tbuckley/cabot-search huggingface dataset:
Prospective, multi-center study of 5-fluorouracil (5-FU) therapeutic drug management (TDM) in metastatic colorectal cancer (mCRC) patients treated in routine clinical practice.
Authors: Salvatore J. Salamone, Ulrich Jaehde, Lothar Mueller, Karin Link, Stefan Holdenrieder, Thomas Bertsch, Yon-Dschun Ko, Volker Kunzmann, Ingo Suttmann, Jan Braess, Max Roessler, Berta Moritz, Stefanie Kraff, Michael Craig Miller, Martin Wilhelm
Journal: Journal of Clinical Oncology (2017)

650 Background: Studies have demonstrated that body surface area (BSA)-based dosing of chemotherapy drugs leads to significant individual exposure variability with a substantial risk of under- or overdosing. This study was initiated to validate use of TDM to personalize 5-FU dosing in mCRC patients treated in routine clinical practice. Methods: 75 mCRC patients from 8 German medical centers received up to 6 administrations of infusional 5-FU according to either the AIO (n = 16), FOLFOX6 (n = 26) or FUFOX (n = 33) regimen. Initial infusional 5-FU dosing for all patients was based on BSA. Individual 5-FU exposure (AUC) was measured by an immunoassay using a blood sample drawn during each infusion. To achieve target AUC of 20 to 30 mg•h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle 5-FU AUC. Tumor markers CEA and CA19-9 were also measured before, during and after treatment. Primary objective was to confirm TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the 4 th versus the 1 st administration. Secondary objective was to determine whether 5-FU TDM reduced treatment-related toxicities compared to historical data. Results: Average 5-FU AUC at 1 st administration was 18 + 6 mg•h/L, with 64%, 33% and 3% of the patients below, within or above target AUC range, respectively. By the 4 th administration average 5-FU AUC was 25 + 7 mg•h/L (p &lt; 0.001), with 54% patients within the target 5-FU AUC range (p = 0.0294). Compared to baseline levels, CEA and CA19-9 remained stable or decreased at the end of treatment in 82% and 84% of the patients, respectively. 5-FU-related grade 3-4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%) and mucositis (0.2%) were reduced compared to historical data inspite of 55% of patients having their doses increased. Conclusions: Personalization of 5-FU dosing via TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested lower 5-FU-related toxicities. Clinical trial information: 2011-003553-26.
Profiling of small intestine neuroendocrine tumors to reveal characteristic miRNAs detectable in plasma.
Authors: Michaela Bowden, Chensheng Willa Zhou, Sui Zhang, Lauren K. Brais, Ashley Rossi, Laurent Naudin, Arunthi Thiagalingam, Ewa Sicinska, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2017)

299 Background: Current blood-based biomarkers for neuroendocrine tumors are limited. We performed a multi-stage study to identify characteristic circulating miRNAs in patients with advanced small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. Methods: Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples. We refined our panel in an independent cohort of plasma samples from 40 patients with advanced small intestine NET and 40 controls, and validated this panel in a second cohort of 120 patients and 120 controls. Results: miRNA profiling of 19 tumors and matched plasma samples revealed 31 candidate miRNAs similarly expressed in both tissue and plasma. We evaluated expression of these 31 candidate miRNAs in 40 independent cases and 40 normal controls, and identified 4 miRNAs (miR-21-5p, miR-22-3p, miR-29b-3p, and miR-150-5p) that were differently expressed in cases and controls (p &lt; 0.05). We validated these 4 miRNAs in a separate, larger panel of 120 cases and 120 controls. High circulating levels of miR-22-3p (p &lt; 0.0001), high levels of miR 21-5p, and low levels of miR-150-5p (p = 0.027) were associated with the presence of advanced small intestine NET. While levels of 29b-3p were lower in cases than in controls in both the initial cohort and the validation cohort, the difference in the validation cohort did not reach statistical significance. We further found that high levels of circulating miR-21-5p, high levels of circulating miR-22-3p and low levels of circulating miR-150-5p were each independently associated with shorter overall survival. A combined analysis using all three markers was highly prognostic for survival (HR 0.47, 95% CI 0.27-0.82). Conclusions: Our study suggests that elevated circulating levels of miR-21-5p and miR-22-3p and low levels of miR-150-5p are characteristic in patients with advanced small intestine neuroendocrine tumors, and further suggests that levels of these miRNAs are associated with overall survival.
Patient perspectives and treatment regret after de-escalated chemoradiotherapy for HPV-positive head and neck cancer: Findings from a phase II trial.
Authors: Narek Shaverdian, John Hegde, Carol Felix, Sophia Hsu, Jordan Garst, Vincent Basehart, Michael L. Steinberg, Allen M. Chen
Journal: Journal of Clinical Oncology (2017)

212 Background: We present the first data evaluating overall treatment priorities, priorities specific to de-escalated therapy, treatment regret, and original expectations versus actual experiences among patients treated with de-escalated chemoradiation for human papillomavirus (HPV)-positive head and neck cancer (HNSCC). Methods: Participants were treated on a prospective phase II trial of induction chemotherapy followed by attenuated chemoradiotherapy for HPV-positive HNSCC. Eligible patients presented with stage III or IV squamous cell carcinoma of the oropharynx, p16-positivity, age ≥ 18 years, and Zubrod score 0-1. A total tumor dose of 60 Gy or 54 Gy was delivered depending on the response to induction chemotherapy. Participants were surveyed with validated measures evaluating their treatment experience. Results: Twenty-four out of 26 (92%) study patients participated with a median post-treatment follow-up of 20 months. 96% (n = 23) of participants selected ‘being cured’ or ‘living as long as possible’ to be their top priority. The highest-ranked priority with respect to treatment de-escalation was ‘to be able to swallow all foods and drinks’. No patient professed to any regret about the decision to enroll and be treated on a de-escalation protocol. 67% (n = 16) of participants reported long-term swallowing function to be either better than or as originally expected. 71% (n = 17) found long-term salivary function to be worse than expected. Overall, 63% (n = 15) of respondents found the severity of short-term side effects to be greater than expected, however, 63% (n = 15) of respondents found overall long-term toxicities to be less than originally expected. Conclusions: Among HPV-positive patients with HNSCC who had completed de-escalated therapy on a phase II protocol, cancer cure was the top overall priority, and preserving swallowing function was the highest priority for de-escalated therapy. No patient endorsed treatment regret, and the majority of patients found long-term swallowing outcomes to be better than or as originally expected. These data support ongoing studies aiming to establish the role of de-escalated therapies for HPV-positive HNSCC.
Laparoscopic retroperitoneal lymph node dissection (L-RPLND) as therapeutic in stage I nonseminomatous germ cell testicular tumors: Findings from a referral center.
Authors: Nicola Nicolai, Francesca Gasperoni, Davide Biasoni, Nicholas Tarabelloni, Mario Catanzaro, Silvia Stagni, Tullio Torelli, Luigi Piva, Afrovita Kungulli, Antonio Tesone, Patrizia Giannatempo, Daniele Raggi, Andrea Necchi, Roberto Salvioni, Giorgio Pizzocaro
Journal: Journal of Clinical Oncology (2017)

411 Background: Active surveillance or one course of BEP are the usual policies in stage I NSGTT. RPLND has been progressively abandoned due to morbidity and, mostly, to its low reproducibility. L-RPLND was introduced aiming at reducing morbidity, but few systematic data are available concerning its therapeutic efficacy. A long-term accrual in a referral center is presented. Methods: Analysis includes patients undergoing primary L-RPLND between 2000 and 2014, performed by 4 different surgeons. Patients underwent unilateral dissection according to a template in use since 1980. Adjuvant chemotherapy was provided in cases with a positive nodal ratio ≥ 25%. Regular follow-up was provided. Performance, safety and effectiveness measures have been analyzed. Results: Out of 225 patients, full data including clinico-pathologic variables and follow-up are available in 188 cases. Mean age is 31 yrs, vascular invasion is present in 37.2%. Left dissections are 52%. Fifteen (8%) cases have been converted to open RPLND. Median duration of RPLND is 200 min. Median number of removed nodes is 15 (IQR: 11-20). Complications of Clavien Dindo grade ≥ 3 are 9. Twenty-six patients have metastatic nodes (pN+) and 6 received adjuvant chemotherapy. After a median follow-up of 40 months (range: 24, 71), 11 relapses occurred: 6 (3.7%) of 162 pN0 and 5 of 20 pN+ not undergoing adjuvant chemotherapy. Infield recurrences are not reported. All relapsed patients have been rescued by first line chemotherapy. Presence of vascular invasion (p .073) and node ratio as continuous variable (p .097) are not associated with recurrence considering all cases, while conversion to open RPLND is significant (p .019), considering patients operated by the two surgeons with homogeneous variables. Conclusions: L-RPLND in a referral centre is a safe procedure and is apparently effective as open surgery, as there is no an excess of relapses in pN0 cases (3.6%), and the proportion of relapses in pN1 (25%) compares with the traditional figures of open surgery. Conversion to open surgery may be a marker predicting recurrence in a mature phase of experience.
Efficacy of docetaxel chemotherapy in metastatic prostate cancer (mPC) patients (pts) experiencing early castration resistance (CR).
Authors: Olivier Huillard, Laurence Albiges, Jean-Christophe Eymard, Christophe Massard, Mario Di Palma, Bernard J. Escudier, Karim Fizazi, Yohann Loriot
Journal: Journal of Clinical Oncology (2013)

5075 Background: mPC pts experiencing a short period of sensitivity to initial androgen deprivation therapy (ADT) have an unfavourable prognosis and lower probability of response to 2nd-line endocrine therapy suggestive of androgen receptor (AR) pathway-independent mechanisms of resistance. Recent studies have shown that docetaxel may kill PC cells through AR targeting. We thus investigated whether docetaxel may have efficacy in pts with early CR. Methods: Two independent prospective databases (Institut Gustave Roussy and Institut Jean Godinot) of mCRPC pts were analyzed. Early CR was defined as progression within the first year of ADT. The primary endpoint was time to progression (TTP) on docetaxel. Secondary criteria were clinical benefit (decrease in 2 points on a 0-to-10-pain-scale or in dose or type of pain medication), PSA response (decrease &gt; 50% in PSA serum level) and overall survival (OS). Pts with early CR were compared to pts with sensitivity to initial ADT &gt; 1 year (t-test for quantitative data, χ-2 test or Fischer’s exact test for qualitative data, Logrank test for TTP and OS). Results: 188 pts were selected for analysis. A higher frequency of unfavourable prognostic factors in pts with early CR as compared with others pts was observed with a median PSA serum level of 81 ng/dl (4-8000) vs 35 ng/dl (4-4260) (p=5.10 -5 ), presence of visceral metastasis in 11% vs 2% of pts (p=0.01) and Gleason score ≥ 8 in 63% vs 41% of pts respectively (p=0.001). Clinical benefit and PSA response on docetaxel were observed in 84% vs 89% of pts (p=0.45) and 67% vs 81% of pts (p=0.10) respectively. Median TTP was 6.1 months (95%CI=6-7.5) vs 7.8 months (95%CI=7-8.3) (p=0.04). Median OS was 22.4 months (95%CI=17.1–28.6) vs 36.1 months (95%CI=26.3–42.4) (p=0.002). Conclusions: mPC pts experiencing early CR have more unfavourable baseline prognostic factors, shorter TTP on docetaxel and shorter OS as compared with pts experiencing time to CR &gt; 1 year. However, similar clinical and biological benefits from docetaxel chemotherapy were observed in this subset of pts. Since they have lower probability of response to second-line endocrine therapy, docetaxel appears as the best option after progression on initial ADT.
A phase 2, multicenter study of FOLFIRINOX followed by ipilimumab in combination with allogeneic GM-CSF transfected pancreatic tumor vaccine in the treatment of metastatic pancreatic cancer.
Authors: Rina Khatri Patel, Andrew H. Ko, Beth Onners, Jennifer N. Uram, Rose Parkinson, Elizabeth Sugar, Eric Lutz, Lei Zheng, Daniel A. Laheru, Elizabeth M. Jaffee, Dung T. Le
Journal: Journal of Clinical Oncology (2014)

TPS4160 Background: Combinatorial strategies aimed at priming tumor antigen-specific T cells while simultaneously blocking negative immune checkpoints may improve immunotherapy for immune tolerant cancers such as pancreatic adenocarcinoma (PDA). In a previously reported trial, concurrent administration of an allogeneic GM-CSF transfected pancreatic tumor vaccine and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, ipilimumab (IPI), which blocks an inhibitory signal on T cells resulted in both CT scan regressions and CA19-9 declines in heavily preteated patients. This proposal will test vaccine + IPI in patients with metastatic PDA who have stable disease (SD) with upfront FOLFIRINOX (5-FU/irinotecan/oxaliplatin) chemotherapy. Integrating immunotherapy after upfront chemotherapy has several advantages. Chemotherapy can debulk the tumor and predispose cancer cells to cell death mediated by immune cells. Immunotherapy can take weeks to months to be effective and is therefore more likely to work in patients with SD. Vaccine + IPI showed promise in heavily pre-treated patients and giving it immediately after front line chemotherapy may improve activity. Methods: This is a phase 2, multicenter, randomized, controlled, open-label trial in patients with metastatic PDA who have SD after 8-12 doses of FOLFIRINOX. 92 patients will be randomized 1:1 to Arm A (vaccine + IPI) or Arm B (continue chemotherapy per standard of care). Patients on Arm A will receive vaccine + IPI (10mg/kg) every 3 weeks for 4 doses then every 8 weeks. The primary objective of the study is to compare the overall survival (OS) of Arm A vs Arm B. Secondary objectives include: assessment of safety, progression-free survival (PFS), immune-related PFS, duration of response, objective response rate by RECIST and immune-related response criteria, and tumor marker kinetics (CA 19-9). Exploratory objectives include: identification of predictors of response and toxicity using proteomic techniques, assessment of T cell responses and genomic and IHC analyses of tumor tissue. (FDA Office of Orphan Products Development, R01FD004819-01). Clinical trial information: NCT01896869.
KRAS aKtive, an Italian network for assessment of KRAS mutations in colorectal cancer patients: Results on 7,432 cases.
Authors: Antonio Marchetti, Carmine Pinto, Gian Luigi Taddei, Claudio Clemente, Giancarlo Troncone, Antonio Russo, Gabriella Fontanini, Luigi Maria Larocca, Marcella Mottolese, Giuseppe Giannini, Luigi Ruco, Elena Roz, Aldo Scarpa, Giuseppe Calabrese, Beatrice Bortesi, Salvatore Vaccarella, Antonio Cossu, Vienna Ludovini, Nicola Normanno
Journal: Journal of Clinical Oncology (2012)

e14042 Background: The KRAS aKtive program was started on March 2009, promoted by the Italian Association of Medical Oncology (AIOM) and the Italian Society of Surgical Pathology and Cytopathologyy (SIAPEC) to support the activity of oncologists and pathologists involved in the management of metastatic colorectal cancer patients who need the assessment of the mutational status of the KRAS gene. Methods: The program was specifically devised to facilitate the exchange of biologic material, clinicopathological data and diagnostic reports within a network of oncologist, pathologists and pathology/molecular biology reference laboratories throughout Italy, connected through the site www.kras-aKtive.it. KRAS mutation analysis was performed by Sanger sequencing (SS), real time PCR or other techniques, including pyrosequencing and hybridization strip assays. Data were collected in a common database. Results: The KRAS aKtive program has involved 478 oncologists, 144 pathologists, and 24 reference laboratories. A total of 7,432 KRAS mutations analyses were performed. The tests were informative in 7,265 cases (98%). The vast majority of tests (5,626 cases, 77.4%) were conducted by SS. In 529 (7.3%) cases a real-time PCR assay was used, other detection techniques were used in 1,110 (15.3%) cases. KRAS mutations at codons 12-13 were detected in 2,874 cases (39,6%). The frequency of mutations detected by real-time PCR or other techniques (45%, and 43%, respectively) was significantly higher (p=0.002, and p=0.008%, respectively) than that observed by SS (38%). The percentage of cases evaluated by non-SS-based methods has increased during the first three years of the program. Conclusions: The results of this large survey allow an accurate estimation of the actual prevalence of KRAS mutations and their types in caucasian colorectal cancer patients. Our data indicate that the frequency of mutations detected by non-SS-based methods is higher than that obtained by SS.
Beneficial trends of second-line chemotherapy in advanced pancreatic cancer.
Authors: Milton Jose B. Silva, Joyce Maria L. Maia, Adriana Regina G. Ribeiro, Ludmilla T. D. Chinen, Tadeu Ferreira Paiva Jr, Fernando Vidigal Padua, Flavio Augusto Ismael Pinto, Elizabeth Santana Santos, Celso Lopes Mello, Daniel Campanha, Augusto Akikubo Rodrigues Pereira, Marcello Ferretti Fanelli
Journal: Journal of Clinical Oncology (2012)

e14680 Background: Despite the lack of high-quality clinical trial data suggesting that second-line chemotherapy (SLC) may affect survival on metastatic pancreatic cancer (mPC), most of centers utilizes them after the failure of initial treatment in patients who maintain a good performance status. The aim of the present study was to review our institutional experience with SLC and estimate its role in overall survival (OS). Methods: We performed a retrospective matched case-control analysis based on search of medical records in 106 consecutive patients with mPC at our institution. Patients received first line chemotherapy (FLC) and SLC (n = 49) or FLC only (n =57) from September 2005 to December 2010. Case matching was performed with respect to age (&lt; 60y versus ≥ 60y), topography (head of the pancreas versus body or tail), sites of metastasis. Overall survival was analyzed by Kaplan-Meier method. Results: Median age was 63 (32-86) and 60 (38-85) for SLC group and FLC group respectively. There was no significant difference between the two groups regarding topography, TNM stage at diagnosis, and sites of metastasis. The main site of metastasis was the liver (24,4%), followed by peritoneum (2,8%).Median follow-up of both groups was 8.4 months (0.23m-54.93m). First line treatment consisted of Gemcitabine (55.1% x 49.1%) and gemcitabine + cisplatin (18.4%x14%) in SLC and FLC group respectively. The most used second line treatment was Capecitabine (32.7%), followed by Folfox (16.3%), and Fluoracil (10.2%). The Kaplan-Meier estimate of the overall median survival, 1-year and 2-years survival rate was 15.72 months versus 7.2 months (p:0.021), and 60% vs. 32%, and 30% vs. 19% in SLC and FLC group, respectively. Conclusions: Our result suggests that second-line chemotherapy may be beneficial to improve overall survival in patients with advanced pancreatic cancer. It’s important that new and ongoing clinical trials clarify which is the best chemotherapy scheme in this setting.
Breaking a Vicious Cycle
Authors: Klaus Ley
Journal: New England Journal of Medicine (2017)

In this issue of the Journal, Moutsopoulos et al.1 report on a patient with leukocyte adhesion deficiency type 1 (LAD1) who was successfully treated with ustekinumab, a monoclonal antibody to the p40 subunit common to interleukin-12 and interleukin-23. Patients with LAD1 have defective neutrophil adhesion, which results in few neutrophils making it into inflamed tissues. Typical locations of chronic inflammation in these patients include mucosal, skin, and periodontal sites. During 14 months of ustekinumab treatment, the patient’s severe chronic periodontitis and a deep sacral ulcer largely resolved.Blocking of p40 is unlikely to restore defective neutrophil function in patients with . . .
The Multiple Myeloma Research Foundation (MMRF) CoMMpassSM Study: A Longitudinal Study in Newly-Diagnosed Multiple Myeloma Patients to Assess Genomic Profiles, Immunophenotypes and Clinical Outcomes
Authors: Michael N. Needle, Beverly Harrison, Carolyn Hoban, Pamela G. Kidd, Scott Jewell, Thomas Monroe, Jonathan J Keats, John Carpten, Louise M. Perkins, Kenneth Anderson, Sagar Lonial
Journal: Blood (2012)
High-dose neoadjuvant intensity modulated radiotherapy/chemotherapy for distal rectal cancer followed by rectal sparing TEM.
Authors: Albert S. DeNittis, Kinjal Parikh, Erik L. Zeger, Gerald J. Marks, John Marks
Journal: Journal of Clinical Oncology (2017)

756 Background: In patients with distal rectal cancer, preoperative chemoradiotherapy remains the standard of care, however intensity modulated radiation therapy (IMRT) followed by trans-anal endoscopic microsurgery (TEM) may be able to provide more conformal and higher hoses of radiation while sparing normal tissue. It is our intent to present 11 years of experience of patients treated concurrently with chemotherapy and IMRT followed by rectal sparing TEM. We will report on local control, disease free survival (DFS), and toxicity. Methods: Forty-two patients at Lankenau Medical Center were treated for distal rectal carcinoma with IMRT and TEM from 2004 to 2016. Patients staged T1-T3 N0 M0 received 5580 cGy to the pelvis using a 9 field plan or volumetric arc therapy targeting rectal tumor and pelvic lymph nodes. The median age was 68. All patients received concurrent 5FU based chemotherapy; 54% received an infusional regimen and 46% received oral capecitabine. All patients went on to surgery with full thickness local excision via TEM. 38 underwent surgery within 7-12 weeks following neoadjuvant therapy, with median time to surgery at 11 weeks. Results: Median time to follow up time was 33 months. Complete pathologic response was achieved in 38% (n=17) of patients, good partial response in 53% (n=22), and moderate response in 6%. 4 patients had local recurrence all achieving long term control with salvage surgery. 5 patients developed distant metastasis, most commonly to the liver. Of those, 1 died from metastatic disease, occurring 11 years after initial diagnosis. 79% of patients are currently alive with no evidence of disease. Mean DFS calculated with Kaplan Meier analysis was 88 months with 95% confidence interval between 76 and 101 months. Toxicity was acceptable with only one grade 2 toxicity (diarrhea), and two patients with grade 1 neutropenia. Conclusions: Our 11 year patient experience has shown that neoadjuvant chemoradiotherapy with IMRT followed by TEM is an effective and well tolerated treatment regimen for distal rectal carcinoma. In the appropriately selected patients, local excision surgery may provide an excellent option for patients other than low anterior resection (LAR).