tbuckley/cabot-search huggingface dataset:
S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: Updated results from a phase 3 trial.
Authors: Young Suk Park, Seung Kim, Yong Sang Hong, Ho Yeong Lim, Jeeyun Lee, Tae Won Kim, Kyu-Pyo Kim, Sun Young Kim, Ji Yeon Baek, Jee Hyun Kim, Keun-Wook Lee, Ik-Joo Chung, Sang-Hee Cho, Kyung Hee Lee, Sang Joon Shin, Hye Jin Kang, Dong Bok Shin, Sook Jung Jo, Jae Won Lee
Journal: Journal of Clinical Oncology (2014)

3608 Background: We report updated progression free survival (PFS) and overall survival (OS) data from the trial which compared capecitabine plus oxaliplatin (COX) vs S-1 plus oxaliplatin (SOX) for first line treatment with metastatic colorectal cancer. Methods: This trial was a randomised, two arm, non-inferiority phase 3 comparison of COX (capecitabine 1000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1) vs SOX (S-1 40mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1). The primary end point was to show non-inferiority of SOX relative to COX in terms of PFS. A follow-up exploratory analysis of PFS and OS was performed. Results: The intent to treat (ITT) population comprised 340 patients (SOX arm: 168 and COX arm: 172). Updated median PFS was 7.1 months (95% CI 6.4-8.0) in the SOX group and 6.3 months (4.9-6.7) in the COX group (hazard ratio[HR], 0.83 [0.66-1.04]; p=0.10). The median OS was 19.0 months (15.3-23.0) in the SOX group and 18.4 months (14.1-20.7) in the COX group (HR, 0.86 [0.68-1.08]; p=0.19). Subgroup analyses according to principal demographic factors such as sex. age, ECOG performance status, primary tumour location, measurability, previous adjuvant therapy and number of metastatic organs and liver metastasis showed no interaction between treatment and any characteristic. Conclusions: Updated survival analysis shows that SOX is similar to COX, confirming the primary analysis for PFS. The SOX regimen could be an alternative first line doublet chemotherapy strategy for patients with metastatic colorectal cancer. Clinical trial information: NCT00677443.
Timing of referral to genetic counseling among women with gynecologic or breast cancer.
Authors: Amy J Bregar, Terri Febbraro, Katina Robison, Jennifer Scalia Wilbur, Jessica Kent Laprise, Vrishali Lopes, Robert Duffy Legare, Ashley Stuckey
Journal: Journal of Clinical Oncology (2013)

1545 Background: The National Comprehensive Cancer Network (NCCN) has established guidelines delineating appropriate candidates for genetic counseling. While genetic predisposition is responsible for a small percentage of cancer, genetic referral at diagnosis may effect treatment decisions. We aim to determine factors associated with timing of referral in women with breast and gynecologic cancers. Methods: Patients from an academic women’s oncology program were identified who met a subset of NCCN referral criteria for genetic evaluation between 2004-2010 (ovarian cancer at any age, breast cancer ≤ 50 years of age, or uterine cancer &lt; 50 years of age). A retrospective chart review was conducted. Statistics were analyzed using SAS v. 9.2 (SAS Institute, Cary, NC); categorical variables were compared by chi-square or Fisher's exact test and continuous variables were compared by ANOVA. The study was approved by the hospital Institutional Review Board. Results: 820 women with cancer (26% uterine, 38% breast, 35% ovarian) were included. The overall referral rate was 22%; more breast than gynecologic cancer patients were referred (34% vs. 28%, p&lt;0.0001). Breast cancer patients were more often referred at diagnosis compared to women with uterine (p&lt;0.0001) and ovarian cancer (p=0.007). Early stage breast cancer patients were more often referred at diagnosis compared to women with late stages (p=0.03). Among ovarian cancer patients, those with late stages were more often referred at diagnosis compared to women with early stages (p=0.02). Age at diagnosis, family history, and parity were not associated with timing of referral. Among women with breast cancer, 26% of referred patients had a prophylactic contralateral mastectomy compared to 8% of those not referred (p&lt;0.0001). Conclusions: Genetic counseling is underutilized in breast and gynecologic malignancies. The timing of referral varies widely and genetic counseling may impact treatment decisions. Breast cancer diagnosis, early stage breast cancer, and late stage ovarian cancer are associated with earlier referral for genetic evaluation. Further research is needed to determine additional factors that may increase referral rates and impact timing of referral.
Phase I clinical trial of temozolomide and methoxyamine (TRC-102) in patients with advanced solid tumors.
Authors: Jennifer Rachel Eads, Smitha S. Krishnamurthi, Joel N. Saltzman, Neal J. Meropol, Joseph A. Bokar, Joseph Gibbons, Henry B. Koon, Neelesh Sharma, Panayiotis Savvides, John Pink, Yan Xu, Jan Hendrik Beumer, Pingfu Fu, Kristi Beatty, Donna Kane, Mary Beth Rodal, Julianne Czalkiewicz, John Riendeau, Stanton L. Gerson, Afshin Dowlati
Journal: Journal of Clinical Oncology (2015)

2558 Background: Temozolomide (TMZ) is an alkylating agent that generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) is a small molecule that potentiates TMZ by binding to apurinic and apyrimidinic sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of apurinic/apyrimidinic (AP) endonuclease. We conducted a phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Methods: Patients (pts) with advanced solid tumors, progression on standard treatment, and no CNS involvement were enrolled. A standard 3+3 design was used to assess TMZ (150-200 mg/m2 orally) and MX (15-150 mg/m2 IV). Dose Levels (DL) 1-3: TMZ day 1, MX day 4 in first 14 day cycle (C), TMZ days 1-5, MX day 1 in subsequent 28 day C; DL 4-7: TMZ days 1-5, MX day 1 of 28 day C. DLT period was 42 days for DL 1-3 and 28 days for DL 4-7. Tumor response assessed per RECIST and AEs by CTCv4. Pharmacokinetics (PK) of 1-hour MX infusion and comet assays on peripheral blood mononuclear cells were performed. Results: 38 pts were enrolled: 45% male, 82% white, 16% African American, 2% Asian, median age 59.5 years (38-76), mean number of C 2.9 (1-13). No DLTs were observed. Grade 3 AEs: fatigue (n = 2), lymphopenia (n = 2), anemia (n = 1), INR (n = 1), leukopenia (n = 1), neutropenia (n = 1), allergic reaction (n = 1), constipation (n = 1), psychosis (n = 1) and paranoia (n = 1). Late grade 4 AEs: thrombocytopenia (n = 2) and confusion (n = 1). Partial response was seen in 1 pt with pancreatic adenocarcinoma (PAC) (8 mo); prolonged stable disease in 1 pt with PAC (4 mo), pancreatic neuroendocrine tumor (NET) (9 mo), small bowel NET (5.5 mo), ovarian cancer (12.5 mo) and non-small cell lung cancer (5.5 mo). MX PK was linear with dose and was not affected by concomitant TMZ. Geometric means (SD) were: t½ 45.6 (11.5) h, Cl 31.7 (15.6) L/h/m2 (n = 31). Conclusions: TMZ 200 mg/m2 may be safely administered with MX 150 mg/m2 with minimal toxicity. Evidence of antitumor activity was observed, particularly in pancreatic adenocarcinoma and neuroendocrine tumors. Further studies assessing this drug combination are warranted. Clinical trial information: NCT00892385.
Standard personalized medicine platform integrating clinical genomics and patient-derived xenograft models for gastric cancer.
Authors: Han-Kwang Yang, Hyuk-Joon Lee, Yun-Suhk Suh, Min Jung Kim, Woo Ho Kim, Deukchae Na, Hansoo Park, Jong-Il Kim, Charles Lee
Journal: Journal of Clinical Oncology (2017)

120 Background: Research and development of patient-derived tumor xenograft (PDX) model has gradually increased for preclinical study as well as tailored treatment of patient individual. We report our experience of development and application of gastric cancer PDX model using NSG mouse. Methods: From May 2014, primary tumor tissue and corresponding normal mucosa were sampled immediately after gastrectomy to reduce ischemic time. Corresponding normal mucosa was obtained as far as possible from tumor. Size of samples for implantation is 2x2x1mm/unit. After harvest, these tissue were injected at both flank of NSG mouse (2 times of injection per each mouse). If engrafted primary tissue (P0) would not grow after 90 days of engraftment or grow up to 2,000mm 3 /unit, model was considered as graduated. Genomic profiles from exome and RNA sequencing was analyzed between human primary tumor and P0. Results: We implanted gastric cancer tissue from 341 patients, and identified 135 P0 cases as tumor growth models (124 cases of primary tumor, 5 cases of metastatic nodes, and 6 cases of paired primary tumor and metastatic nodules). The mean time between fresh tissue sample and reposition at refrigerator was 18 min. The success rate of implantation was 39.6% (135/341). Out of P0 tumor growth models, 51 cases were diagnosed as adenocarcinoma, and 49 cases as lymphoid proliferation pathologically. Compaing pathologic and genomic data between primary tumors and P0 tumors identified as adenocarcinomas, we observed a similar frequency of genome-wide copy number (gain/loss) across overall cases. Moreover, genomic variations between each primary and P0 sample was also similar as shown in a Circos plot indicating somatic mutations, loss of heterozygosity and copy number variations. Relative high expression levels of cancer-related genes including MET and ERBB2 of primary tumors maintained in corresponding P0, when compared to expression levels in normal tissues. Conclusions: We successfully established gastric cancer PDX model which will be a useful tool for tumor biology study and the preclinical study in gastric cancer.
Scientific Drought, Golden Eggs, and Global Leadership — Why Trump’s NIH Funding Cuts Would Be a Disaster
Authors: Ingrid T. Katz, Alexi A. Wright
Journal: New England Journal of Medicine (2017)

President Trump’s proposal to cut the NIH budget has far-reaching implications for public and global health, research and drug development, and America’s economic growth. It also threatens young scientists who are academia and industry’s future leaders.
Identification of independent negative prognostic factors in stage IV non-small cell lung cancer.
Authors: Ahmed Ashour Badawy, Sejong Bae, Stefan C. Grant
Journal: Journal of Clinical Oncology (2015)

e19133 Background: Advanced non-small cell lung cancer (NSCLC) is a worldwide problem and appropriate resource allocation is a particular problem where access to care is limited. We sought to identify simple prognostic indicators to predict outcome with systemic therapy usable in healthcare systems to facilitate optimal use of limited resources for the treatment of advanced NSCLC Methods: A retrospective analysis was performed on patients (pts) with stage IV NSCLC receiving systemic treatment at UAB from 2002 to 2012. Sixty pretreatment factors, including presenting symptoms, laboratory values, disease sites and associated comorbidities were evaluated for their effect on survival. Comparisons were made by log-rank and chi square testing, using SAS and SPSS software Results: 409 pts who received systemic treatment were identified. Pleural effusion or deposits were present in 22.5%, metastases to brain in 22.7%, to liver in 14.4%, to adrenal in 13%, to abdominal lymph nodes in 5.4%, to subcutaneous tissue or muscle in 5.6%, to other abdominal viscera in 1.2% and. cardiac involvement in 2% of pts. The pretreatment factors that were associated with statistically significant lower overall survival by univariate analysis were male gender (p 0.02), high maximum PET SUV (p = 0.014), metastases to liver (p < 0.001), adrenal (p = 0.011) or abdominal lymph nodes (p = 0.014), high body surface area (p = 0.011), smoking history (p = 0.001), poor performance status (p = 0.011), leucocytosis (p = 0.006), thrombocytosis (p = 0.002), elevated SGOT ( p = 0.003), SGPT (p = 0.001), or alkaline phosphatase (p = 0.04), or low albumin (p = 0.001), sodium (p < 0.001), chloride (p = 0.005) or magnesium (p < 0.001). In multivariate analysis the only factors associated with shorter survival were presence of intra-abdominal metastases, smoking status, low albumin or sodium and elevated SGPT. The most important prognostic factor was the presence of intra-abdominal metastases (p = 0.001) Conclusions: Intra-abdominal metastases confer a poor prognosis in stage IV NSCLC treated with systemic therapy and may identify patients in whom aggressive treatment beyond first line therapy is not appropriate. These results are being validated in an independent dataset.
Safety and efficacy of the addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma multiforme.
Authors: James J Vredenburgh, Annick Desjardins, Katherine B. Peters, David A. Reardon, James Emmett Herndon, April D. Coan, John Kirkpatrick, Leighann Bailey, Stevie Threatt, John Howard Sampson, Allan H. Friedman, Henry S. Friedman
Journal: Journal of Clinical Oncology (2012)

2094^ Background: Glioblastoma (GBM) has a very poor prognosis, and the majority of patients die within 2 years of diagnosis. GBMs have high concentrations of vascular endothelial growth factor (VEGF), and the more VEGF, the worse the prognosis. Bevacizumab is a humanized antibody to VEGF and is active in recurrent GBMs. The study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with radiation and temozolomide, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to temozolomide post-radiation therapy. Methods: Patients received standard radiation and temozolomide at 75 mg/m 2 /day, with bevacizumab at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of radiation therapy, patients received 6-12 cycles of bevacizumab, temozolomide and irinotecan. Each cycle was 28 days. Bevacizumab was given at a dose of 10 mg/kg days 1 and 15, temozolomide 200 mg/m 2 days 1-5 and irinotecan on days 1 and 15 at 125 mg/m 2 for patients not on an enzyme inducing anti-epileptic (EIAED) and 340 mg/m 2 for patients on an EIAED. The statistical design was a goal of 60% overall survival at 16 months. Results: 125 patients were enrolled between 8/07 and 3/09. All the patients have completed therapy. Nine patients had thromboembolic complications (DVT or PE). Two patients had wound dehiscence, one bowel perforation, one secondary AML and two pneumocystis carinii pneumonias (PCP). Seventeen had grade 4 hematologic toxicity requiring dose decrements. There were 4 toxic deaths, one each with a myocardial infarction PCP, PE and sepsis. At a median follow-up of 40 mos, the median overall survival was 20.9 mos, the median progression-free survival was 13.8 mos and the 2-year overall survival was 42.4%. Conclusions: Adding bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide with irinotecan is tolerable and efficacious.
Conditional survival estimates for small cell lung cancer receiving prophylactic cranial irradiation in the U.S. (1988-1997).
Authors: Yan Xing, Kailash Mosalpuria, Chung-Yuan Hu, Vijaya Raj Bhatt, Apar Kishor Ganti
Journal: Journal of Clinical Oncology (2015)

7577 Background: Conditional survival (CS) has emerged as a clinically useful measure of prognosis for cancer patients with poor prognosis. We examined the efficacy of prophylactic cranial irradiation (PCI) on cancer-specific CS estimates for small cell lung cancer (SCLC) patients. Methods: SCLC patients on whom PCI data was available were identified from the Surveillance Epidemiology and End Results registry (SEER) from 1988-1997. PCI data were not available after 1997. Multivariate Cox regression models were built separately by each stage to calculate the adjusted 1-6 year cancer-specific survival and overall survival. The multiplicative law of probability was then used to compute the X-year conditional survival where the (x+y) year survival is divided by y years of patients who have survived. Variables adjusted for included age, sex, ethnicity, marital status, SEER region, year of diagnosis, and radiation. Results: Data on 9,134 patients was included. Utilization of PCI in limited stage (LS)-SCLC increased from 18% in 1988 to 23% in 1997 (P < 0.001). Patients with LS-SCLC from Midwest were less likely to receive PCI (36% vs. 40%, p < 0.001) compared to other SEER regions and those aged 50-79 years with LS-SCLC were less likely to receive PCI (59% vs. 16%, p < 0.001). The 3- year conditional overall survival (COS) from diagnosis (time 0) to 3 years for LS-SCLC receiving PCI improved from 23% (all patients at diagnosis) to 54% (patients alive at 3 years from diagnosis) whereas similar estimates for those not receiving PCI were 17% and 48%. For extended stage (ES) SCLC receiving PCI, the 3-year COS improved from 4% to 49% whereas the 3-year COS for those not receiving PCI improved from 5% to 50%. Three-year conditional cancer-specific survival (CCSS) for LS-SCLC receiving PCI improved from 28% to 65% and for those not receiving PCI improved from 20% to 59%. For ES-SCLC receiving PCI, the 3-year CCSS improved from 5% to 60% whereas in those not receiving PCI, it improved from 6% to 62%. Conclusions: Three-year COS and CCCS estimates improve dramatically over time for SCLC survivors. These prognostic data provide more accurate prognosis helping clinicians and patients with informed decision making.
Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric cancer patients.
Authors: Dana Marie Walker, Yimei Li, Yuan-Shung Huang, Alix Eden Seif, Marko Kavcic, Kari Torp, Brian Fisher, Richard Aplenc
Journal: Journal of Clinical Oncology (2012)

1504 Background: Dexrazoxane (DXZ) is an effective cardioprotectant in children with leukemia and solid tumors. However, the potential risk of secondary acute myeloid leukemia (AML) limits DXZ use. We compared the incidence of secondary AML in pediatric cancer patients with and without DXZ exposure to estimate the risk of DXZ-associated secondary AML. Methods: We conducted a retrospective cohort study of anthracycline exposed pediatric cancer patients (excluding de novo AML) hospitalized from January 1999 to March 2011 in 43 freestanding children’s hospitals in the Pediatric Health Information System (PHIS) database. Secondary AML was defined as an ICD9 code for AML that occurred at least 90 days after first anthracycline exposure. Proportions of patients with secondary AML were compared between patients with and without an exposure to DXZ after the initial anthracycline exposure. Results: During the study period of interest, 15,532 pediatric cancer patients were exposed to anthracycline, of which 1404 (9.04%) subsequently received DXZ. Secondary AML was identified in 235 (1.51%) patients. Patients ≥ 10 years of age, black patients, patients in New England and the Midatlantic regions, and those with bone tumors were significantly more likely to have received DXZ. The unadjusted incidence of secondary AML in the DXZ exposed and unexposed patients did not differ significantly (1.21% v. 1.54%, p=0.3308). After adjusting for these variations in demographics, the incidence of secondary AML still did not significantly differ between DXZ exposed and unexposed patients (p=0.6224). Conclusions: Our findings suggest that DXZ exposure does not lead to an increased risk of secondary AML in children. These data are important given the conflicting results from individual clinical trials about the risk of DXZ-associated secondary AML. While subject to well-known limitations of administrative database analyses, these data represent the largest cohort of DXZ exposed patients with available data on the occurrence of secondary AML. Additional multivariate analyses of chemotherapeutic covariates and time to secondary AML are ongoing.
Sixty seconds on . . . happiness
Authors: Anne Gulland
Journal: BMJ (2017)

Of course you are—you’re Norwegian. The World Happiness Report 2017 says that Norway is the happiest country in the world (although Denmark, Iceland, and Switzerland come very close, with no statistical difference from Norway).1 The US ranks 14th of 155 countries, the UK is 19th, and France is 31st. The poor old Central African Republic is last, and the bottom of the list is dominated by African …
The role of MACC1 in regulating gastric cancer cell senescence.
Authors: Xi Chen, Li Lin, Min Shi, Qiang Zuo, Dayong Zheng, Wangjun Liao
Journal: Journal of Clinical Oncology (2014)

e15027 Background: Metastasis-associated in colon cancer-1 (MACC1) is known to promote metastasis in colon cancer. It was reported that MACC1 activates MEK/ERK signaling, which is known to further regulate nuclear factor kB (NF-kB) and cellular senescence. However, it is unknown whether it participates in cell senescence regulation in gastric cancer. Methods: Senescent cells were assessed by senescence-associated β-galactosidase dye. Thelevel of NF-kB in the nucleus was measured by western blot, ELISA and immunofluorescence. The level of senescence-related factors, including p53, p21 and p16, was evaluated by PCR and western blot. Reactive oxygen species and DNA damage was also measured. Results: MACC1 silencing induced gastric cancer cell senescence and MACC1 overexpressing inhibited the senescence. As to the mechanism, MACC1 is found to inhibit NF-kB nuclear translocation, and induce p53, p21 and p16 downregulation. Moreover, we verified that MACC1 inhibited senescence by reducing reactive oxygen species and suppressing DNA damage. Conclusions: Our results demonstrated that MACC1 suppressed gastric cancer cell senescence, which probably contributes to gastric cancer progression.