tbuckley/cabot-search huggingface dataset:
Management of skin toxicity and cetuximab-based regimen compliance in first-line chemotherapy of metastatic colorectal cancer (mCRC) patients (pts): Results of observer study.
Authors: Carmine Pinto, Francesca Di Fabio, Gerardo Rosati, Ivan Lolli, Enzo Ruggeri, Libero Ciuffreda, Daris Ferrari, Salvatore Tumolo, Giovanni Rosti, Paolo Tralongo, Raimondo Ferrara, Oscar Alabiso, Silvana Chiara, Giovanni Paolo Ianniello, Francesco Di Costanzo, Antonio Frassoldati, Carmelo Iacono, Vincenzo Adamo, Rodolfo Mattioli, Michele Valeri
Journal: Journal of Clinical Oncology (2013)

e14557 Background: Cetuximab significantly improves efficacy when added to chemotherapy in mCRC pts. The ObservEr Study evaluated quality of life (QoL), skin toxicity management and treatment compliance of cetuximab-based regimens in first-line treatment of mCRC pts. Methods: ObservEr is a non-interventional, multicenter, prospective study. Primary endpoint is change in QoL during first-line treatment, with focus on the impact of dermatological toxicity. QoL (Dermatology Life Quality Index/DLQI and EORTC QLQ C30) is assessed at baseline and weekly for the first 8 weeks of treatment, then at every evaluation visit until PD or withdrawal. Secondary endpoints are efficacy, rate of liver metastasis resections, incidence of serious adverse events. Results: Between Apr 2011 and Nov 2012, 29 Italian centers enrolled 233 pts, with 226 evaluable pts. Pt characteristics: 152(67.3%) males, 74(32.7%) females; median age 65 (39-81) years; PS ECOG 0-1 95.5%; potentially resectable liver metastasis 59(27.1%); irinotecan regimens 129(57.1%), oxaliplatin regimens 60(26.5%), other regimens 37(16.4%). Median interval between request and result of KRAS test was 10 (6-15) days. Prophylactic skin treatment with vitamin K1 cream was used in 159(70.4%) pts, reactive treatment included vitamin K1 in 59(26.1%). Grade (gr) 1-2 skin toxicity was observed in 128(56.6%) pts, gr 3 in 28(12.4%); no gr 4 was detected. No significant difference in gr 3 skin toxicity was observed between males vs females (13.8 vs 9.5%; p=0.351), age &lt;60 vs ≥60 years (18.1 vs 9.7%; p=0.077), irinotecan vs oxaliplatin regimens (12.4 vs 18.3%; p=0.278), prophylactic vs reactive treatment (15.1 vs 6.8%; p=0.339). Dose reduction, temporary and permanent discontinuation of cetuximab due to skin toxicity was required in 9(4.0%), 32(14.2%) and 7(3.1%) pts respectively; cetuximab compliance ≥70% of dose was reached in 208(92.0%) pts. Conclusions: These results suggest that appropriate skin toxicity management and prophylactic or reactive treatment with Vitamin K1 cream can improve the gr 3 skin toxicity control and the cetuximab compliance. QoL results will be shown at the 2013 ASCO Meeting. Clinical trial information: ID239.
Methodology and results of a pain-assessment process for patients receiving radiation therapy treatment.
Authors: Angela McDuffie, Eleanor Elizabeth Harris, Anita Proctor, Leann Potter, Timothy Barnes, Michael Holloman, James Naves
Journal: Journal of Clinical Oncology (2017)

105 Background: Patients receiving radiation therapy treatment often exhibit pain as a consequence of their cancer or treatment, and is a major factor affecting the patient’s quality of life and functional status. Accreditation standards require pain to be assessed and managed, which are key components in successful implementation of a radiation therapy plan of care. Multifactorial causes for cancer pain, the subjective nature of pain assessment, and the protracted nature of radiation delivery make it necessary to routinely evaluate patient pain using quantifiable metrics. These evaluations can then be used to develop and evaluate effectiveness of interventional strategies. Methods: Internal “spot check” chart review in early 2015 showed deficits in 16 of 37 charts (43.2%) reviewed for pain assessments, revealing documentation well below the required threshold (95%). As a result, the Department of Radiation Therapy revised the process for the accepted 10-point intensity scale to evaluate patient pain. This revised process included staff re-education, workflow adjustments, and nursing evaluation prior to, during, and the end of the radiation treatment course using a standardized pain scale form. Documentation was accomplished by means of vital sign template encounter tool used by Nursing at the time of initial consult, for weekly on-treatment visits (OTVs), and end of treatment (EOT) encounter. Results: Data were monitored for the period of April-June 2015 and reported as a continuous quality improvement (CQI) activity to the department’s Quality Committee. Amassed data showed a total of 186 unduplicated patients were treated during this period, and 181 (97.3%) were assessed for pain. Conclusions: Ongoing monitoring is an important strategy to assure complete evaluation, treatment and outcomes of patient pain while receiving radiation treatment. A clearly defined and quantifiable process is important to facilitate monitoring and ongoing pain management. Improvements in consistency of pain assessment and management promote enhanced focus on patient pain and contribute to delivery of care, and patient quality of life and performance status.
Ethics and international research (multiple letters) [2]
Authors: E. C.O. Edi-Osagie, N. E. Edi-Osagie, P. Lurie, S. M. Wolfe, J. Burdon, R. Baraza, M. J. Landray, N. A. Halsey, A. Sommer, R. E. Black, P. Godfrey-Faussett, A. Mwinga, M. Hosp, R. Baggaley, M. Quigley, J. Porter
Journal: BMJ (1998)
The Maternal Health Compact
Authors: Susan Mann, Kimberlee McKay, Haywood Brown
Journal: New England Journal of Medicine (2017)

Interview with Dr. Heather Kovich on the challenges facing patients and physicians in rural areas of the United States. (10:07)Download Many pregnant women in the rural United States have access only to low-resourced, low-volume hospitals. Linking such hospitals with tertiary care hospitals through telehealth services, quality-improvement aid, and transport may reduce morbidity and mortality.
<i>MLH1 </i>hypermethylation assay should be considered when evaluating mismatch repair deficient tumours.
Authors: Michael P. Farrell, Catherine Clabby, Rosie O Shea, Andrew J. Green, David James Gallagher
Journal: Journal of Clinical Oncology (2015)

e12524 Background: Tumours from patients with Lynch syndrome (LS) have characteristic features resulting from underlying defective mismatch repair (MMR), that results in microsatellite instability (MSI) and absence of MMR protein expression by immunohistochemistry (IHC). Most MSI is due to biallelic somatic hypermethylation of the MLH1 promoter in older patients with no family history of CRC. The presence of BRAF (V600E) mutation MLH1 makes a diagnosis of LS less likely. In addition, “germline epimutation” represents a novel mechanism for disease in which the affected allele of a gene is rendered silent in the germline by an epigenetic aberration. In this pilot study we describe the molecular workup to differentiate between sporadic colon tumours with MSI and LS. Methods: LS work-up in Ireland traditionally includes IHC, MSI, BRAF testing and genetic testing. CRC databases in two hospitals were reviewed and cross referenced with molecular data from the NCMG to identify individuals who additionally had MLH1 hypermethylation assays completed on both tumour and lymphocytic DNA and diagnostic sequencing of MLH1 and PMS2. Medical records were reviewed for personal and family history of cancer. Results: Fourteen probands (4 women and 10 men)had full molecular workup including MLH1 hypernethylation and genetic testing. Eight individuals (all men) tested negative for BRAF, tumour hypermethylation and MLH1 and PMS2 mutations. Six probands (4 women and 2 men) had MLH1 promoter hypermethylation identified. Median age of diagnosis of this cohort was 62.5 years. No pathogenic mutations were detected however one variant of uncertain (VUS) was reported. All six cases were wildtype for the BRAF activating mutation. All tumours showed hypermethylation of greater than 10% which is considered significant. One male had significant MLH1 promoter hypermethylation detected in lymphocyte DNA which is consistent with Lynch syndrome due to a constitutional MLH1epimutation. Conclusions: Tumour BRAF mutation is not present in all sporadic MMR deficient tumours. MLH1 promoter hypermethylation appears a more sensitive assay to discriminate between sporadic MSI colon tumours and LS and can identify germline epimutation of MLH1.
Phase II trial of cisplatin (C), fixed-dose rate gemcitabine (G) and gefitinib for advanced transitional cell carcinoma (TCC) of the urothelial tract: Preliminary results of CALGB 90102
Authors: G. Philips, S. Halabi, B. Sanford, D. Bajorin, E. Small
Journal: Journal of Clinical Oncology (2004)

4540 Background: The GC combination has become a standard of care for advanced TCC. The epidermal growth factor receptor (EGFR) is frequently expressed in TCC and is associated with a poor prognosis. While gefitinib alone has minimal activity in advanced TCC, C has demonstrated pre-clinical synergy with gefitinib. The combination of GC and gefitinib has been shown to be safe. Because a fixed dose rate infusion of G appears to be more effective compared to standard dosing for the treatment of pancreatic cancer, we sought to test the efficacy of C, fixed dose-rate G and gefitinib in the treatment of patients with advanced TCC. Methods: Eligible patients had measurable N2, N3 or M1 disease; PS of 0–2; CrCl of > 50 ml/min; adequate hematologic and liver function; no brain metastases; no prior systemic combination chemotherapy. The treatment regimen consisted of C 70mg/m2 D1, G 1000mg/m2 D1+8 administered at a fixed dose rate of 10 mg/m2/min every 3 weeks concurrent with gefitinib 500 mg/day PO for a maximum of 6 cycles. Responders were continued on maintenance gefitinib 500 mg/day until progression. Results: A total of 27 patients were accrued before the study was halted because dose-limiting toxicity (DLT) exceeded pre-established stopping rules. The DLT events observed were 2 Gr 5 (1 neutropenic infection, 1 CVA) and 3 Gr 4 non-hematologic toxicities (1 hyperuricemia, 1 fatigue, 1 dyspnea). Grade 3 diarrhea and skin rash were observed in 2 (8%) and 4 (16 %) patients respectively. Of 24 evaluable patients there were 12 responses for an ORR of 50 % (95% CI= 29 –71%). Median time to progression is 6.9 months (95% CI: 3.8–8.9). Conclusions: The combination of GC and gefitinib is active in advanced TCC, although the relative contribution of gefitinib cannot be determined. However, this regimen was associated with excessive toxicity, possibly due to the fixed dose rate infusion of G. Accrual has therefore continued employing a standard G dosing schedule. No significant financial relationships to disclose.
Role of vascular endothelial growth factor (VEGF) 189 in liver metastasis of human colon cancer
Authors: Masahiro Matsuyama, Yasuhisa Oida, Hozumi Matsumoto, Tsuyoshi Chijiwa, Hitoshi Yamazaki, Toshihide Imaizumi, Hiroyasu Makuuchi, Makoto Monnai, Hiroshi Suemizu, Masto Nakamura
Journal: Cancer Research (2008)

277   Angiogenesis or new blood vessel formation is a process required for tumor growth as well as for metastasis. Tumor cells secrete pro-angiogenicfactors such as vascular endothelial growth factor (VEGF) that act by binding to their cognate receptors on endothelial cells. Recent studies have demonstrated that VEGF-A is closely associated with the progression of various malignant neoplasms including non-small cell lung cancer, colon cancer, renal cell cancer and osteosarcoma. VEGF189, an isoform of VEGF-A, is most potent for vascularization in various cancers. We investigated metastasis-related molecules including VEGF 189 in liver metastasis of colon cancer. We established the highly liver-metastatic human colon cancer cell line (SW48-LM2) from low metastatic cell lines (SW48) by serial intrasplenic injections with splenectomy using immunodeficient NOD/SCID/gamma(c)(null) (NOG) mice. SW48-LM2 showed signifcantly highly liver metastasis than wild-type SW48. There was no significant difference in cell growth between SW48 and SW48-LM2. Activities of matrix metalloproteinases (MMP) and plasminogen activators were examined using zymography, and matrigel invasion/migration assay. Furthermore, gene expression of various cancerous molecules related to metastasis was evaluated by real-time PCR. Significant differences in activities of MMP and plasminogen activators, and gene expression of TSP-1, TSP-2, S100A4, E-cadherin, VEGFA-all were not seen between SW48 and SW48-LM2. The expression of VEGF-A isoforms (VEGF121, VEGF165 and VEGF189) was also examined by real-time PCR. SW48-LM2 had 3-fold increased expression of VEGF189 mRNA than wild-type SW48 (P
Pooled analysis (n=8,377) evaluates predictive impact of uPA and PAI-1 for response to adjuvant therapy in breast cancer
Authors: N. Harbeck, R. E. Kates, M. P. Look, J. A. Foekens
Journal: Journal of Clinical Oncology (2004)

523 Background: The prognostic impact of invasion factors uPA and PAI-1 in primary breast cancer has been demonstrated at the highest level of evidence by the prospective clinical Chemo N0 trial and a large pooled analysis. Recent results also suggested a predictive impact of these factors. Methods: In order to validate the predictive impact of uPA and PAI-1 in primary breast cancer, a pooled analysis was performed on 18 observational data sets (n=8,377) provided by members of the EORTC Receptor and Biomarker Group. uPA and PAI-1 were determined in primary tumor tissue extracts using ELISAs and ranked by center. Decisions to administer adjuvant therapy did not utilize uPA/PAI-1. Median follow-up was 79 months. Results: Time-varying survival analysis stratified by center showed that adjuvant chemotherapy (CT) was associated with an enhanced benefit (HR 0.60, CI 0.41–0.87) in patients with high uPA/PAI-1, particularly for preventing relapses during the first 3 years -in addition to its benefit in the cohort as a whole. In the 0–3 node subgroup, the enhanced benefit was also strong (HR 0.51, CI 0.31–0.85). No interaction between adjuvant endocrine therapy (ET) and uPA/PAI-1 was found in Cox analysis. However, a low-risk subgroup of N0, hormone-receptor positive, low uPA/PAI-1 patients receiving ET was identified with 10-year OS and DFS of about 92 %. Conclusions: A strong and independent predictive impact of uPA and PAI-1 regarding adjuvant chemotherapy in breast cancer was validated in this pooled analysis. However, we did not see evidence for a subgroup defined by uPA and PAI-1 for which adjuvant endocrine therapy should not be given. Our data suggest that all patients with high uPA/PAI-1 -regardless of their nodal status -should receive adjuvant chemotherapy. Moreover, in patients where the decision between endocrine and chemo-endocrine therapy is clinically open, uPA and PAI-1 could provide decisive evidence. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration American Diagnostica, Inc. American Diagnostica, Inc.
Promoter polymorphisms of the SWI/SNF chromatin remodeling complex molecule, BRM, and esophageal adenocarcinoma outcome.
Authors: Grzegorz Korpanty, Xin Qiu, Lawson Eng, Olusola Olusesan Faluyi, Dangxiao Cheng, Daniel John Renouf, Jennifer J. Knox, Rebecca Wong, Gail Darling, Wei Xu, Lorin Dodbiba, Abul Kalam Azad, David Reisman, Sinead Cuffe, Geoffrey Liu
Journal: Journal of Clinical Oncology (2013)

4077 Background: Better understanding of the biology of esophageal cancer may help improve its treatment. The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development and outcome. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM -741 and BRM -1321) have been correlated with BRM loss and elevated cancer risk in upper aerodigestive cancers (Wang et al, Carcinogenesis, 2012) and more recently in lung cancer outcome (Cuffe et al, ESMO, 2012) by our research teams. Objectives: We evaluated BRM polymorphisms and their role in the survival of esophageal cancer patients. Methods: 223 histologically-confirmed esophageal adenocarcinoma patients of all stages were evaluated. The two BRM polymorphisms utilized Taqman genotyping. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 85% were male; the mean age was 63 years. 37% had stage IV advanced tumors. The median PFS was 1.03 years, while median OS was 1.82 years. After adjustment for known prognostic clinical variables, carrying homozygous variants of both BRM polymorphisms (double homozygotes) was associated with a worse outcome: aHR 1.84 (1.06-2.34, p=0.03) for OS and aHR 1.93 (1.10-2.48, p=0.02) for PFS. The direction and magnitude of associations were similar in subsets of patients by age, gender, smoking status, use of platinum agents, and disease stage. Non-significant trends in the same direction but of aHR magnitudes 1.34-1.54 were seen in the patients who carried one homozygous variant or who were double heterozygotes. Conclusions: We report the initial association of BRM polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.
Bevacizumab (Bev) alone or in combination with TRC105 for metastatic renal cell cancer (mRCC): A California Cancer Consortium clinical trial.
Authors: Tanya B. Dorff, Jeff Longmate, Sumanta Kumar Pal, Walter Michael Stadler, Mayer N. Fishman, Ulka N. Vaishampayan, Amol Rajeev Rao, James Hu, David I. Quinn, Primo Lara
Journal: Journal of Clinical Oncology (2015)

4542 Background: Inhibition of vascular endothelial growth factor (VEGF) pathway is effective in mRCC, but resistance inevitably develops. CD105 (endoglin) is highly expressed on endothelial cells and has been shown in preclinical models to mediate resistance to VEGF pathway inhibitors, in part due to TGF-beta signaling. TRC105 is a monoclonal antibody against CD105 which has been shown to be tolerable in combination with Bev at full doses. Methods: Eligible mRCC patients (pts) with any histologic subtype may have received 1-4 prior systemic therapies including cytokines, VEGF, or mTOR agents. Bev was administered at 10 mg/kg IV on day 1 and 15 of 28-day cycles as a single agent (Arm A) or with TRC105 10 mg/kg IV on days 1, 8, 15, and 22 (Arm B). Primary endpoint was progression-free survival (PFS). A total of 88 pts were to be randomized to detect a halving of PFS with 80% power and α = 0.1. An interim analysis for futility was conducted after 44 pts had PFS evaluated. Results: Enrollment was halted after interim analysis with 61 pts randomized; 45 were men. Median age was 60 (24-83). 20 (32%) of pts had received 3 or more prior lines of therapy (median = 2 on both arms). 44 patients had clear cell RCC and 15 had non-clear cell histology. One subject on each arm had a confirmed PR (3%) and 2 patients on each arm had stable disease lasting > 9 cycles. For the 56 evaluable pts, the PFS (including early treatment termination as progression) at 12 weeks was 48% +/- 9% on Bev compared to 50% +/- 9% on Bev + TRC105. Survival did not differ significantly (p = 0.5) between arms, being 81% at 24 weeks for both arms. Grade > 3 toxicities were more common in Arm B and included anemia (8 vs 2 pts), electrolyte abnormalities (6 vs 2 pts), dyspnea (4 vs 2 pts), nausea/vomiting (4 vs 0 pts), hyperglycemia (2 vs 0 pts) and infusion reaction (2 vs 0 pts); hemorrhage, hypertension, and proteinuria were more common in Arm A. Conclusions: TRC105 failed to prolong PFS when added to Bev. Further analysis will examine biomarkers of potential TRC105 benefit in this population. TRC105 is being studied in combination with VEGF receptor tyrosine kinase inhibitors in mRCC to determine whether there is an additive effect on PFS. Clinical trial information: NCT01727089.
Lung cancer in patients ≤30 years of age
Authors: S. Umemura, K. Kiura, Y. Segawa, M. Tabata, A. Bessho, M. Aoe, K. Gemba, T. Shinkai, H. Ueoka, M. Tanimoto
Journal: Journal of Clinical Oncology (2004)

7262 Background: The ages at diagnosis in cancer patients with germ-line gene mutations were often two to three decades earlier compared to those without germ-line mutations. To compare the clinical background of very young patients with lung cancer to that of the general population of lung cancer is essential before the assessment of genetic background. Methods: Retrospectively, 20 patients with lung cancer aged ≤30 years reviewed from three institutions were compared with 1848 patients aged >30 years admitted to National Shikoku Cancer Center between 1981 and 2001. Median survival time (MST) and other factors were assessed using the Cox regression model and the Χ2test, respectively. Results:In a multivariate analysis of the general population (n=1851), male gender, clinical symptoms, weight loss, a high LDH level, performance status (PS) of ≥2, and advanced-stage were independent negative prognostic factors. We found four patients with mucoepidermoid carcinoma among 20 patients aged ≤30 years. Mucoepidermoid carcinoma was excluded because of a high incidence (p<0.001) in the very young population, relatively early stage and longer survival time. The incidence of nonsmokers (p<0.001) and poorly differentiated non-small cell lung cancer (p=0.018) was also high in the very young group. In a multivariate analysis (n=16), clinical symptoms, LDH levels, and PS were also independent prognostic factors. There was no difference in survival between the young population and the general population. According to LDH levels and clinical symptoms, we classified the very young patients into three groups; Group I: LDH (normal) and no clinical symptoms, Group II: LDH (normal) and clinical symptoms, and Group III: LDH (high) and clinical symptoms. The MST for group I, II and III were 50.0, 13.4, and 2.5 months, respectively (p=0.002). Conclusions: Excluding mucoepidermoid carcinoma, patients with a high LDH level and clinical symptoms showed poor prognosis in the very young population. Survival in the very young population was similar to that in the general population. In the future, the genetic study of this population is needed for elucidating the carcinogenesis of lung cancer in the general population. No significant financial relationships to disclose.