV-6 pts. Tumor was grade 1 in 4, grade 2 in 20 and grade 3 in 18 cases. Additional therapies were chemotherapy (n=5), radiotherapy (n=1) and combined chemo-radiotherapy (n=19). Immunohistochemistry revealed increased expression of EGFR in 27.9%, MAPK in 89.5%, p-MAPK in 26.8%, AKT in 39.5% and p-AKT in 13.9% of cases. The cumulative logit model showed that EGFR expression correlated with high tumor grade (OR=6.7, p=0.0101). Data analysis using Kaplan-Meier method and log rank test revealed that high p-MAPK expression (n=14) correlated with shorter median survival (10 months) than low expression (n=26, 21 months, p=0.0049). High expression of p-AKT (n=21) was associated with longer median survival (24 months) than low expression (n=21. 9 months, p=0.0025). Multivariate analysis using the Cox-proportional hazard model identified age (HR = 1.13, p=0.0005), p-AKT (HR=0.05, p=0.0005) and p-MAPK (HR=7.94, p=0.0011) as predictors of survival. Conclusions: EGFR and its downstream proteins are often activated in pancreatic carcinoma. Expression of p-MAPK, advanced age and high tumor grade are associated with poor survival after pancreatico-duodenectomy. Supported by NIH grants CA62502 and CA16056. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech, Roche
Pediatric oncology admission to pediatric intensive care unit (PICU). A 4-year experience at King Khalid National Guard Hospital (KKNGH), Jeddah, Saudi Arabia
Authors: T. M. Khattab, S. K. Felimban, D. L. Baker, A. R. Abutaleb
Journal: Journal of Clinical Oncology (2004)

8567 Background: Cardiorespiratory decompensation is an ominous complication in the immune compromised pediatric cancer patient. Methods: A retrospective review of all PICU admissions from the KKNGH pediatric oncology unit between 6/1997 and 8/2001. To analyse pediatric oncology patients admitted to PICU with respect to cancer type, indication for admission, cardio-respiratory support required and overall outcome. Results: Over this 50 month period, 40% (79/196) of the newly diagnosed pediatric oncology patients were admitted to PICU. Cancers included ALL (50), AML (7), NHL (8), NBL (4), RMS (3), Wilms (2) and EWS, HBL, HD, CML and Abd. mass (1 each). They were divided into 2 groups based on the precipitating event: respiratory compromise or cardiovascular decompensation. Group I (n=38). 66% (25/38) required ventilation for a median of 3 days (0.25 to 14 days). 12/38 ( 32 % ) required inotropic support and 8/12 >one inotrop. Mortality in the ventilated group was 67% vs. 27% in the non-ventilated cohort. Overall mortality was 55% (21/38) and 8 deaths (38%) were relapsed / resistant disease. Group II, (n=41). 61% (25/41) required inotropic support, 14/25 > one inotrop. 5/41 (12% ) required ventilatory support. Overall mortality in this group was 32% (13/41) and in 11 of the deaths (85%) resistant/relapsed disease was present. The overall mortality for the entire cohort was 43% (34/79) and resistant/relapsed disease was a contributing factor in 56% (19/34) of these deaths. Conclusions: Over a 50 mo. period 40% of ped.oncology patients required PICU admission for ventilatory and/or inotropic support at sometime during their therapy. Infection with or without shock was the major precipitating factor. Early recognition of sepsis with aggressive management of cardio-respiratory function including early ventilatory support may reduce the high mortality rate. No significant financial relationships to disclose.
A phase II study of vorinostat (NSC 701852 ) in patients (pts) with relapsed non-small cell lung cancer (NSCLC)
Authors: A. M. Traynor, S. Dubey, J. Eickhoff, J. M. Kolesar, S. M. Marcotte, L. C. Hammes, C. M. Hallahan, C. E. Moore, J. Zwiebel, J. H. Schiller
Journal: Journal of Clinical Oncology (2007)

18044 Background: Vorinostat is a small molecule inhibitor of histone deacetylase (HDAC). HDAC inhibitors have shown preclinical activity in lung cancer and are postulated to have an antitumor effect by alteration in acetylation status of histone and non-histone proteins. Methods: Pts with relapsed NSCLC who failed no more than 1 prior cytotoxic therapy were eligible. Treatment: vorinostat, 400 mg po daily in a 21 day cycle. Primary objective: response rate (RR), with goal of at least one responder in first 14 evaluable pts. Secondary objectives: time to progression (TTP), overall survival (OS), safety, and correlative assays. Results: 14 pts enrolled from 12/05- 12/06. Median age 59.5 yrs (range 47–79). 11 females. PS 0:1, 10 pts:4 pts. Thirteen of 14 pts had only 1 prior cytotoxic regimen; 1 pt had only prior erlotinib. Best response to prior treatment: stable disease (SD; 11 pts), progressive disease (PD; 3 pts). Median time since last prior therapy: 2.1 mo (range 0.2–78.5). Vorinostat treatment compliance: 95.8 %. Two pts were not evaluable for response due to not completing Cycle 1 of treatment due to PD. No objective antitumor responses have been seen in the first 12 evaluable pts. Seven pts experienced SD (median 4.2 mo, range 2–10.7). Median TTP: 2.8 mo (range 1–10.7+); median OS 6.5 mo (range 1.4–10.7+); estimated 6 mo OS rate 50% (SE 16%). Grade (Gr) 5 toxicity: CVA (1 pt). Gr 3/4 toxicities: neutropenia (Gr 4–1 pt), lymphopenia (Gr 3–2 pts), fatigue (Gr 3–1 pt), elevated alk phos (Gr 3–1 pt), memory impairment (Gr 3–1 pt), PE/DVT (Gr 3–1 pt; Gr 4–2 pts), dehydration (Gr 3–1 pt). Data from the following correlative studies will be updated: p53 status, gene expression, H3 acetylation, transcription of p21, Nur77, Hsp70, erbB1 and 2, and Akt, cell cycle arrest, and assay of isoprostanes generated by treatment with vorinostat. Conclusions: Vorinostat 400 mg daily is tolerable with more than 80% of patients completing Cycle 1. Vorinostat yields TTP in relapsed NSCLC similar to that of other targeted agents. Although 4 of 14 pts experienced vascular events on treatment, these occurrences are common in this disease setting. At least two additional pts are still to be accrued. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents. No significant financial relationships to disclose.
The interaction between smoking status and disease stage on non-small cell lung cancer (NSCLC) survival.
Authors: A. M. Horgan, Y. V. Wang, F. A. Shepherd, D. Brenner, J. J. Knox, J. McLaughlin, G. Liu, R. J. Hung
Journal: Journal of Clinical Oncology (2010)

e18021 Background: In cancer, accumulation of somatic and genomic changes occurs from early to late stage disease. Recent data suggest that never smokers (NVS) vs. ever smokers (EVS) develop biologically distinct NSCLCs. We studied whether smoking status (EVS vs. NVS) modified prognosis differently in early (stage I-II) vs. late stages (stage III-IV) of NSCLC. Methods: Detailed smoking history was collected prospectively from patients with newly diagnosed NSCLC as part of a molecular-epidemiologic study (1997-2002) that specifically oversampled never-smokers. Survival data were collected from the Ontario Cancer Registry. Cox proportional hazard models identified variables with prognostic significance. Analyses of patients with early and late stage NSCLC were first performed separately, followed by a model that included a stage- smoking status interaction term. Results: Among 381 patients, 34% were NVS. NVS were younger (median age 60 vs. 65 years in EVS; t- test p = 0.0001), more likely to be female (68% NVS vs. 45% EVS) and non-Caucasian (38% NVS vs. 18% EVS); stage distribution was similar (26% NVS vs. 22% EVS were Stage I/II). Pack-years, intensity or duration of smoking, and years since quitting were not significant univariate predictors of outcome, by stage. Multivariate models were adjusted for significant univariate covariates of age, sex, treatment and stage, along with current vs. former smoking status and race. In early stage patients, NVS had longer survival (adjusted hazard ratio [AHR] 0.43; 95% CI, 0.18-1.03), while in late stage patients, the opposite effect was observed (AHR 1.47; 95% CI, 1.08-2.00). The interaction between disease stage (early vs. late) and smoking status (NVS vs. EVS) was significant (p = 0.006). In the same interaction model, age and sex were no longer significant, after adjusting for smoking, disease stage, and the interaction of these two variables. Conclusions: Never-smokers appear to have better prognosis than ever-smokers in early stage lung cancer, an effect that is reversed in late stage disease; age and gender were not predictive of survival after accounting for smoking and stage. These effects may reflect smoking subpopulations that are biologically heterogeneous. No significant financial relationships to disclose.
Results of a phase IIb study in recurrent or refractory glioblastoma patients with the TGF-beta-2 inhibitor AP 12009
Authors: P. Hau, U. Bogdahn, V. E. Olyushin, A. Mahapatra, V. E. Parfenov, K. Venkataramana, S. Ludwig, P. Jachimczak, H. Heinrichs, K. Schlingensiepen
Journal: Journal of Clinical Oncology (2007)

12521 Background: The antisense phosphorothioate oligonucleotide compound AP 12009 targets TGF-beta2. Since TMZ is now used in the adjuvant setting in GBM there is a high need for new treatment options in recurrence. In three Phase I/II dose escalation trials with AP 12009 in high-grade glioma (HGG) patients complete and long lasting tumor responses had been observed. Methods: The study G004 is an international open-label, randomized, active controlled, dose-finding Phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy. A total of 145 patients with histopathologically confirmed recurrent or refractory HGG (WHO Grades III and IV) were randomized into three treatment arms. Patients received treatment with low dose AP 12009 (10 μM), high dose AP 12009 (80 μMM), or standard chemotherapy TMZ or PCV. AP 12009 was applied by convection-enhanced delivery during using 7-day-on, 7-day-off cycles. Maximum number of cycles was 11. Results: Here we report on patients with recurrent or refractory glioblastoma (GBM, WHO Grade IV; AA patients see separate abstract). Out of 95 GBM patients treated, 28 pts received 10 μM AP 12009, 34 pts AP 12009 80 μM, and 33 pts standard chemotherapy (28 TMZ, 5 PCV). Median age differed between treatment groups (see table ). Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table ). Comparable hazard ratios for survival were seen in the three treatment groups (see table ). Long lasting responses were observed in both AP 12009 groups. Conclusions: The safety profile of AP 12009 in GBM patients was good. The durable responses in both AP 12009 groups and the survival data confirm the proof of concept obtained in Phase I/II trials for treatment of recurrent GBM patients with AP 12009. [Table: see text] No significant financial relationships to disclose.
Management of established pathological grief reaction after stillbirth
Authors: J T Condon
Journal: American Journal of Psychiatry (1986)

This paper focuses on the etiology, recognition, and treatment of established pathological grief reactions in parents bereaved by stillbirth. Bereavement in this situation differs in a number of aspects from conventional bereavement, and these dictate that the style of grief therapy be modified. Four such aspects are discussed: the unique psychological properties of the lost object, the complexity of the emotional attachment that expectant parents develop toward their unborn child, the unusual psychobiological climate in which the loss occurs, and the sociocultural definition of the meaning and significance of the loss.
The correlation of the AKT/mTOR/p70S6K1 pathway and VEGF in human epithelial ovarian cancer
Authors: X. Trinh, W. A. Tjalma, L. Y. Dirix, P. B. Vermeulen, G. G. Van Den Eynden, S. J. Van Laere, I. Van Der Auwera, P. A. van Dam
Journal: Journal of Clinical Oncology (2007)

16081 Background: The Akt/mTOR/p70S6K1 (Amp) pathway is activated in a proportion of epithelial ovarian cancers. The ribosomal protein pS6 and p4EBP1 are downstream targets and presumed representative for the pathway's activity. VEGF and angiogenesis in ovarian cancer play an important role as bevacizumab induces high response rates and prolongs progression-free survival in women with relapsed ovarian cancer in two phase II trials. The Amp pathway has proven to be correlated with HIF1alfa and VEGF A expression in vitro. Material and Methods: Our primary objective was to evaluate correlation between this pathway in human subject tissues and angiogenesis using VEGF A and pVEGFR2. Our second objective was to evaluate if different metastatic abdominal (peritoneal and/or omental) lesions show the same pathway hyperactivity and/or angiogenesis as the primary tumour, because relapses usually involve metastatic abdominal lesions. Epithelial ovarian cancer paraffin imbedded material from 1999–2004 was collected. A tissue micro array was build with three samples per paraffin block. Immunohistochemical staining was performed using pS6, p4EBP1, pAKT, VEGF and pVEGFR2. Results: 89 patients were collected with a median age of 69.8y. Patients were FIGO stage I in 21%, stage II in 4%, stage III in 62% and 11% stage IV. Histological examination showed in 53% serous papillary tumours, 25.8% endometroid tumours, clear cell carcinoma in 11.2% and mucinous tumours in 4.5%. 65 patients had available tissue material of both primary tumour as well as other (multiple) metastatic abdominal disease tissue. The results of the immunohistochemical staining as well as the correlation analysis will be presented. Conclusion: Although anti-angiogenesis seems to be very active against human epithelial ovarian cancer, it is at present associated with unacceptable treatment induced toxicities. Inhibiting the Amp pathway with mTOR inhibitors could potentially also inhibit angiogenesis in ovarian cancer with the potential of more manageable side effects. This study will provide some evidence on the relationship between the Amp pathway and the VEGF pathway in human epithelial ovarian cancer. No significant financial relationships to disclose.