tbuckley/cabot-search huggingface dataset:
A phase I study of gemcitabine and bendamustine in relapsed/refractory Hodgkin's lymphoma.
Authors: Jonathon Brett Cohen, Lai Wei, Kami J. Maddocks, Leonard T. Heffner, Amelia A. Langston, Christopher Flowers, Steven M Devine, Kristie A. Blum
Journal: Journal of Clinical Oncology (2015)

8534 Background: Salvage regimens for Hodgkin lymphoma (HL) can be challenging due to either need for inpatient admission or frequent dosing. Based on previously reported single agent activity of bendamustine (benda) and gemcitabine (gem), we conducted a phase I study of benda and gem in patients (pts) with relapsed/refractory classical HL who failed at least 1 prior therapy to determine the maximum tolerated dose. Methods: Utilizing a cohorts of 3 design, pts received gem dosed at 1000mg/m2 on day 1 and benda doses of 60mg/m2 to 120mg/m2on days 1 and 2 of each cycle for up to 6 cycles, with cycle lengths of 28 (dose levels [DL] 1-3) and 21 (DL 4-5) days. Dose limiting toxicity (DLT) was determined during cycle 1. Results: Fourteen pts (8 males) with a median age of 38.5 years (range: 23-60) and a median of 4 (range: 1-7) prior lines of therapy have completed a median of 4 cycles at DL 1 (n = 3), 2 (n = 3), 3 (n = 3), 4 (n = 4), and 5 (n = 1). Seven pts had a prior autologous transplant (ASCT), and 1 pt had a prior ASCT and allogeneic transplant. One pt only received day 1 of therapy in cycle 1 at DL 4 and was thus not considered in dose escalation determination. The benda dose was 60mg/m2 for 3 pts, 90mg/m2 for 6 pts, and 120mg/m2 for 4 pts. No DLTs have been observed. Four pts have required hospitalization, including 2 heavily pretreated pts with pulmonary symptoms after cycle 2. One underwent a biopsy that was consistent with a drug-induced pneumonitis likely gem-related, while the other had grade 5 respiratory failure that was deemed secondary to infection although a relationship with gem could not be ruled out. Additional grade 3-4 toxicities include: lymphopenia (n = 10) thrombocytopenia (n = 2), atrial fibrillation (n = 1), fever (n = 1), renal failure (n = 1), hypotension (n = 1), pneumonia (n = 1), hypoalbuminemia (n = 1), hypokalemia (n = 1), and rash (n = 1). In 13 evaluable pts, the response rate was 77% (CR, n = 3; PR, n = 7; SD, n = 2; PD, n = 1). Two pts have had an ASCT with collection of 5.1 x 106 CD34+ cells over 2 days and 4.94 x 106CD34+ cells over 3 days. Conclusions: The combination of benda 120mg/m2 with gem 1000mg/m2 is tolerable and appears efficacious. We continue to monitor closely for additional pulmonary toxicity as we complete accrual to our final dose level using a 21-day cycle. Clinical trial information: NCT01535924.
Use of DNA repair pathway analysis to predict overall survival in head and neck cancer patients treated with TFHX chemoradiotherapy
Authors: T. Seiwert, D. T. Weaver, X. Wang, J. Kutok, E. Cohen, K. Stenson, E. Vokes
Journal: Journal of Clinical Oncology (2009)

6033 Background: Concurrent chemoradiotherapy is a standard-of-care for head and neck cancer. Radiotherapy and chemotherapeutic agents damage DNA; lack of adequate repair induces tumor cell death. The network of DNA repair pathways was examined to predict TFHX chemoradiotherapy outcomes. Methods: Biopsy specimens (paraffin) from 60 HNC patients were evaluated from tissue microarrays. Samples originated from patient groups from phase I/II studies: 1) poor-prognosis radiation-naïve, 2) re-irradiation. All were treated with TFHX-based chemoradiotherapy. DNA repair biomarkers XPF, pMK2, PAR, pH2AX, FANCD2, ATM, BRCA1, RAD51, ERCC1 (clone 8F1), and p53 were explored using IHC, automated image processing, and machine reading (&gt;500 cells/read), for nuclear and cytoplasmic quantity, area, and intensity, and correlated with clinical outcome. Results: There was low inter-core variability per tumor with median patient ranking signal to noise ratio of 15.0 across all markers. Patients were stratified into short and long survival groups by determination of critical marker thresholds. Five DNA repair biomarkers (RAD51, ATM, BRCA1, XPF, FANCD2) exhibited univariate significance for overall survival (p = 2.65e-3, 1.53e-2, 4.77e-4, 8.57e-5, 1.32e-3)(additional clinical parameters multivariate analysis was not feasible due to sample size). ERCC1 was not statistically significant (p = 1.0). Pairwise biomarker combinations improved survival group discrimination. Combination of 4 DNA repair biomarkers (FANCD2, BRCA1, ATM, XPF) was also significant (p = 1.31e-4). Discriminant analysis demonstrated higher fractions of correctly identified patients in good/poor survival groups from four-marker tests. Conclusions: Five DNA repair biomarkers predicted overall survival following TFHX-based chemoradiotherapy. By contrast ERCC1 (8F1) was not significant. Combination of markers improved predictive ability in this study. The analysis of DNA repair pathways, particularly in homologous recombination, DNA damage response, and nucleotide excision repair, may be clinically useful. Validation in a larger, homogeneous patient population, and using platinum-based chemoradiotherapy, is indicated and currently ongoing. [Table: see text]
The Prostate Cancer Project (PC Project): Translational genomics through direct patient engagement.
Authors: Stephanie Anne Mullane, Corrie Painter, Michael Dunphy, Elana Anastasio, Tania Simoncelli, Kristen Zarrelli, Anthony Philippakis, Rana R. McKay, Toni K. Choueiri, Todd Golub, Eric Lander, Nikhil Wagle, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2017)

199 Background: While there has been substantial advancement in the genomic understanding of prostate cancer (PCa), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically annotated genomic data. As PCa is often treated in a community setting, where research samples are not collected, we are starting a direct-to-patient nationwide research initiative where patients can donate their medical records and biospecimens to accelerate research. Previously, we launched the metastatic breast cancer project (MBCproject; mbcproject.org) that leverages social media to engage the MBC community. Based on the initial success with this approach, we now aim to build out the PCproject. Methods: In collaboration with patients, we are developing a website to enable participation in the PCproject. Enrolled patients will be sent a saliva kit, used for germline DNA. We will also obtain medical records. Metastatic patients will also be sent a blood draw kit for circulating tumor DNA (ctDNA). Whole exome sequencing of the ctDNA will be performed. We will use the recruitment infrastructure, clinical record abstraction, and biospecimen processing developed for the MBC project. The data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: In the first year of the MBCproject, 2912 MBC patients from all 50 states enrolled. 2766 (95.0%) completed the 16-question survey about their cancer, treatments, and demographic information. 1716 (58.9%) completed the online consent form permitting acquisition and analysis of medical records, tumor tissue, and saliva samples. 936 (68.8% success rate) saliva samples have been received. To date, we have obtained medical records from 155 patients (72.1% success rate) and tumor samples from 60 patients (72.3% success rate). Based on initial recruitment and surveys among PCa patients, we estimate that 500 patients will enroll in 2017. Conclusions: Based on experience from the MBC project, we will partner directly with patients to recruit and drive the PCproject forward. Remote acquisition of medical records, saliva samples, and tumor tissue for patients located throughout the US is feasible.
Association of treatment facility case volume with survival in patients undergoing radiotherapy/chemoradiotherapy for muscle-invasive bladder cancer: An analysis of the National Cancer Database.
Authors: Amishi Bajaj, Alec Block, Brendan Martin, Mark Korpics, Courtney Hentz, Robert H Blackwell, Ellen R. Gaynor, Elizabeth Henry, Gopal Nand Gupta, Matthew M. Harkenrider, Abhishek Ashok Solanki
Journal: Journal of Clinical Oncology (2017)

295 Background: Excellent outcomes with bladder-preserving trimodality therapy have been demonstrated at centers with expertise and high-volume. Some argue that these results may not be replicated at other centers with lower case volumes. We analyzed the National Cancer Database to determine if treatment at a high-volume facility is associated with improved overall survival (OS) for patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT) for non-metastatic muscle-invasive bladder cancer (MIBC). Methods: Patients with cT2-4 N0-3 M0 transitional cell MIBC treated with RT or CRT were selected. The case volume variable was derived by calculating a count of patient records by each facility using the entire database of 439,188 patients. Multivariate analysis (MVA) was performed using the Cox proportional hazards model, which was used to assess the association of case volume with OS while controlling for clinicodemographic and treatment factors associated with OS on univariate analysis, including clustering of patients within their treatment facility type. Results: 872 patients treated with radiotherapy from 2008-2012 at 452 unique facilities were identified. 502 (58%) patients received RT, and 370 (42%) patients received CRT. The median case volume at each unique facility was 376 cases with an interquartile range of 235 – 579 cases. In the entire radiotherapy cohort, MVA controlling for patient case load, age, sex, education, T Stage, N Stage, cumulative radiotherapy dose, Charlson-Deyo comorbidity score, and geographic location, demonstrated that treatment at a facility with a higher case volume was associated with improved OS. For every 250 patient increase in facility case volume, the hazard of death at any given time for patients receiving radiotherapy decreased by 7% (HR = 0.93, 95% CI: 0.87 – 0.98, p = .01). Conclusions: To the authors’ knowledge, this is the first analysis demonstrating an association between treatment facility case volume and OS in the treatment of MIBC patients with RT or CRT. Consideration should be given to referring patients to high volume facilities for treatment of MIBC.
A phase I trial of a local delivery of siRNA against k-ras in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.
Authors: Talia Golan, Ayala Hubert, Amotz Shemi, Amiel Segal, Alan Dancour, Elina Zorde Khvalevsky, Eliel Ben-David, Stephen Raskin, Yuri Goldes, Yael Inbar, Maor Lahav, Avi Domb, Eithan Galun
Journal: Journal of Clinical Oncology (2013)

4037 Background:K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-Ras G12D (siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - miniature biodegradable polymeric matrix that encompasses anti-K-RasG12D siRNA drug, is placed with Endoscopic US biopsy and designed to continuously release the drug regionally over a period of 4 months. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in dose escalation cohorts: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m 2 IV was given weekly, following siG12D LODER insertion. The RP2D (recommended phase II dose) was further examined in 3.0 mg dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2, Fluorouracil infusion 2,400mg/m2 46 hours, every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results:15 patients have been enrolled. 2 patients were omitted from study due to metastatic disease detected on day 1 post siG12D LODER implant imaging . Median age = 70 (range 52-85); male:female 8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE), one procedure related. No DLTs were observed. MTD was not reached. CT performed 8-10 weeks following the procedure showed stable disease in all patients. Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. The median survival of 13 patients was 16 months ( 8/13 patients still alive at analysis). Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced PDAC with durable responses. Phamocodynamic endpoints are currently being examined in an expansion cohort in operable patients. A phase II randomized trial is planned in order to investigate efficacy of siG12D LODER in locally advanced non-operable PDAC. Clinical trial information: NCT01188785.
Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future
Authors: Marcus J. Schultz, Martin W. Dunser, Arjen M. Dondorp, Neill K. J. Adhikari, Shivakumar Iyer, Arthur Kwizera, Yoel Lubell, Alfred Papali, Luigi Pisani, Beth D. Riviello, Derek C. Angus, Luciano C. Azevedo, Tim Baker, Janet V. Diaz, Emir Festic, Rashan Haniffa, Randeep Jawa, Shevin T. Jacob, Niranjan Kissoon, Rakesh Lodha, Ignacio Martin-Loeches, Ganbold Lundeg, David Misango, Mervyn Mer, Sanjib Mohanty, Srinivas Murthy, Ndidiamaka Musa, Jane Nakibuuka, Ary Serpa Neto, Mai Nguyen Thi Hoang, Binh Nguyen Thien, Rajyabardhan Pattnaik, Jason Phua, Jacobus Preller, Pedro Povoa, Suchitra Ranjit, Daniel Talmor, Jonarthan Thevanayagam, C. Louise Thwaites
Journal: Intensive Care Medicine (2017)
Association of MiR-1290 and its potential targets with characteristics of estrogen receptor α-positive breast cancer.
Authors: Yumi Endo, Tatsuya Toyama, Satoru Takahashi, Nobuyasu Yoshimoto, Mai Iwasa, Tomoko Asano, Yoshitaka Fujii, Hiroko Yamashita
Journal: Journal of Clinical Oncology (2013)

614 Background: Recent analyses have identified heterogeneity in estrogen receptor (ER) α-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. Methods: In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissue were compared between ER high Ki67 low tumors and ER low Ki67 high tumors by miRNA and mRNA microarrays. Results: Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs. We identified a down-regulation of miR-1290 and up-regulations of 6 miRNAs in ER high Ki67 low tumors. We picked up 11 genes that were potential target genes of the selected miRNAs. Protein expression patterns of the selected target genes were analyzed in ER-positive breast cancer samples by immunohistochemistry: miR-1290 and its 4 putative targets, BCL2, forkhead box A1 (FOXA1), microtubule associated protein tau (MAPT) and N-acetyltransferase-1 (NAT1) were identified. Transfection experiments revealed that introduction of miR-1290 into ER-positive breast cancer cells decreased mRNA and protein expression of NAT1 and FOXA1. Conclusions: Our results suggest that miR-1290 and its potential targets, NAT1 and FOXA1, might be associated with characteristics of ER-positive breast cancer.
Marrow-ablative chemotherapy followed by tandem autologous hematopoietic cell transplantation (AuHCT) in pediatric patients with malignant brain tumors.
Authors: Jhon Guerra, Girish Dhall, Araz Marachelian, Esmeralda Castillo, Jemily Malvar, Richard Sposto, Kenneth Wong, Jonathan L. Finlay
Journal: Journal of Clinical Oncology (2013)

2049 Background: In an effort to both improve cure rates and quality of survival in young children with malignant brain tumors, irradiation-avoiding or at least minimizing marrow-ablative chemotherapy with AuHCT has been incorporated in both up-front as well as recurrent therapies. To decrease the toxicity of single cycle marrow-ablative chemotherapy regimens, and possibly enhance cure through overall dose intensification, use of fractionated multiple (tandem) cycles of marrow-ablative chemotherapy with AuHCT has been explored. Methods: In this retrospective analysis, we investigated the outcome of children with malignant brain tumors treated with marrow-ablative chemotherapy and tandem AuHCT at Children’s Hospital Los Angeles between June 1999 and July 2012. Results: Forty-four children (24 males) with a median age of 7.1 years (range 0.6- 19.0 years) with malignant brain tumors were studied. Twenty-one had medulloblastomas/primitive neuro-ectodermal tumors, 8 atypical teratoid/rhabdoid tumors, 5 high-grade gliomas, 4 malignant germ cell tumors, 3 ependymomas and 3 choroid plexus carcinomas. Twenty-nine patients receive 3 and 15 received 2 tandem transplants, respectively. Twenty-seven patients were newly-diagnosed and 17 recurrent disease. Thirty-one patients received irradiation at some time. The 5-year post-transplant progression-free (PFS) and overall survivals (OS) for all patients were 46.3±8.2% and 51.7±8.5% respectively. The PFS and OS for newly-diagnosed patients were 68.9 ± 9.9% and 73.5±9.3% respectively, compared with those transplanted at relapse 11.8±9.8 (p &lt;0.001) and 15.1±12.3% (p = 0.0231) respectively. The 5-year post-transplant PFS and OS in unirradiated patients was 74.0±13.0% and 74.0±13.0% versus33.2±9.8% and 40.2+/-10.6% in irradiated patients (p = 0.11 and p = 0.239 respectively). One patient (2.3%) died of transplant-related toxicity. Conclusions: Marrow-ablative chemotherapy with tandem AuHCT is feasible and safe in children with malignant brain tumors with encouraging irradiation-free survival in newly-diagnosed children.
Neoadjuvant therapy with nanoparticle albumin-bound (nab)-paclitaxel to enhance the resectability of locally advanced pancreatic cancer (LAPC).
Authors: Prasad Cooray, Andrew Peter Dean
Journal: Journal of Clinical Oncology (2012)

e14644 Background: Resection offers the only probability of cure for pancreatic adenocarcinoma but only a minority have resectable disease at diagnosis. Effective neo-adjuvant therapy for LAPC could down-size the tumor rendering it resectable. Neo-adjuvant therapy may retard cancer dissemination thought to occur early in pancreatic cancer. The aim of this study was to retrospectively evaluate if neo-adjuvant treatment with nab-paclitaxel in patients with LAPC could result in tumor down-sizing to allow resection and improve outcomes. Methods: Data was collected from the medical records of pancreatic cancer patients who presented to two clinics from 06/2009 to 12/2011 and were treated with nab-paclitaxel (n = 63). Resectability was assessed by review of imaging by the radiologist and the treating surgeon. Twenty three of 63 patients had LAPC and 40/63 had stage IV disease. Of the LAPC patients, 8/23 (35%) were classified as borderline resectable (BR) and 15/23 (65%) were classified as unresectable (UR). Patients received nab-paclitaxel (100-125 mg/m 2 D1,8,15) in combination with gemcitabine or carboplatin. The BR/UR patients (n=23) received a median 5 cycles of chemotherapy. They were re-evaluated for suitability for surgical resection. Results: Following neo-adjuvant treatment, 16/23 (69%) had a radiological PR and 17/23 (74%) had a major biochemical response (defined as &gt;70% decline in Ca19.9 level). A total of 6/23 patients (26%) were then able to undergo surgical resection, with resections planned for further 2/23 (8%) patients.Of the 6 resected patients, 4 had R0 resections and 2 had R1 resection. After a median follow up of 18 months, all 6 resected patients are alive and 4 of them remain free of cancer recurrence. The median survival for patients who remained unresectable (15/23) was 9 months. The median survival for converted patients (6/23) has not yet reached. Conclusions: These results suggest that a subgroup of patients with LAPC could be converted to a resectable stage with the use of nab-paclitaxel as neo-adjuvant therapy. Such converted patients may enjoy durable improved outcomes and this approach warrants further investigation in a phase II clinical trial.
TPF induction chemotherapy and pathologic response for patients with locally advanced and resectable oral squamous cell carcinoma.
Authors: Lai-ping Zhong, Chen-ping Zhang, Zhi-yuan Zhang, Guo-xin Ren, Wei Guo, Wen-yong Tu, Jian Sun, Han-guang Zhu
Journal: Journal of Clinical Oncology (2012)

5593 Background: The role of induction chemotherapy in locally advanced and resectable oral squamous cell carcinoma has not been well issued. Methods: A prospective, open label, parallel, and interventional randomized control trail has been performed to evaluate the induction chemotherapy of TPF protocol in resectable oral squamous cell carcinoma (OSCC) patients at clinical stage III and IVA. The patients received two cycles of TPF induction chemotherapy (75 mg/m 2 docetaxel d1, 75mg/m 2 cisplatin d1, and 750mg/m 2 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy with a dose from 54 to 66 Gy (the experimental group) or surgery and post-operative radiotherapy (the control group). Post-surgical pathologic examination was performed to determine a positive response or negative response. A positive response was defined as absence of any tumor cells (pathologic complete response) or presence of scattered foci of a few tumor cells (minimal residual disease with &lt;10% viable tumor cells). The primary endpoint is the survival rate; the secondary endpoint is the local control and safety. This study has been approved by institutional ethics committee at Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University. Survival analysis was conducted with the Kaplan-Meier method. Results: 256 patients were enrolled in this trail and 224 patients (111 in experiment group and 113 in control group) finished the whole treatment protocol. After a median follow-up of 21 months (ranging 6-43 m). The pathologic positive response rate was 29.7% (33/111), and negative response rate was 70.3% (78/111). The patients with positive response had a better disease free survival (38.5±2.1m, 95%CI 34.4-42.6m, P=0.003) compared with those with negative response (24.6±2.1m, 95%CI 20.6-28.7m) and control group (31.0±1.6m, 95%CI 27.9-34.1m). The toxicity of induction chemotherapy could be tolerated. Conclusions: Pathologic positive response to TPF induction chemotherapy could benefit the patients with locally advanced and resectable OSCC. However, further long-term follow-up is needed to confirm the benefit on survival and local control.