tbuckley/cabot-search huggingface dataset:
Effect of preoperative antiangiogenic treatment and subsequent discontinuation on angiogenesis in the primary tumor in patients with RCC.
Authors: Axel Bex, Arjan W. Griffioen, Laurie A. Mans, Annemarie M. A. de Graaf, Patrycja Nowak-Sliwinska, Steven Bosch, Celine de Hoog, Trees A. M. de Jong, Florry Vyth-Dreese, Eric Jonasch
Journal: Journal of Clinical Oncology (2012)

350 Background: Angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy has not been previously studied. Methods: A total of 57 primary tumor samples from various retrospective and prospective studies of presurgical sunitinib or bevacizumab were used. In these studies targeted therapy was given with the primary tumor in situ prior to cytoreductive nephrectomy, to investigate impact of therapy on primary tumors. Primary tumor tissues were assessed for microvessel density (MVD), proliferating endothelial cells, pericyte coverage, apoptosis of tumor or endothelial cells and molecular expression of angiogenesis regulators. Results of tumors pretreated with sunitinib discontinued at different intervals before surgery, were compared to similar analyses of untreated and bevacizumab-pretreated tumors. Results: Sunitinib and bevacizumab pretreatment resulted in a significant reduction of MVD, as well as an increase in vascular pericyte coverage in the primary tumor (sunitinib samples) consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis were found to be suppressed in sunitinib pretreated tissues, among which VEGFR-1 and -2, angiopoietin-1 and -2 and PDGF-B. Apoptosis was induced both by sunitinib and bevacizumab pretreatment. Interestingly, in sunitinib pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab pretreated and untreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment. Conclusions: This study describes the antiangiogenic response in human primary renal cancers upon treatment with VEGF targeted therapy. Treatment discontinuation of tyrosine kinase inhibitors with short half life leads to accelerated angiogenesis. The results of the current study contribute important data to the ongoing discussion on the discontinuation of treatment with tyrosine kinase inhibitors.
Predicting toxicities from adjuvant treatment in a population-based cohort of early colon cancer (CC) patients (pts): A strategy to improve use of curative chemotherapy.
Authors: Gillian Gresham, Jasleen Sidhu, Navraj Malhi, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

412 Background: CC pts treated with chemotherapy are at risk of experiencing a number of toxicities. The identification of pts who may be at a higher risk of developing toxicities allows clinicians to be more vigilant in preventing and managing side effects early, thus enabling more optimal delivery of chemotherapy. Our aim was to determine clinical factors associated with toxicities from adjuvant FOLFOX in early CC. Methods: Pts diagnosed with stage III CC from 2005 to 2008, seen at any 1 of 5 regional cancer centers of the British Columbia Cancer Agency, and treated with adjuvant FOLFOX chemotherapy were reviewed. We evaluated various toxicities, including gastrointestinal, hematologic, cardiovascular, and neurological side effects. Baseline and clinical factors were assessed in univariate and multivariate models to determine potential predictors for each of the different chemotherapy toxicities. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged &gt;70 years, and 54.5% were men. In terms of function, the majority (90.1%) was ECOG 0/1. Time to adjuvant chemotherapy (TTAC) &gt;8 weeks (OR 1.91, 95% CI 1.8-3.1, p=0.006) and renal dysfunction with a GFR &lt;50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038) were significantly associated with higher odds of any GI toxicity. Likewise, TTAC &gt;8weeks (OR 2.8, 95% CI 1.5-5.2, p=0.002), ECOG PS &gt;1 (OR 2.86, 95% CI 1.2-6.7, p=0.016), and low white blood cell count &lt;6.4 (OR 2.32, 95% CI 1.3-4.0, p=0.0043) were correlated with a greater risk of significant neutropenia. Multiple toxicities were more prevalent among those who waited &gt;8 weeks to initiate adjuvant FOLFOX (OR 1.69, 95%CI 1.1-2.7, p=0.03). Further, advanced age &gt;70 years was an indepenent risk factor for worse nausea and diarrhea. Conclusions: Consideration of important baseline characteristics such as TTAC, advanced age, renal function, and specific laboratory parameters when recommending adjuvant FOLFOX can be useful in identifying patients with increased likelihood of toxicities. This group of patients may benefit from increased monitoring in order to enable optimal doses of curative chemotherapy to be delivered.
Methylated <i>BCAT1</i> and <i>IKZF1</i> DNA in tissue and plasma from colorectal cancer cases.
Authors: Erin L Symonds, Rohan Baker, Dawn Bastin, Libby Bambacas, Susan Byrne, Graeme P Young, Susanne Kartin Pedersen
Journal: Journal of Clinical Oncology (2016)

543 Background: We have previously described a 2-gene blood test based on the detection of methylated BCAT1 and IKZF1 for colorectal cancer (CRC). This study explored the relationship between the presence of these methylated DNA biomarkers in plasma and tissue from CRC patients. Methods: Blood (pre-resection) and samples of tumor and adjacent non-cancer tissue (NCT) were collected from 75 patients diagnosed with CRC. Extracted DNA was assessed for presence of methylated BCAT1 and IKZF1. Results: Methylated BCAT1 and IKZF1 were detected in 68 (91%) and 69 (92%) tumor tissues, respectively, with one or both methylation biomarkers being present in 74 (99%) of the 75 tumor tissues. Combined methylation levels (mean %methylated DNA per 5ng total DNA) were significantly higher in tumor than NCT: 56% methylated DNA (95%CI: 47-67) versus 3% (2.7-4) (t-test, p &lt; 0.001). In the matching plasma samples, methylated BCAT1 and IKZF1 were detected in 35/75 and 36/75, respectively, with a combined presence of 48/75 (64%; 95%CI: 52-75). Appearance of methylated BCAT1/IKZF1 DNA in plasma and tissue was not significantly correlated (p &gt; 0.05). Tissue methylation levels were independent of morphology, whereas the presence of biomarkers in plasma was associated with tumor size (Chi 2 p = 0.02) and depth of invasion (Chi 2 p = 0.003). There was no association with tumor differentiation, lymphovascularity or lymph node invasion. The one tumor tissue sample negative for BCAT1/IKZF1 methylation was also negative in plasma. For one metastatic case, primary tumor, plasma and liver samples were available and analysed, which confirmed methylated BCAT1/IKZF1 in all samples. It is worth noting that no methylation was detected in adjacent non-cancer liver tissue. Conclusions: BCAT1 and IKZF1 are highly methylated in tumor tissues, regardless of morphology. The low methylation levels in the surrounding NCT suggest that these changes are tumor specific with no obvious field effect. Appearance of the methylated biomarkers in blood depends on the primary tumor displaying invasive morphological features indicative of the tumor having access to shedding into the blood stream.
Phase II multicenter study of nonpegylated liposomal doxorubicin (A) and docetaxel (T) as neoadjuvant chemotherapy in patients with stage II - III and inflammatory breast cancer (BC)
Authors: R. Andres, J. M. Garcia-Bueno, A. Modolell Catalina Madroñal, J. I. Mayordomo, I. Machengs M Centelles, J. Belon, H. Palombo, M. Burillo, I. Alvarez, R. Lastra Eugenia Ortega Elena Aguirre
Journal: Journal of Clinical Oncology (2005)

798 Background: AT is one of the most active chemotherapy regimens for BC. This study was designed to evaluate clinical and pathological response rates and toxicity of neoadjuvant AT in patients with BC. Methods: Patients with histologically confirmed BC (stage II-III or inflammatory), age > 18 years, left ventricular ejection fraction > 45% and adequate bone marrow, renal, and hepatic function were eligible. Radiotherapy, surgery, and prior systemic therapy for BC were not allowed. Treatment: T (75 mg/m2, iv) and A (Myocet) (75 mg/m2, iv) on day 1, every 21 days for 4 courses, followed by surgery. G-CSF (5 mcg/kg/day) was administered on days 5–9 of each cycle. Results: Of the 36 patients enrolled to date, 25 with mature data were included in this interim analysis. Median age was 54 years (range, 34–76); 88% had ECOG PS 0; 12% had ECOG PS 1; 71% were peri-postmenopausal; 38% were ER/PR+, 17% ER+ and 4% PR+. In 84 cycles delivered (median 4, range 2–4), median RDI was 98% for T and for A. Grade 3–4 hematologic toxicities per patient were neutropenia (9%), leukopenia (4%), thrombocytopenia (4%), and febrile neutropenia (13%). Grade 3–4 non-hematologic toxicities were nausea (9%), infection (9%), asthenia (4%) and arthralgia (4%). Six patients were not evaluable for response (3 too early, 2 consent withdrawal, 1 lost of follow-up). Of 19 evaluable patients, 4 achieved CR (21%), 9 PR (48%), 5 SD (26%), and 1 PD (5%), resulting in an ORR of 69% (95% CI: 48–89). Of the 15 patients who underwent surgery, 1 (7%) was found to have a pCR. Conclusion: Docetaxel plus A (Myocet) every 21 days for 4 cycles as neoadjuvant chemotherapy is an active and well-tolerated regimen for stage II and III and inflammatory BC. No significant financial relationships to disclose.
Pilot trial of adjuvant paclitaxel (T) and estramustine phosphate (EMP) for high-risk prostate cancer patients after radical prostatectomy (RP)
Authors: G. M. Lubiniecki, S. B. Malkowicz, M. Hendricks, L. Bearn-Miranda, K. van Arsdalen, A. Wein, D. J. Vaughn
Journal: Journal of Clinical Oncology (2005)

4775 Background: A previous study from our center demonstrated that preoperative prostate specific antigen (PSA) and prostatectomy pathology can identify patients with a high risk of 2-year PSA failure (D’Amico, et al., J. Urology, 1998). We hypothesize that chemotherapy active in hormone-refractory prostate cancer could decrease this risk. We are performing a pilot trial of adjuvant T plus EMP in patients with a 2-year PSA failure risk of ≥50%. Methods: Men within 12 weeks of RP with a ≥50% predicted risk of 2-year PSA failure, as predicted by the above study, received T 90mg/m2 days 2, 9, and 16 every 28 days, and EMP 420mg orally days 1–3, 8–10, and 15–17 every 28 days. Four cycles were given. Men were followed with serial PSA examinations every three months after completing therapy. Results: As of December 2004, 15 patients have been accrued. Median age: 60 (51–69). Median predicted 2-year PSA failure risk: 70 (52–99). 13 patients have completed therapy with a median follow-up of 12 (1.5–31) months. Prolonged neutrophil recovery required a dose reduction of therapy in 1 patient. There were no grade 4 adverse events. Grade 3 toxicities included a deep venous thrombosis (1 patient). 3 patients have had PSA failure (pretreatment risks: 70%, 80%, 99%) at 17, 17, and 11 months, respectively. They have been treated with salvage radiation therapy to the prostatic bed (3 patients) and salvage hormonal therapy (2 patients). Conclusions: It is feasible and safe to administer adjuvant weekly paclitaxel and estramustine phosphate to men after RP. Further patient enrollment and follow-up are required for assessment of risk reduction (Supported by Bristol-Myers Squibb). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
A randomized phase II trial of capecitabine plus cisplatin (XP) versus S-1 plus cisplatin (SP) as a first-line treatment for advanced gastric cancer: XP ascertainment versus SP randomized PII trial (XParTS II).
Authors: Michiya Kobayashi, Akira Tsuburaya, Kazuhiro Nishikawa, Junji Kawada, Tsutomu Namikawa, Ryoji Fukushima, Hiroshi Kojima, Kazuaki Tanabe, Kazuya Yamaguchi, Shigefumi Yoshino, Masazumi Takahashi, Naoki Hirabayashi, Seiji Sato, Hiroshi Nemoto, Yasushi Rino, Takaki Yoshikawa, Junta Nakajima, Satoshi Morita, Junichi Sakamoto
Journal: Journal of Clinical Oncology (2015)

105 Background: Capecitabine plus cisplatin (XP) is a standard global regimen for first-line treatment of advanced gastric cancer, however its efficacy compared to S-1 plus cisplatin (SP), a standard treatment in Japan has not been reported. To evaluate the efficacy of XP treatment, we conducted a multicenter randomized phase II trial comparing XP with SP for patients with advanced gastric cancer (ClinicalTrials.gov Identifier NCT0140624). Methods: Patients with unresectable metastatic or recurrent gastric cancer, 20–74 years of age and HER2-negative, were assigned to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), time to treatment failure, overall response rate (ORR) and safety. Planned sample size was 100 (50 in each arm) according to PFS at 24-weeks. Immunohistochemical evaluation of biomarkers was also implemented. Results: From November 2011 to June 2013, 116 patients were randomized: median age, 65 years; 79 (68%) male; 63 intestinal and 53 diffuse cancer subtypes. In 109 eligible patients, 24-week %PFS was higher in both groups than the protocol-specified threshold of 40%. Median PFS for SP vs. XP was 25 weeks vs. 23 weeks (HR, 0.76; 95%CI, 0.5-1.16; p=0.203); OS was 58 weeks vs. 56 weeks (HR, 0.90; 95%CI, 0.52-1.57; p=0.712); and ORR was 27.5% vs. 32.7% (p=0.562), respectively. Sub-group analysis by histological classification showed that SP gave better PFS than XP in the diffuse type (HR, 0.42; 95%CI, 0.20-0.86; p=0.015) with no other statistical difference. Most common grade ≥3 adverse events with SP and XP were anemia (16%/ 19%), neutropenia (9%/17%), anorexia (18%/13%), diarrhea (11%/0%), nausea or vomiting (11%/15%), fatigue (5%/6%) and hyponatremia (7%/13%), respectively. Conclusions: XP and SP are comparable and can be recommended as 1 st line treatments for advanced gastric cancer. Further analysis for biomarkers related to histology is warranted. Clinical trial information: NCT0140624.
Physical activity to counteract the impact of alcohol intake on overall mortality risks
Authors: Johanna M Gostner, Dietmar Fuchs, Barbara Strasser
Journal: British Journal of Sports Medicine (2017)

In their excellent study1 based on eight British population-based surveys, Perrault and coworkers report on a direct association between alcohol consumption and cancer mortality risk starting from drinking within guidelines versus hazardous drinking and that this association was attenuated among individuals who met the physical activity recommendations. The authors concluded that there are several biological mechanisms by which alcohol is believed to contribute to carcinogenesis, and that the preventive effect of physical activity originates from affecting the same processes, but driving the responses in the opposite direction.

Manipulation of oxidative stress and inflammatory …
A phase II trial of continuous-infusion 5-fluorouracil, mitoxantone and cisplatin for metastatic hepatocellular carcinoma
Authors: M. Ikeda, T. Okusaka, H. Ueno, Y. Takezako, C. Morizane
Journal: Journal of Clinical Oncology (2004)

4081 Backgrounds: Chemotherapy for hepatocellular carcinoma (HCC) has only limited value in clinical practice, because no chemotherapy regimen has been shown to have predictable activity against this cancer. The aim of this study was to evaluate the anti-tumor activity and toxicity of continuous-infusion 5-fluorouracil, mitoxantone and cisplatin (FMP therapy) in chemo-naïve patients with metastatic HCC. Methods: Fifty-one patients with metastatic HCC who had no prior systemic chemotherapy with measurable extrahepatic metastasis, adequate liver and renal function, and adequate bone marrow reserve were enrolled in this study. The therapy consisted of cisplatin 80 mg/m2 and mitoxantrone 6 mg/m2 intravenously on day 1, and continuous intravenous infusion 5-FU 450 mg/m2/day on days 1 through 5. Treatment was repeated every 4 weeks to a maximum of 6 courses with dose adjustments based on the toxic effects observed, if there was no evidence of tumor progression or unacceptable toxicity. Results: Of all 51 enrolled patients, 14 patients achieved a partial response (27%; 95% confidence interval, 17% to 54%) with a median duration of 7.6 months (range, 2.3 to 18.4). Twenty-seven patients (53%) showed no change and nine (18%) showed progressive disease. Serum AFP level was reduced more than 50% in only 21% of the patients who had shown a pretreatment level of 100 U/ml or greater, but serum PIVKA II level was reduced more than 50% in 58% of the patients who had a pretreatment level of 100 mAU/ml or greater. The median survival time, 1-year survival and median time to progression for all patients were 11.6 months, 44.5%, and 4.0 months respectively. The main grade 3 and 4 toxicities suffered by patients were leukocytopenia (67%), neutropenia (71%), thrombocytopenia (27%), glutamic oxaloacetic transaminase (37%), and glutamic pyruvic transaminase (41%). These toxicities were generally brief and reversible with the exception of one treatment-related death of acute hepatic failure due to neutropenic sepsis. Conclusion: FMP therapy has significant anti-tumor activity with tolerable toxicity in patients with metastatic HCC. No significant financial relationships to disclose.
Thrombocytosis as a predictor of poor prognosis in colorectal cancer patients.
Authors: Ravi Ramjeesingh, Amie Jones, Christine Orr, Corey Sean Bricks, Wilma M Hopman, Nazik Hammad
Journal: Journal of Clinical Oncology (2016)

540 Background: Thrombocytosis has been identified as a prognostic factor in many cancer types including ovarian, breast, and lung cancers. In colorectal cancer (CRC), the literature is divided. Several smaller case studies suggest a negative prognosis in CRC patients with pre-operative thrombocytosis, a larger population study contradicts this. Methods: We performed a retrospective chart review of CRC patients treated at the Cancer Center of Southeastern Ontario diagnosed from January 2005 to December 2011. 1304 confirmed CRC patient charts were identified and patient, tumor, blood work and treatment variables were extracted. Results: 1,096 patients had platelet count available at the time of oncology consult. 222 (20.3%) were characterized as having thrombocytosis (&gt;400x10 9 /L). No difference was identified between those with normal and with thrombocytosis with regards to age, sex, comorbidities, and BMI. However, a statistically significant difference was identified when looking at several pathological characteristics. Significantly more patients with thrombocytosis presented with stage 4 disease (p&lt;0.0001). Additionally less early T-stage (T1: p&lt;0.05, T2: p&lt;0.001), lymph node positivity (p&lt;0.05) and LVI (p&lt;0.05) was identified. Univariate analysis identified a significant difference in survival (1yr: 71.6% vs 88.1%, p&lt;0.0001; 2 yr: 58.1% vs 78.1%, p&lt;0.0001; 5yr: 48.2% vs 64.7%, p&lt;0.0001). Multivariate Cox regression analysis, identified a statistically significant effect of thrombocytosis on risk of dying (HR=1.434, C.I 1.153-1.784, p=0.001). A survival difference was primarily identified in the Stage 4 population (1yr: 55.8% with thrombocytosis vs 72.9% with normal platelet count, p=0.0058; 2 yr: 36.0% vs 50.2%, p=0.0388; 5yr: 26.7% vs 32.0%, p=0.4042). There were no differences in the number of metastatic sites or the number of days on chemotherapy to account for the survival difference. Conclusions: Thrombocytosis, at the time of oncology consultation appears to predict a lower chance of survival in CRC patients, especially in the stage 4 population. Further work is required to elucidate the mechanism of action between elevated platelet counts and survival.
N0234: Phase II study of erlotinib (OSI-774) plus gemcitabine as first-or second-line therapy for metastatic breast cancer (MBC)
Authors: D. L. Graham, D. W. Hillman, T. J. Hobday, S. R. Rousey, S. G. Nair, G. S. Soori, T. M. Sabagh, E. A. Perez
Journal: Journal of Clinical Oncology (2005)

644 Background: Based on favorable preclinical interaction of the HER1 inhibitor erlotinib with chemotherapy, and previously demonstrated single agent activity of gemcitabine as therapy for metastatic breast cancer (MBC), a phase II study of the combination was conducted by the North Central Cancer Treatment Group. Goals were to evaluate the anti-tumor activity and tolerability of erlotinib 150 mg P.O. daily in combination with gemcitabine at 1000 mg/m2 days 1 and 8 of 21 day cycles. Eligibility: MBC, measurable disease as defined by RECIST. Prior adjuvant chemotherapy and up to 1 prior chemotherapy for MBC allowed (1 of which had to include an anthracycline or taxane). Results: 59 evaluable patients were enrolled. Patient characteristics: median age: 57 (range: 28–82), prior adjuvant chemotherapy (68%), prior anthracycline (81%), prior taxane (78%), prior anthracycline and taxane (61%); 0 prior chemotherapy for MBC (44%), 1 prior chemotherapy for MBC (56%). Median number of cycles treatment administered: 4 (range: 1–17). Severe (CTC grade 3/4) hematologic adverse events: neutropenia (35%), thrombocytopenia (9%), and anemia (7%). Severe (CTC grade 3/4) non-hematologic adverse events: fatigue (14%), dyspnea (12%), diarrhea (9%), rash (7%), and infection (4%). 10 pts are still receiving study treatment (tx). Reasons for discontinuing tx: disease progression (76%), patient refusal (12%), adverse event (4%), new primary (2%), symptomatic deterioration (4%), and patient no return (2%). Response: 8 partial responses for an overall response rate of 14% (95% CI: 6–25%). Median duration of response was 4.6 months. At last contact, 12 pts were alive without progression and 28 alive with progression (median length of follow-up 4.3 months; max follow-up of 12 months), and 19 died. Median PFS was 2.8 months (95%CI: 1.9–4.2 months). The 6-month survival rate was 75% (95%CI: 63–89%). Conclusions: The combination of Erlotinib plus gemcitabine was well tolerated. This combination has lower than expected activity as 1st or 2nd-line therapy for MBC, based on historical controls of gemcitabine based combination treatment. Partial support by Breast Cancer Research Foundation and NIH (CA25224). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Pfizer
Comparison of Outcome of Unselected Patients with Diffuse Large B-Cell Lymphoma Diagnosed before and after Approval of Rituximab in France in This Indication.
Authors: Hervé Ghesquières, Catherine Sebban, Catherine Chassagne, Liana Carausu, Thérèse Gargi, Bertrand Favier, Irène Philip, Jean Yves Blay, Pierre Biron
Journal: Blood (2005)