tbuckley/cabot-search huggingface dataset:
Angiogenesis polymorphisms profile in the prediction of clinical outcome of advanced HCC patients receiving sorafenib: Combined analysis of VEGF and HIF-1α—Final results of the ALICE-2 study.
Authors: Luca Faloppi, Andrea Casadei Gardini, Gianluca Masi, Nicola Silvestris, Cristian Loretelli, Paola Ulivi, Caterina Vivaldi, Maristella Bianconi, Riccardo Giampieri, Alessandro Bittoni, Kalliopi Andrikou, Michela Del Prete, Mario Scartozzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2016)

280 Background: HIF-1α plays a crucial role in tumour angiogenesis triggering the transcription of several genes including VEGF. The overexpression of HIF-1α in HCC is associated with tumour angiogenesis, invasion, metastasis, treatment resistance and poor prognosis. The therapeutic stronghold of advanced HCC is the TKI sorafenib. In our previous report (ALICE-1 study) SNPs rs2010963 and rs4604006 of VEGF have been shown to predict clinical outcome in HCC patients treated with sorafenib. Methods: 210 patients from a multicentre database were eligible for our analysis. Tumour samples were tested for 8 HIF-1α SNPs. Patients PFS and OS were analysed. Results: At univariate analysis CC &gt; AA+AC of rs1951795, TT &gt; CC+CT of rs10873142, AA+AG &gt; GG of rs12434438 SNPs of HIF-1α were statistically significant for PFS and OS. The extended analysis of VEGF and VEGFR SNPs confirms the results of ALICE-1 study. At multivariate analysis rs12434438 of HIF-1α, rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors. At the combined analysis of significant SNPs the presence of 2 favourable alleles of rs2010963 and rs4604006 of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p &lt; 0,0001) and OS (respectively: 19.0 vs. 13.5 vs. 7.5 months; p &lt; 0,0001). Furthermore the presence of GG genotype of rs12434438 (HIF-1α) select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs (PFS: 2.6 months, p &lt; 0,0001; OS: 6.6 months, p &lt; 0,0001). Conclusions: This investigation on HIF-1α SNPs, following our previous discoveries on VEGF and VEGFR, may represent a clinical tool to identify patients with favourable response to sorafenib. In the presence of a favourable genotyping, clinicians would administer sorafenib as soon as clinically indicated, instead of delaying it with other treatments. Conversely patients with unfavourable genotyping may not be optimal candidates for sorafenib. These patients should be preferably included in clinical trials exploring new treatment options.
Oxaliplatin- or irinotecan-based combination therapy versus 5-fluorouracil/leucovorin alone in the treatment of advanced colon cancer patients age 66 and older: An analysis using SEER-Medicare data.
Authors: F. S. Hsiao, C. D. Mullins, N. B. Pandya, E. Onukwugha, B. S. Seal, N. Hanna
Journal: Journal of Clinical Oncology (2010)

3613 Background: Clinical trials have demonstrated a survival benefit of oxaliplatin (OX)- or irinotecan (IRI)-based combination chemotherapy regimens for treatment of stage IV colon cancer patients. Increasingly, patients, physicians, insurers, and policy decision-makers are requesting comparative effectiveness research (CER) to assess the relative benefits of chemotherapies for stage IV colorectal cancer in real world settings. Methods: This retrospective cohort study investigated the impact of chemotherapy regimens, comparing OX or IRI based combination therapy to 5-fluorouracil/leucovorin (5FU/LV) alone, on stage IV colorectal cancer survival using surveillance, epidemiology, and end results (SEER)-Medicare data from 1997 to 2007 for patients diagnosed through 2005. The primary outcomes of interest were survival time from initiation of chemotherapies to all-cause death survival, colon cancer-specific death, and non-colon cancer death. Cox proportional hazards models were used to assess the association between chemotherapies and survival. Results: Patients were categorized into 5FU/LV (n = 2,834), OX-based (n = 621), and IRI-based (n = 945) subgroups, based on the regimen they received. After adjusting for demographic factors, comorbidities and cancer-related factors, there were improved overall survival associated with both combination regimens, specifically OX-based regimen (HR, 0.637; 95% CI, 0.545-0.745; p < 0.0001) and IRI-based regimen (HR, 0.795; 95% CI, 0.655-0.966; p = 0.021) compared to 5FU/LV. Colorectal cancer-specific survival also was better with combination regimens [OX-based regimen (HR, 0.481; 95% CI, 0.384-0.604; p < 0.0001) and IRI-based regimen (HR, 0.671; 95% CI, 0.535-0.843; p = 0.001)]. There was no association between OX-based or IRI-based regimen and non-colon cancer survival compared to 5FU/LV alone. Conclusions: Real world CER results reinforce clinical trial results of improved overall survival and colon cancer specific survival of combination therapies using OX or IRI compared with 5FU alone among elderly stage IV colon cancer patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis AHIMA Foundation, Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis
Technetium-99m sulfur colloid (TSC) as a phenotypic probe for the pharmacokinetics (PK) and pharmacodynamics (PD) of pegylated liposomal doxorubicin (PLD) in patients (pts) with recurrent epithelial ovarian cancer (EOC).
Authors: M. D. Walsh, H. Giovinazzo, A. Sheikh, M. Ivanovic, A. B. Whitlow, S. E. Newman, N. M. La-Beck, R. J. Kowalsky, B. A. Zamboni, D. L. Clarke-Pearson, W. R. Brewster, L. Van Le, V. L. Bae-Jump, P. A. Gehrig, W. Zamboni
Journal: Journal of Clinical Oncology (2011)

2582 Background: There is significant inter- and intra-patient variability in the PK and PD (efficacy and toxicity) of PLD in pts with EOC and other malignancies. This has been attributed to age and gender, but more specifically, may be related to the mononuclear phagocyte system (MPS). Clearance (CL) of PLD has been proposed to occur primarily via uptake by monocytes, dendritic cells, and macrophages mainly located in the liver, spleen, and blood. TSC is a radioactive colloid used clinically for diagnostic and functional imaging of the MPS. Our aim is to evaluate TSC as a phenotypic probe of MPS activity, which may predict PLD PK and PD in pts with EOC. Methods: Prior to (day -7 to -1) administration of PLD on cycle 1 day 1 (C1D1), TSC was administered at 10 mCi IV × 1. Dynamic planar and SPECT/CT images of the liver and spleen were acquired using a gamma camera. Blood samples were collected up to 60 min after TSC and analyzed for radioactivity using a gamma counter. On C1D1, PLD was administered at 40 mg/m2 alone or at 30 mg/m2 in combination with carboplatin IV over 1 to 1.5 h. Serial blood samples were collected up to 28 days after PLD. Plasma samples were processed to measure encapsulated (encap) and released doxorubicin via HPLC with fluorescence. Results: Six pts have undergone TSC imaging and blood PK, and PLD plasma PK studies. Mean ± SD encap doxorubicin CL and TSC CL were 25.4 ± 4.1 mL/h and 18.9 ± 5.4 mL/h, respectively. There was a positive linear relationship between TSC CL and encap doxorubicin CL (R2 = 0.58). Mean ± SD of encap doxorubicin area under the concentration versus time curve (AUC) and TSC splenic outflow were 2.4 ± 0.5 mg/mL·h and 0.5 ± 0.1 s-1, respectively. There was a positive linear relationship between TSC splenic outflow and encap doxorubicin AUC (R2 = 0.85). There was no relationship between TSC AUC in the liver and spleen and PLD PK. Conclusions: These results suggest that TSC is a probe for MPS function and PLD PK and may be used to individualize PLD therapy in pts with EOC and other malignancies. Evaluation of the relationship between TSC and PLD PD is undergoing further investigation.
Long-term outcomes of active surveillance for prostate cancer: 10 years later.
Authors: David D. Buethe, Christopher Russell, Binglin Yue, Hui-Yi Lin, Julio M. Pow-Sang
Journal: Journal of Clinical Oncology (2013)

170 Background: Prostate cancer (CaP) has exhibited a downward stage migration during the PSA era. Approximately 70% of those newly diagnosed with CaP, harbor tumors of low-risk. Such tumors often prove to be of low-volume and of clinical insignificance at time of radical prostatectomy (RP), suggesting over treatment and excessive exposure to the morbidity associated with definitive management. Over the last decade, active surveillance (AS) strategies have become a more accepted practice when addressing low-risk tumors. We present the long-term oncologic outcomes of patients placed on AS. Methods: An IRB approved retrospective chart review identified 114 patients placed on AS for their CaP between November of 1997 and November of 2000. Of those, 96 patients meet study inclusion criteria mandating a Gleason sum of &lt; 7, tumor presence in &lt; 4 sextets, and involvement of &lt;50% of any single biopsy core. Eligible patients were surveyed by serum PSA , digital rectal exam, and surveillance transrectal ultrasound (TRUS)-guided biopsies at physician determined intervals. Results: At diagnosis, the mean age was 70.3 (SD±5.3) years with a mean PSA value of 8.2 (SD±8.2) ng/dL. Surveillance patterns approached acquisition of a PSA at a mean of 9 months and a TRUS-guided biopsy of the prostate every 1.5 years. The median total number of PSA’s and biopsies obtained while on surveillance were 6.0 (SD±5.72) and 3.5(SD±2.02), respectively. At a median follow-up of 134.8 months (95%CI: 114.5, 148.7), 52 (54%) of patients had been reclassified or demonstrated disease progression. The median progression-free and overall survival for the cohort were 68.7 (95%CI: 53.2, 97.3) months and 156.9 (95%CI: 139.9, 161.5) months, respectively. Only one prostate cancer specific mortality was identified. Conclusions: AS presents a reasonable management strategy option for low-risk prostate cancer in appropriately selected patients. However, treatment at time of disease progression did not improve survival. A significant percentage of men on AS are exposed to progression of their disease if alive beyond 10 years from their diagnosis.
A phase II trial with cetuximab, bevacizumab, and irinotecan for patients with primary glioblastomas and progression after radiation therapy and temozolamide
Authors: U. Lassen, B. Hasselbalch, M. Sørensen, M. Holmberg, S. Hansen, M. Kosteljanetz, H. Laursen, H. S. Poulsen
Journal: Journal of Clinical Oncology (2008)

2056 Background: Recent data has shown that bevacizumab (B) and irinotecan (I) induces significant responses in recurrent GBM. Primary GBM is very often associated with amplification of EFGR (40–50%) and alterations in the EGFR gene. In vivo experiments have shown that cetuximab (C) increases apoptosis, decreases cell proliferation and decrease vascular endothelial growth factor expression in EGFR-amplified GBM cells in vitro. The use of the combination of C and I has shown a significantly higher response rate compared to irinotecan as monotherapy in colorectal cancer. In addition, adverse events (AE) have been acceptable and the BOND-2 study has shown the feasibility of combining C, B and I. In this phase II study we examine the safety and efficacy of CBI in recurrent GBM. Methods: Patients (pts) with recurrent GBM after standard primary treatment (surgery/biopsy, followed by radiotherapy and temozolamide) were included after signed informed consent and standard inclusion criteria. The pts received C 400 mg/m2 on day 1, followed by weekly C 250 mg/m2; B 10mg/kg every other week (first 10 pts received 5 mg/kg) and I 125 mg/m2 in pts not treated with enzyme inducing antiepileptic drugs (EIAED) or 340 mg/m2 in pts treated with EIAED, every other week. Evaluation was performed according to MacDonald criteria with MRI every 8 weeks and safety according to CTCAE v.3.0. Results: A total of 32 pts were included between August 2006 and January 2008. After safety analysis of the first 10 pts B was increased from 5 to 10 mg/kg and this regimen was well tolerated. 3 pts experienced grade III-IV allergic reaction during first C administration despite pre-medication. In January 2008, 27 were evaluable for response. One CR and 8 PR were observed (RR 33%) and 5 pts (19%) had minor responses (25–50% regression and clinical improvement). Median TTP was 24 weeks. Five pts had thromboembolic complications. Conclusions: The CBI regimen was well tolerated, with encouraging response rates, including 1 CR. However, the efficacy of the combination seems to be similar to BI alone, therefore is further evaluation of this regimen not planned. No significant financial relationships to disclose.
The Risk of Organ Specific Graft-Versus-Host Disease Can Be Predicted by the Multiple Single Nucleotide Polymorphism Based Predictive Models.
Authors: Dennis Dong Hwan Kim, Hong-Hee Won, Wei Xu, Jieun Uhm, Vikas Gupta, John Kuruvilla, Hans A. Messner, Jeffrey H. Lipton
Journal: Blood (2012)
Oral nelfinavir before and during radiation therapy for rectal cancer: Changes in tumor perfusion and correlation between tissue and radiological markers of response.
Authors: Esme J. Hill, Monica Enescu, Nicholas West, Jamie M. Franklin, Kwun-Ye Chu, Jun Li, Deborah Whittington, Thomas P. Macgregor, Shazad Ashraf, Claire Blesing, Somnath Mukherjee, Margaret Betts, Andrew Slater, Ewan M. Anderson, Gina Brown, Julia A. Schnabel, Mike Partridge, Philip Quirke, Ricky A. Sharma
Journal: Journal of Clinical Oncology (2014)

491 Background: Nelfinavir, an inhibitor of AKT in the PI3-kinase pathway, is a radiosensitizer which increases tumor blood flow and reduces hypoxia in preclinical models. We conducted a pilot study of nelfinavir before and during hypofractionated pelvic radiotherapy (RT) in patients with rectal cancer to evaluate the safety of the combination, changes in tumor perfusion and a tissue biomarker of radiosensitization, tumor cell density (TCD). Methods: Eight patients with T3-4 N1-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Safety was evaluated by CTCAE v 4.0. Dynamic contrast enhanced (DCE) CT and MRI scans were performed pre-treatment, after 7 days nelfinavir and prior to last fraction of RT. TCD was performed in biopsies taken pre-treatment and 7 days post-radiotherapy (West N et al. Br J Cancer. 2010, 102; 1519-23). Radiological response and tumor regression grade (TRG) was assessed on MRI 8 weeks from end of RT (Patel UB et al. J Clin Oncol. 2011, 29:3753-60). Results: This was the first clinical trial to combine nelfinavir with hypofractionated RT. There were 3 grade 3 adverse events (diarrhea, rash, lymphopenia). After 7 days of nelfinavir, there was a 40% increase in mean K trans on DCE-MRI (p = 0.029, paired t test). On DCE-CT, there was a 30% increase in mean blood flow from before RT to the last day of RT (p = 0.028). The median TCD in biopsies decreased from 41.2% (IQR = 23.5, 53.0%) at baseline to 9.2% (IQR = 2.8, 18.2%) after RT (p = 0.007, paired t test). By RECIST criteria, 3/8 patients treated had complete radiological responses and 4/8 had partial responses. TRG was associated with the magnitude of decrease in TCD measured in paired biopsies for individual patients (p = 0.029, Fisher’s Exact Test). Conclusions: These data suggest that the radiosensitizing drug, nelfinavir, can increase blood flow to rectal cancer when given prior to RT. Nelfinavir added to hypofractionated pelvic radiotherapy has acceptable toxicity and is associated with radiological and tissue biomarker responses. Funded by Oxford NIHR BRC, OCIC, Yorkshire Cancer Research, Oxford and Leeds ECMCs. Clinical trial information: 2010-020621-40.
Effect of zoledronic acid exposure on Ki-67 expression and proliferation in MCF7 cells resistant to apoptosis induction.
Authors: U. Haus, R. Ebert, J. Meissner-Weigl, S. Zeck, L. Klein-Hitpass, T. D. Rachner, P. Benad, A. Athari, L. Hofbauer, F. Jakob
Journal: Journal of Clinical Oncology (2011)

e21129 Background: Bisphosphonates (BP) and the RANK-ligand antibody denosumab (D) are used for the treatment of bone metastases. Low to high concentrations of zoledronic acid (ZA) can induce tumor cell apoptosis in vitro via inhibition of the mevalonate pathway and/or accumulation of the ATP analog ApppI. Clinical studies indicate a benefit in tumor relapse and survival with the supportive treatment of ER-positive breast cancer using zoledronate (ZA), but the molecular mechanisms involved are under debate. Methods: MDA-MB-231 and MCF-7 breast cancer cells were treated for 3 h (pulse treatment) and 72 h (permanent treatment) with 5 – 100 µM ibandronate (IBN), alendronate (ALN), risedronate (RIS) and ZA and 1 – 100 ng/ml D for comparison. Apoptosis and proliferation was determined after 72 h. Rescue experiments for the BP effects were done using geranylgeranyl-pyrophosphate (GGPP) and atorvastatin (Ator). Microarray hybridizations were performed to identify target genes in MCF-7. Results: Permanent and pulse exposure to ZA induced apoptosis in MDA-MB-231 and inhibited proliferation in MCF-7 without affecting apoptosis. While IBN, ALN and RIS were inferior to ZA in apoptosis induction in MDA-MB-231, they were equipotent in proliferation inhibition in MCF-7. GGPP rescued ZA effects in MDA-MB-231 but not the antiproliferative effects in MCF-7, while Ator rescued the latter. qPCR and immunocytochemistry identified KLF2, KLF4, KLF6 and Ki-67 as target genes of ZA in MCF-7. RANKL did not induce proliferation in MCF-7 cells and D did not affect the untreated or RANKL pretreated cells in terms of proliferation and apoptosis. Conclusions: In summary we show here direct effects of ZA and other BP on cell proliferation and expression of tumor relevant genes in MCF-7 cells, which are relatively resistant to ZA-induced apoptosis in comparison with MDA-MB-231. Ator but not GGPP rescued these effects, possibly indicating that these effects are rather due to the accumulation of ATP analogs than to the inhibition of protein prenylation. D had no effects under these basal conditions but future experiments should address the effects in the context of estrogens and gestagens and also in coculture with bone cells.
Variations in the perioperative management of pancreatoduodenectomy between academic and community institutions: An IHPBA/AHPBA web-based survey.
Authors: Sandeep Anantha, Fransisco Igor Macedo, Alice J Race, Awinderpreet Singh, Vijay K Mittal, Janak A Parikh, Michael J Jacobs
Journal: Journal of Clinical Oncology (2016)

448 Background: Pancreatoduodenectomy is the surgical treatment for pancreatic head and periampullary malignancy and is performed by surgeons practicing in all kinds of hospital settings, academic, community and hybrid. The perioperative management is varied amongst surgeons owing to diverse training experience. We aim to evaluate these variations by comparing the hospital settings. Methods: A pilot 25-item survey questionnaire was electronically distributed using Survey Monkey to IHPBA and AHPBA members between May and August 2015 regarding practice patterns and perioperative care of pancreatoduodenectomy. Results: We received 285 responses with participants from academic (56.1%), community (12.6%) or hybrid institutions (31.2%). Most participants performed 10-25 cases annually in each group (46.9%, 50%, 51.7%, respectively). Surgeons from academic institutions routinely culture bile intraoperatively more often than in community institutions (46.3% vs. 22.2%, p&lt;0.01). However, surgeons from community programs tend to continue prophylactic antibiotics beyond 24 hours (30.6% vs. 44.4%, p&lt;0.01) and are more likely to use antibiotic abdominal irrigation (2.5% vs. 11.1%, p&lt;0.01) as compared to those from academic institution. Routine postoperative culture and measurement of amylase rich drain fluid, types of drains (self-suction or gravity), length of postoperative antibiotic regimen, type of skin closure and wound care were statistically similar Conclusions: Our survey included a wide range of members from academic, community and hybrid centers. Practice patterns vary significantly among surgeons practicing in academic, community or hybrid institutions and are not standardized. Further studies are warranted to elucidate the impact of these variations on surgical outcomes of patients undergoing pancreatoduodenectomy.
Pathologic complete response rates following neoadjuvant chemotherapy in the treatment of locally advanced breast cancer.
Authors: S. R. Prabhudesai, A. V. Malini, R. M. Raghavendra, N. R. Ashwini, V. P. Geetha, S. Patil, R. B. Diwakar, K. S. Gopinath, B. S. Srinath, N. Raizada, B. Somorat, R. Naik, S. P. Giri, B. S. Ajaikumar
Journal: Journal of Clinical Oncology (2011)

e11012 Background: Patients who achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) for locally advanced breast cancer have favorable disease-free survival rates. In this study we analyzed if number of NACT cycles have any influence on pCR. Methods: We analyzed 98 breast cancer patients with LABC for pCR treated with NACT followed by surgery. Pathological response was determined using NSABP grading in both the breast tissue and axillary lymph nodes in these patients. Patients received anywhere between 2 cycles to 6 cycles with anthracycline and taxane based NACT. Results: The likelihood ratio of a pCR (17.7%, χ2=9.4, p=0.009) and lymph node negativity (23%, χ2= 4.34, p=0.04) in node positive disease was significant in subjects receiving more than three cycles of NACT vs. those receiving less than 3 cycles. Type of chemoprotocol used did not seem to influence pCR. In subjects with an initial node positive disease there were significant chemotherapy related pathological changes (fibrosis, desmoplasia, necrosis) with more than 3 cycles of NACT (80.8%, χ2=3.8, p=0.05). Log rank Mantel Cox test showed significant pCR (χ2=7.29, p=0.03) with equality of response distributions for different levels of tumor T size. Conclusions: The study indicates a favourable pCR for more than 3 cycles of NACT especially in node positive tumors irrespective of tumor size. Molecular markers that predict pCR to NACT are needed.