tbuckley/cabot-search huggingface dataset:
Evaluation of Novel Prostate-Specific Membrane Antigen-Targeted Near-Infrared Imaging Agent for Fluorescence-Guided Surgery of Prostate Cancer
Authors: Sumith A. Kularatne, Mini Thomas, Carrie H. Myers, Pravin Gagare, Ananda K. Kanduluru, Christa J. Crian, Brandy N. Cichocki
Journal: Clinical Cancer Research (2018)

The ability to locate and remove all malignant lesions during radical prostatectomy leads not only to prevent biochemical recurrence (BCR) and possible side effects but also to improve the life expectancy of patients with prostate cancer. Fluorescence-guided surgery (FGS) has emerged as a technique that uses fluorescence to highlight cancerous cells and guide surgeons to resect tumors in real time. Thus, development of tumor-specific near-infrared (NIR) agents that target biomarkers solely expressed on prostate cancer cells will enable to assess negative tumor margins and affected lymph nodes.Because PSMA is overexpressed in prostate cancer cells in >90% of the prostate cancer patient population, a prostate-specific membrane antigen (PSMA)-targeted NIR agent (OTL78) was designed and synthesized. Optical properties, in vitro and in vivo specificity, tumor-to-background ratio (TBR), accomplishment of negative surgical tumor margins using FGS, pharmacokinetics (PKs) properties, and preclinical toxicology of OTL78 were then evaluated in requisite models.OTL78 binds to PSMA-expressing cells with high affinity, concentrates selectively to PSMA-positive cancer tissues, and clears rapidly from healthy tissues with a half-time of 17 minutes. It also exhibits an excellent TBR (5:1) as well as safety profile in animals.OTL78 is an excellent tumor-specific NIR agent for use in fluorescence-guided radical prostatectomy and FGS of other cancers.
Heart-Breaking Telomeres
Authors: Paula Martínez, Maria A. Blasco
Journal: Circulation Research (2018)

Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Accumulation of critically short telomeres is proposed to be a primary molecular cause of aging and age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as or telomeropathies. The rate of telomere shortening throughout life is determined by endogenous (genetic) and external (nongenetic) factors. Therapeutic strategies based on telomerase activation are being developed to treat and prevent telomere-associated diseases, namely aging-related diseases and telomeropathies. Here, we review the molecular mechanisms underlying telomere driven diseases with particular emphasis on cardiovascular diseases.
Quantification of the independent prognostic value of Charlson Comorbidity Index among patients with non-small cell lung cancer.
Authors: Jianfeng Meng, James X Zhang, Yonglin Pu
Journal: Journal of Clinical Oncology (2018)

e21164 Background: Comorbidities reflect patients’ underlying multiple-disease growth curve and influence outcomes of treatment. However, it is unclear if there is and how much independent prognostic value of the Charlson Comorbidity Index (CCI) present among patients with non-small cell lung cancer (NSCLC). We aimed to evaluate the independent prognostic value of CCI using a large sample of NSCLC patients. Methods: From the database of our Cancer Center Cancer Registry, we found 2,510 patients with NSCLC who were diagnosed and treated at our institution from 2004 to 2014. The patients were enrolled based on the following inclusion criteria: 1) had undergone a baseline FDG PET/CT, 2) had no evidence of brain metastasis, and 3) did not have concurrent diagnosis or a history of other primary cancer. A total of 949 patients were enrolled for this retrospective study to identify 19 comorbidities defined by the Charlson, et al., for calculating CCI at the baseline. Overall survival (OS) was determined from the FDG PET date to the death from any cause. Other covariates included age, gender, and race, smoking history, and tumor histology, clinical TNM stage (7th edition) and treatment types. Survival analyses using Cox Proportional Hazard models were performed to determine the independent prognostic value of the CCI. Results: Among the 949 NSCLC patients, 429 (45%) were male, 452 (48%) black, with mean age 67 (s.d. 11), and median survival of 24 months. The number of patients with TNM stage IA, IB, IIA, IIB, IIIA, IIIB, and IV were 171 (18%), 103 (11%), 67 (7%), 40 (4%), 164 (17%), 107 (11%), and 297 (31%), respectively. 353 (37%) patients had no comorbidity at the baseline; 251 (26%) patients had a CCI of 1; 171 (18%) of patients had a CCI of 2; and 99 (10%) had a CCI of 3; and 75 (8%) patients had a CCI of 4 or higher. Controlling for TNM stage, age, gender, race, tumor histology, and treatment types, the adjusted hazard ratio of CCI on OS is 1.09 (95% CI 1.03, 1.15, p = 0.01). When CCI was modeled as a categorical variable, the effect size of CCI became increasingly larger as the value of CCI increased. Conclusions: CCI is a significant prognostic factor with increasing magnitude of effect on OS as the value of comorbidities increases.
Treatment patterns and survival among patients with extensive disease small cell lung cancer (ED-SCLC).
Authors: Mark D. Danese, Michelle L. Gleeson, Deborah P. Lubeck, Beata Korytowsky, Sarah Bobiak
Journal: Journal of Clinical Oncology (2017)

e20026 Background: There has been little change to the ED-SCLC treatment landscape in the past 30 years. Patients with ED-SCLC have limited treatment options after recurrence and poor overall survival (OS). Prior work has described OS in patients with ED-SCLC but did not report OS beyond first-line (1L) therapy. Methods: This study used linked data from the Surveillance, Epidemiology, and End Results program and Medicare claims. Patients aged ≥66 years with a first primary, pathologically confirmed ED-SCLC diagnosis between 01/01/2007 and 12/31/2011 and who had Medicare Parts A and B coverage were included. Patients were followed from diagnosis until death, end of follow-up, second primary cancer diagnosis, or switch to managed care coverage. OS from ED-SCLC diagnosis and from initiation of 1L and second-line (2L) outpatient chemotherapy were estimated. Cox proportional hazards models were used to identify factors associated with OS from diagnosis. Results: Of 5498 patients with ED-SCLC (mean age: 75 years [range: 66, 98]) included in this study, 49% were male, 86% were white, 40% had ≥1 indicator of mobility limitations, and 23% lived in an area with high poverty (≥20%). Median OS for all patients was 4.7 months (untreated [n = 2484]: 1.3 months; treated with outpatient chemotherapy within 90 days of diagnosis [n = 3014]: 8.3 months). Among all patients, factors associated with shorter OS included older age, male sex, ≥1 indicator of mobility limitations, and residence in a high poverty area. In the 3014 patients who received 1L outpatient chemotherapy (86% platinum/etoposide; 4% platinum/irinotecan; 10% other), median OS from initiation of 1L therapy was 7.9 months overall (platinum/etoposide: 8.0 months; platinum/irinotecan: 7.8 months; other: 6.4 months). A total of 1162 patients received 2L chemotherapy (38% topotecan monotherapy; 28% platinum regimens; 34% other). Median OS from initiation of 2L therapy was 4.4 months overall (topotecan: 4.0 months; platinum regimens: 6.4 months; other: 3.7 months). Conclusions: OS was poor in this cohort of real-world patients with ED-SCLC especially in those not treated with outpatient chemotherapy. These findings underscore the need for new treatments for this population.
Phase 1/2 study of the selective TRK inhibitor larotrectinib in pediatric patients with cancer.
Authors: Noah Federman, Catherine Michelle Albert, Brian Turpin, Leo Mascarenhas, Ramamoorthy Nagasubramanian, Birgit Geoerger, Michela Casanova, Maria Soledad Gallego Melcon, Julia Chisholm, Cornelis M. Van Tilburg, Neerav Narendra Shukla, Sheri L. Spunt, Michael Craig Cox, Douglas S. Hawkins, Alberto S. Pappo, Stefan S. Bielack, Francois P. Doz, Gianni Bisogno, Theodore Willis Laetsch, Steven G. DuBois
Journal: Journal of Clinical Oncology (2017)

TPS10577 Background: Neurotrophin ligands and their receptors TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3) are important for growth regulation, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, and amplifications of NTRK, have been described in diverse tumor types and may contribute to tumorigenesis. A broad range of pediatric malignancies have been found to harbor NTRK fusions, including infantile fibrosarcoma (IFS), spindle-cell sarcoma, congenital mesoblastic nephroma, pediatric papillary thyroid cancer, pediatric gliomas and Ph-like acute lymphoblastic leukemia. Larotrectinib is the first small-molecule selective inhibitor of TRKA, -B, and -C in clinical development and preliminary data from the adult phase 1 trial demonstrate prolonged responses in patients with TRK fusions and a favorable safety profile. Methods: We have initiated an open-label, multi-center, international Phase 1/2 study with larotrectinib in pediatric patients with solid tumors and primary CNS tumors (NCT02637687). Patients with advanced cancer between the ages of 1 year and 21 years are eligible, as well as patients as young as 1-month of age with a documented NTRK fusion. Patients with IFS who have not had definitive surgery are also eligible. Larotrectinib is administered orally twice daily on a continuous 28-day schedule. Dosing is based on body surface area. Larotrectinib is available in an oral liquid formulation and capsules. Following identification of the maximum tolerated dose of larotrectinib in the phase 1 portion, the phase 2 portion will commence. The phase 2 portion will enroll patients with NTRK-translocated tumors and measurable disease into three cohorts: 1) infantile fibrosarcoma; 2) extracranial solid tumors; and 3) primary CNS tumors. The primary endpoint for the phase 2 portion is objective response rate, with duration of response and progression free survival as secondary efficacy endpoints. Each phase 2 cohort will enroll in a single stage of up to 10 patients per cohort. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in December 2015 and is ongoing. Clinical trial information: NCT02637687.
Safety and feasibility of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) for the ablation of relapsed or refractory pediatric solid tumors.
Authors: AeRang Kim, Karun Sharma, Pavel Yarmolenko, Haydar Celik, Rosandra Kaplan, Jeffrey S. Dome, Amanda Mahoney, Ari Partanen, Lizette Warner, Peter C W Kim
Journal: Journal of Clinical Oncology (2016)

TPS10588 Background: Acute toxicities and late effects of current multi-modal therapy in pediatric cancer are substantial. MR-HIFU is an innovative technique that allows for non-invasive thermal ablation of tissue. Advantages over conventional local tumor control such as surgery, radiation therapy, or radiofrequency ablation are that MR-HIFU is non-invasive, non-ionizing, and enables ablation of large tumor volumes. A transducer focuses ultrasound beams into a selected target site resulting in thermal ablation at the focus (temperature ≥ 55°C). Integration of MR imaging provides real-time spatio-temporal guidance and thermometry allowing for accurate targeting and monitoring. This results in predictable areas of coagulative necrosis without affecting surrounding tissue. HIFU has been studied in a variety of solid tumors in adults and for relief of pain from bone metastases. There is evidence that HIFU may improve systemic disease by stimulating an anti-tumor immune response. MR-HIFU could provide an alternative to local treatment strategies in pediatric solid tumors. Methods: This is the first-in-pediatric trial to evaluate the safety and feasibility of MR-HIFU in children with relapsed solid tumors (NCT02076906). Patients ≤ 30 years of age with histologically confirmed relapsed/refractory solid tumors with no known curative treatment are eligible. Tumor target lesions are limited to those located in bone or close proximity to bone at sites accessible to MR-HIFU. Target lesions in skull, spine, and contraindication for MRI are exclusion criteria. Patients undergo HIFU treatment of selected lesion(s) under sedation. Tolerability is defined during the 14 days following MR-HIFU ablation. Patients may undergo additional HIFU treatment for other target lesion(s) after the 14-day observation period if the patient has not had any treatment related limiting toxicity. Disease status is evaluated using standard imaging techniques post treatment. Secondary objectives evaluate changes in functional imaging, quality of life, and immune markers in children treated with MR-HIFU. Clinical trial information: NCT02076906.
Increasing access to NGS tests for women and racial minorities to lift barriers to molecular driven clinical trial enrollment.
Authors: Jared Cotta, Bat-Ami Gordon, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2018)

6561 Background: Molecular-driven oncology clinical trials are a rapidly growing category of clinical research. These trials are focused on generating evidence for the relationship between molecular markers and targeted therapies, often requiring patients to have Next-Generation Sequencing (NGS) results before being considered for qualification. This requirement adds another barrier to clinical trial enrollment for populations that already face healthcare disparities. Methods: Defining Platforms for Individualized Cancer Treatment (DePICT) is an IRB approved observational trial designed to monitor outcomes of Broward County, FL residents with late-stage refractory cancer who undergo NGS. Rather than requiring NGS results, DePICT subsidized NGS testing to ensure access to all patients. Enrollment demographics were analyzed to see if these conditions improve gender and minority representation. Results: DePICT has recruited 176 patients. 70% of the total cohort is female, compared to 39% female in the institute's accrual of Broward residents. Table 1 shows the base line demographic data for DePICT in comparison to the institutional recruitment. DePICT produced a 26% relative increase in minority recruitment.102 DePICT patients had at least one 12 week follow up (65% women; 13% Black, 25% Hispanic). The follow-up determined which patients pursued an MTB recommended targeted treatment or clinical trial. 12 patients continued on to interventional trials; 50% were women, 50% identified as minorities. An additional 10 patients continued on to targeted therapies; 64% were women and 64% identified as a minority. Conclusions: By providing access to NGS testing DePICT accrued underrepresented patients who face healthcare disparities. Targeting underrepresented populations for NGS may improve the enrollment of women and racial minorities to oncology clinical trials. Healthcare providers may encourage testing through education or subsidy programs. Employing these methods to reduce disparities will improve generalizability of clinical research. Black Non-Hispanic White Hispanic Minority recruitment DePICT 15% 57% 23% 38% SCCC 11% 62% 19% 30%
Every Trauma System Is Perfectly Designed to Get the Results It Gets
Authors: Steven M. Steinberg
Journal: JAMA Surgery (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Systemic therapy use and outcomes after relapse from accelerated hemithoracic radiation and surgery for malignant pleural mesothelioma (MPM).
Authors: Sara V. Soldera, John Kavanagh, Melania Pintilie, Ronald Feld, Natasha B. Leighl, John Cho, Marc de Perrot, Penelope Ann Bradbury
Journal: Journal of Clinical Oncology (2017)

8559 Background: The prognosis of patients (pts) with MPM remains poor. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy and adjuvant chemotherapy in ypN2 disease (SMART) provides encouraging results. The ability to administer systemic therapy (Tx) and response rate (RR) after recurrence remains unclear. We therefore examined subsequent lines of Tx and outcomes following relapse after SMART. Methods: A retrospective analysis of pts diagnosed with recurrent MPM following SMART was conducted at a single institution. OS was determined from date of relapse to death and was estimated using the Kaplan-Meier method. Potential prognostic variables were tested utilizing the log-rank test. Results: Out of 86 pts undergoing SMART from 2008 to 2016, 53 (62%) developed recurrent disease of which 36% had pathological confirmation. Two cases with initial epithelial subtype on surgical specimen relapsed with different histology (sarcomatoid and small cell). In 48% of pts, relapse was unclear at first imaging (n = 42) and a median of 98 days (range 6-966) lapsed between first suspicion and final diagnosis. The median age at relapse was 66 years (range 45-79), 47% had a performance status (PS) ≥2 (n = 45) and 64% were of epithelial subtype. After a median follow up of 7.6 mo, the median OS was 5.2 mo. PS ≥2 was associated with worse OS (2.8 vs 10.7 mo, p &lt; 0.001). Of 42 pts followed after relapse, 36% received any Tx (19% 1 line; 12% 2 lines; 5% ≥3 lines). Tx was omitted in 62% of pts due to poor PS (26/42). First line Tx consisted of platinum doublet in 93% of pts (n = 15). Of 13 pts with response evaluable disease, RR was 15% (0 CR, 15% PR). Of note, 0/13 pts had neoadjuvant Tx and 3/13 pts had adjuvant Tx (10, 13 and 38 mo lapsed between end of adjuvant Tx and start of Tx in the relapsed setting). 6/15 pts discontinued Tx due to toxicity, 5/15 due to progression and median number of cycles was 4. Conclusions: Pts with relapsed MPM following SMART have poor prognosis and low RR to first line Tx. Poor performance status at relapse is a poor prognostic factor. Earlier detection, novel diagnostic markers of relapse and consideration of maintenance strategies should be investigated in future studies.
Validation of the denaturing capillary electrophoresis (DCE) assay for non-invasive liquid biopsy in lung carcinoma: A study of concordance with the cobas EGFR mutation test v2.
Authors: Marek Minarik, Barbora Belsanova, Ondrej Fiala, Milos Pesek, Lucie Benesova
Journal: Journal of Clinical Oncology (2017)

e23040 Background: The detection of circulating tumor DNA (ctDNA), referred to as “liquid biopsy” is becoming a preferred option for some patients with lung adenocarcinomas. The key for a suitable technology is high sensitivity enabling to detect small fractions of mutated alleles, the method has to be solid against false-positives. The aim of this work was to compare our method based on capillary electrophoresis under denaturing conditions (DCE) to FDA and CE IVD approved commercial kit - cobas EGFR Mutation Test v2. Methods: A total of 44 plasma samples were acquired from patients with clinicaly confirmed stage IV lung adenocarcinoma. There were samples from patients prior to receiving therapy (with a known tissue EGFR genotype) as well as several ones showing progression on a previously administered antiEGFR-therapy (with no tissue info available at the time of plasma sampling). DNA was isolated from multiple 2 mL aliquots of each plasma. The first aliquot was run on cobas z480 real-time instrument using unmodified manufacturer's protocol. Another 2ml aliquot was run by DCE assay (accredited method under ISO 15189:2012), which is based on a PCR followed by a fragment analysis on an ABI capillary analyzer (Sanger sequencer). Results: The mutual concordance was 84.1% (37/44). cobas assay identified 11 EGFR-positive plasma samples (6 x Ex19del, 3 x L858R, 1x T790M combined with Ex19del and 1x T790M combined with L858R). DCE identified 8 EGFR-positive samples (6 x Ex19del, 1 x L858R, 1xT790M combined with L858R). DCE missed 5 of cobas-positive samples (2x Ex19del, 2x L858R and 1x T790M) while in turn identifying 2x Ex19del plasma samples that were concordant with tissue, but missed by cobas. Overall concordance with tissue was 73.3% (22/30) for cobas, 70.0% (21/30) for DCE assay and 80.0% (24/30) for both combined. Conclusions: DCE approach is reliable for low levels of mutations in plasma of lung cancer patients and comparable (and complementary) to cobas. Its advantage is simplicity, low cost and a universal, straighforward adaptability to virtually any mutation at any site allowing to detect oncogenic as well as tumor supressor mutations in ctDNA. Supported by grant 17-30748A.
Role of resection following focal progression with standard doses of imatinib in patients with advanced gastrointestinal stromal tumor: Results of propensity score analyses.
Authors: Hyungwoo Cho, Min-Hee Ryu, Ki-Hun Kim, Yongjune Lee, Jwa Hoon Kim, Minjung Kim, Sun Mi Lee, Yangsoon Park, Chan Wook Kim, Beom Su Kim, Moon-Won Yoo, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2018)

11532 Background: Although the benefits of resection for focally progressive advanced gastrointestinal stromal tumors (GISTs) during imatinib (IM) treatment have been suggested, those benefits over IM alone have not been proven. We compared the clinical outcomes of resection plus IM dose escalation or maintenance (S group) with IM dose escalation alone (NS group) in patients (pts) with advanced GIST following focal progression (FP) with standard doses of IM. Methods: Between April 2003 and October 2016, 98 pts with histologically documented initially metastatic or distant recurrent GISTs experienced FP with standard doses of IM in Asan Medical Center, Seoul, Korea. Eight pts who received sunitinib without IM dose escalation after FP were excluded; 90 pts were thus included in this analysis. The primary endpoints were time to IM treatment failure (TTF) and overall survival (OS). TTF was defined as the duration from the date of FP to the date of disease progression on IM dose escalation or intolerance. Results: The median age was 61 years (range, 31–78) and 60 pts (66.7%) were male. The small bowel (n = 51, 56.7%) was the most common primary site followed by the stomach (n = 35, 38.9%). Compared to pts in the NS group (n = 52), pts in the S group (n = 38) had a higher proportion of primary tumor site involvement (26.3% vs. 7.7%, p = 0.02) and lower tumor burden (median largest tumor size: 34 mm vs. 52 mm, p = 0.04) at FP. With a median follow-up duration of 31.0 months, pts in the S group had significantly better TTF and OS than pts in the NS group (median TTF: 24.2 vs. 6.5 months, p < 0.01; median OS: 53.2 vs. 35.1 months, p = 0.009). Multivariate analysis revealed that along with low initial tumor burden, pts in the S group independently demonstrated better TTF (hazard ratio [HR] 0.29, p < 0.01) and OS (HR 0.47, p = 0.04). Even after applying inverse probability of treatment-weighting adjustments, pts in the S group demonstrated significantly better TTF (HR 0.36, p < 0.01) and OS (HR 0.58, p = 0.049). Conclusions: Our results strongly suggested that resection following FP with standard doses of IM in pts with advanced GIST may provide additional benefits over IM dose escalation alone.