tbuckley/cabot-search huggingface dataset:
Delivery and effectiveness of adjuvant therapy for stage III colon cancer in routine clinical practice.
Authors: Valerie Heong, Michael Jefford, Hui-Li Wong, Joseph James McKendrick, Jayesh Desai, Jeanne Tie, Suzanne Kosmider, Kathryn M. Field, Ben Tran, Susie Bae, Matthew Croxford, Ian Jones, Malcolm Steel, Peter Gibbs
Journal: Journal of Clinical Oncology (2014)

e14540 Background: Many retrospective studies have concluded that adjuvant chemotherapy for stage III colon cancer is underutilised in routine clinical practice, particularly in elderly patients. Reasons for this are not fully understood, but limited data confirming the efficacy of adjuvant therapy in routine care may be impacting clinician recommendations. Methods: Data related to treatment and outcomes was prospectively collected on consecutive patients with colorectal cancer attending five Australian hospitals between January 2003 and December 2013. Every patient was discussed with or referred to a medical oncologist. For any patient where adjuvant therapy was not delivered, reason(s) were documented by clinicians. Variation with age was assessed comparing young (less than 65 years), mid range (65-75 years) and elderly (over 75 years) patients. Results: Of 5,107 patients with colorectal cancer 987 had stage III colon cancer. Median age was 67.8 years (range 15 - 92) with 52.9% male patients. Overall, 822 (78.4%) received adjuvant therapy, including 95.3% of young patients, 90.6% of mid range and 57.6% of the elderly. Age alone was the reason for not recommending treatment in 33 elderly patients (24.6%), with comorbidity being a more important consideration. The percentage of patients declining recommended treatment increased with age, 1.7% young versus 5.2% mid range vs 9.1% elderly patients. Gender, risk of recurrence (N1 vs N2 nodal disease) and socioeconomic status (IRSAD score) did not appear to impact clinician recommendations or patient acceptance. Receipt of adjuvant therapy was associated with an improved distant recurrence free survival (68.3% vs 54.2%, p<0.0001) and overall survival (75.6% vs 37.8%, p<0.0001) at 5 years. Conclusions: In routine clinical practice administration of adjuvant chemotherapy for stage III colon cancer declines with advancing age. Clinician recommendation is the dominant factor, considering age and co-morbidity. However, older patients are more likely to decline recommended treatment. When accepted, delivery of adjuvant therapy in routine clinical care is associated with a significant recurrence free and overall survival benefit.
Effect of 3 years of biannual mass drug administration with albendazole on lymphatic filariasis and soil-transmitted helminth infections: a community-based study in Republic of the Congo
Authors: Sébastien D S Pion, Cédric B Chesnais, Gary J Weil, Peter U Fischer, François Missamou, Michel Boussinesq
Journal: The Lancet Infectious Diseases (2017)
A phase I dose-escalation and pharmacokinetic study of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) carboplatin at the time of primary cytoreductive surgery for advanced ovarian, fallopian tube, and peritoneal carcinomas.
Authors: Leslie M. Randall, Dan Gillen, Fong Wu Liu, Krishnansu Sujata Tewari, Ramez Hassef Eskander, Kristine Renee Penner, Robert Bristow
Journal: Journal of Clinical Oncology (2015)

TPS5615 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) administered at the time of cytoreductive surgery (CRS) for ovarian cancer has the potential to permit immediate regional therapy to the lowest achievable disease burden. Though evidence supporting its efficacy in ovarian cancer is lacking, HIPEC is gaining popularity in the clinical setting. Doses and agents administered are chosen empirically without pharmacokinetic (PK) data. Therefore, we are conducting a phase I dose-escalation and pharmacokinetic study of HIPEC carboplatin (NCT02199171) to inform a follow-on randomized phase II study. Methods: Women (n = 30) with presumed stage IIC-IVA ovarian, tubal, or peritoneal carcinomas who are planned for primary or interval CRS following neoadjuvant chemotherapy are eligible. Those optimally or completely cytoreduced and stable for continued anesthesia receive a 60-minute, closed-abdomen infusion of carboplatin at 41oC according to a novel, continual reassessment dose escalation schema that is flexible to interpret adverse events attributable to surgery vs. those of HIPEC. Serum and peritoneal perfusate are collected for PK studies at time 0 and at every 15 minutes for the duration of the infusion. DNA platinum uptake is measured by inductively coupled plasma mass spectroscopy (ICP-MS). Median, range and interquartile range will be reported for the amount of carboplatin absorbed from the perfusate, the rate of drug absorption from the peritoneal cavity into the systemic circulation, the 0-to-60 min AUC’s for peritoneal and plasma platinum concentration curves, the total body clearance, and regional advantage. Three small, easily resectable tumors are left in situ during the perfusion for correlative studies which include direct measurement of tissue temperature in tumors and control avascular mesentery, levels of platinated DNA by ICP-MS in tumors exposed to HIPEC, and expression of Hsp90 in tumors before and after HIPEC. Clinical trial information: NCT02199171.
Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials
Authors: Carolyn Taylor, Candace Correa, Frances K. Duane, Marianne C. Aznar, Stewart J. Anderson, Jonas Bergh, David Dodwell, Marianne Ewertz, Richard Gray, Reshma Jagsi, Lori Pierce, Kathleen I. Pritchard, Sandra Swain, Zhe Wang, Yaochen Wang, Tim Whelan, Richard Peto, Paul McGale
Journal: Journal of Clinical Oncology (2017)

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.
In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-Guide RNAs in Animal Models
Authors: Chaoran Yin, Ting Zhang, Xiying Qu, Yonggang Zhang, Raj Putatunda, Xiao Xiao, Fang Li, Weidong Xiao, Huaqing Zhao, Shen Dai, Xuebin Qin, Xianming Mo, Won-Bin Young, Kamel Khalili, Wenhui Hu
Journal: Molecular Therapy (2017)

CRISPR-associated protein 9 (Cas9)-mediated genome editing provides a promising cure for HIV-1/AIDS; however, gene delivery efficiency in vivo remains an obstacle to overcome. Here, we demonstrate the feasibility and efficiency of excising the HIV-1 provirus in three different animal models using an all-in-one adeno-associated virus (AAV) vector to deliver multiplex single-guide RNAs (sgRNAs) plus Staphylococcus aureus Cas9 (saCas9). The quadruplex sgRNAs/saCas9 vector outperformed the duplex vector in excising the integrated HIV-1 genome in cultured neural stem/progenitor cells from HIV-1 Tg26 transgenic mice. Intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 excised HIV-1 proviral DNA and significantly reduced viral RNA expression in several organs/tissues of Tg26 mice. In EcoHIV acutely infected mice, intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 reduced systemic EcoHIV infection, as determined by live bioluminescence imaging. Additionally, this quadruplex vector induced efficient proviral excision, as determined by PCR genotyping in the liver, lungs, brain, and spleen. Finally, in humanized bone marrow/liver/thymus (BLT) mice with chronic HIV-1 infection, successful proviral excision was detected by PCR genotyping in the spleen, lungs, heart, colon, and brain after a single intravenous injection of quadruplex sgRNAs/saCas9 AAV-DJ/8. In conclusion, in vivo excision of HIV-1 proviral DNA by sgRNAs/saCas9 in solid tissues/organs can be achieved via AAV delivery, a significant step toward human clinical trials.Graphical abstract
High Rate of Engraftment Syndrome in Elderly Patients with Multiple Myeloma Receiving Autologous Peripheral Blood Stem Cell Transplantation
Authors: Phyllis McKiernan, David Siegel, David H. Vesole, Themba Nyirenda, Scott D. Rowley, Alan P Skarbnik, Ann Ferolin-Ocot, Daniel Kim, Neil Shah, Michele L. Donato
Journal: Blood (2015)
Eribulin in advanced urothelial cancer (AUC) patients (pts): A California Cancer Consortium trial—NCI/CTEP 7435.
Authors: David I. Quinn, Nora Ruel, Przemyslaw Twardowski, Susan G. Groshen, Tanya B. Dorff, Sumanta Kumar Pal, Walter Michael Stadler, Ana Aparicio, Primo Lara, Edward M. Newman
Journal: Journal of Clinical Oncology (2015)

4504 Background: There is an unmet need for new agents in AUC. We previously reported that eribulin, a microtubule modulator derived from black Pacific sea sponge toxin, is highly active against metastatic UC in frontline and previously treated settings (ASCO 2010; ECC 2013). Here we report composite results of 150 AUC pts treated in a single phase II trial. Methods: Eligible pts with AUC, calculated CrCl ≥ 20mL/min were treated in 3 cohorts of first line, 2nd line with or without tubulin exposure. Eribulin 1.4mg/m2 IV on d1 & 8, q3 wks. In each cohort RR > 20% considered promising; 41 pts in a Simon 2-stage design. PFS & OS were secondary endpoints. Results: Pt characteristics: Median age 68 yrs (range: 25-90); Males: 71%; KPS ≥ 90%: 57%; Transitional cell histology: 90%; Lower tract 88%, Visceral mets 67%, Bajorin risk groups: 0: 30%, 1: 61%, 2: 9%. Bajorin risk group, visceral mets +/- KPS associated with OS & PFS (p < 0.01) while renal fn, age, line of therapy & prior tubulin exposure did not. Toxicities included Gr3/4 neutropenia: 57%, FN: 4%, Gr3 Hb: 13%, Gr1/2 sensory neuropathy: 45%. Age > 70 associated with Gr3+ neutropenia, no factors including tubulin exposure predicted neuropathy, developing any Gr3+ toxicity associated with age > 70 & KPS. Conclusions: Eribulin exceeded the prespecified benchmark in all strata with highly encouraging single agent activity in AUC. Phase III evaluation of eribulin in AUC is warranted. (NCT00365157; UM1 CA186717; U01 CA062505; P30 CA014089; P30 CA033572). Clinical trial information: NCT00365157.Endpoint summary. Overall (n = 150) Normal renal fn# (n = 121) Moderate renal dysfn (n = 17) Severe renal dysfn (n = 12) First line (n = 52) Tubulin naïve (n = 53) Tubulin exposed (n = 45) Median OS months (95%CI) 9.6 (7.6, 2.4) 9.2 (7.1,11.9) 16.8 (4.3,40.0) 11.3 (5.1,27.4) 11.3 (7.2,40.1) 9.6 (6.2,12.6) 8.7 (6.0,14.0) Median PFS months (95%CI) 4.1 (3.5, 5.0) 4.0 (3.0, 5.0) 4.2 (2.8, 8.3) 6.1 (1.5,17.0) 4.2 (3.1, 5.6) 4.2 (2.8, 6.4) 3.9 (2.8, 5.1) % Responded (95%CI) 32 (24, 40) 31 (22, 39) 41 (15, 67) 33 (2, 65) 42 (28, 56) 28 (16, 41) 24 (11, 38) Median Stable disease wks 13.9 13.6 12.5 17.3 12.7 14.9 17 Stable disease > 12 wks/# pts with SD 42/60 31/47 6/8 5/5 13/21 16/24 13/15 # Normal renal fn: serum creat < 1.5 ULN or calc crcl > 60, Moderate 40-60, Severe 20-40
Prognostic and predictive significance of CD15 and neutrophil/lymphocyte ratio (NLR) in metastatic colorectal cancer (mCRC) patients (pts) undergoing to first-line chemotherapy (CT).
Authors: Guido Giordano, Antonio Febbraro, Eugenio Tomaselli, Domenico Parente, Nicola Forte, Dario Scrocco, Michele Venditti, Maria Lucia Sarnicola, Pietro Parcesepe, Erminia Manfrin, Andrea Remo, Massimo Pancione
Journal: Journal of Clinical Oncology (2014)

e22199 Background: Both local and systemic inflammatory response are known to occur in mCRC patients. The role of Tumor Associated Neutrophils (TANs) in peritumoral microenvironment as well as their relation with systemic inflammatory response and mCRC pts outcome is poorly understood. Methods: Tumor specimens from 50 mCRC pts (M/F:24/26) were collected and analysed by Immunohistochemistry (IHC) for inflammatory cells infiltrate. Tumor associate macrophages (CD68), tumor associated lymphocytes (CD3) and TANs (CD15) were quantified at the central part and at the invasive margin of the tumor. Aberrant CD15 and CD68 expression by cancer cells was graded as negative (NEG, up to 25%), partially positive (PP, up to75%), diffusely positive (DP, up to 100%). NLR, as expression of systemic inflammatory response, was determined on peripheral blood at the time of diagnosis. Pts outcome was evaluated both in terms of Disease Control Rate (DCR, defined as Partial Response + Complete Response + Stable Disease / PR+CR+SD) and Progression Free Survival (PFS). Results: Median age was 66 (range 48 - 85) and ECOG Performance Status (PS) was 0/1/2 in 19/18/13 pts respectively. 67.5% of pts had liver metastases and 52.5% had multiple metastatic involvement. 47% had K-Ras Wild Type status. All pts received first line CT with standard doublets alone (32.5%) or in combination with targeted agents (67.5%). Unexpectedly aberrant cancer cells CD15 positivity was detected in 75% of specimens. CD15 DP and CD3 NEG expression was related to median NLR (mNLR) of 15 (mNLR in CD15 NEG and CD3 DP was 11; p=0.032). mNLR was 8.6 in pts who achieved SD, PR or CR vs mNLR of 15.4 in pts with Progression Disease (p=0.001). Interestingly DCR was 90% in CD15 NEG pts, 50% in CD15 PP and 30% in CD15 DP (p=0.04) and mPFS was 15, 8 and 7 months in CD15 NEG, PP and DP respectively (p=0.022). Conclusions: To our knowledge, these data provide the first evidence that cancer cell immunophenotypic CD15 positivity is related to higher systemic inflammatory response. Both aberrant expression of CD15 in tumor microenvironment and high NLR could be considered as predictive of poor response and lower PFS in mCRC.
A phase 2 study of docetaxel in combination with indoximod in metastatic breast cancer.
Authors: Hatem Hussein Soliman, Susan E. Minton, Roohi Ismail-Khan, Hyo S. Han, Nicholas N. Vahanian, William Jay Ramsey, Eugene Kennedy, Charles J. Link, Daniel Sullivan, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2014)

TPS3124 Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that tumors use to create a state of immunosuppression. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have shown that indoximod combined with chemotherapy was more effective in causing tumor regressions than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer patients. Based on this data a phase 2 trial in metastatic breast cancer was initiated. Methods: The study is a 1:1 randomized, placebo controlled two arm phase 2 study. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo. Primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate per RECIST 1.1, and immune response correlative assays. Patients with measurable, histologically confirmed metastatic breast cancer, no prior chemotherapies for metastatic disease, ER+ or ER – HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients and it is currently enrolling patients in multiple clinical sites all around the US. Clinical trial information: NCT01792050.
A lexicon for hepatocellular carcinoma surveillance ultrasonography: benign versus malignant lesions
Authors: Chansik An, Gulbahor Rakhmonova, Kyunghwa Han, Nieun Seo, Jin Young Lee, Myeong-Jin Kim, Mi-Suk Park
Journal: Clinical and Molecular Hepatology (2017)

To suggest a lexicon for liver ultrasonography and to identify radiologic features indicative of benign or malignant lesions on surveillance ultrasonography.This retrospective study included 188 nodules (benign, 101; malignant, 87) from 175 at-risk patients identified during surveillance ultrasonography for hepatocellular carcinoma. We created a lexicon for liver ultrasonography by reviewing relevant literature regarding the ultrasonographic features of hepatic lesions. Using this lexicon, two abdominal radiologists determined the presence or absence of each ultrasonographic feature for the included hepatic lesions. Independent factors associated with malignancy and interobserver agreement were determined by logistic regression analysis and kappa statistics, respectively.Larger tumor size (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.183; P<0.001), multinodular confluent morphology (OR, 7.712; 95% CI, 1.053-56.465; P=0.044), thick hypoechoic rim (OR, 5.878; 95% CI, 2.681-12.888; P<0.001), and posterior acoustic enhancement (OR, 3.077; 95% CI, 1.237-7.655; P=0.016) were independently associated with malignant lesions. In a subgroup analysis of lesions <2 cm, none of the ultrasonographic features were significantly associated with malignancy or benignity. Interobserver agreement for morphology was fair (κ=0.36), while those for rim (κ=0.427), echogenicity (κ=0.549), and posterior acoustic enhancement (κ=0.543) were moderate.For hepatic lesions larger than 2 cm, some ultrasonography (US) features might be suggestive of malignancy. We propose a lexicon that may be useful for surveillance US.
Low pre-operative absolute monocyte count to predict overall survival benefit for oral cavity squamous cell carcinoma.
Authors: Timothy Bui, Jennifer Lobo Shah, Michael Kaplan, A. Dimitrios Colevas, Quynh-Thu Le, Wendy Hara
Journal: Journal of Clinical Oncology (2015)

6077 Background: With the advent of immunotherapy, the role of the immune system in cancer patients is increasingly being investigated. The role of lymphocytes as indicators of the adaptive immune response has been reported; however, the relevance of the innate immune response is unclear. Monocytes are the precursor cells to dendritic cells and macrophages. As a crude metric, we sought to determine the predictive value of the pre-operative absolute monocyte count (AMC) in patients being treated for oral cavity squamous cell carcinoma. Methods: We retrospectively reviewed 551 consecutive patients treated at the Stanford Cancer Institute from 1998-2013 for oral cavity squamous cell carcinoma with surgical resection followed by adjuvant therapy if indicated. Patients treated for recurrent disease and metastatic disease were not included. The reference range for AMC is 0.3-0.95 K cells per microliter. For this study, a low AMC was defined as less than 0.5 K cells per microliter. Survival estimates were determined using the Kaplan-Meier method, and recurrence rates were determined using cumulative incidence estimates including competing-risk analyses. Results: In this cohort, 160 patients had a low AMC, and 391 patients had an AMC greater than or equal to 0.5 K cells per microliter. There was no statistically significant difference in T stage and N stage between patients with a low AMC compared to the remainder of the cohort. For the 119 patients who underwent adjuvant radiation therapy, those with a low AMC had improved overall survival at 2 years, 83% vs 53%, and at 5 years, 62% vs 33% (p = 0.02). For patients who did not undergo adjuvant radiation therapy, low AMC did not impact overall survival (p = 0.24). Conclusions: In addition to the adaptive immune system, the innate immune system may be relevant to cancer outcomes. Further investigation is required to understand the mechanisms leading to these observations.
Rehabilitation of cognitive dysfunction in brain tumor patients.
Authors: Nadine M. Richard, Lori J. Bernstein, Warren P. Mason, Normand Laperriere, Caroline Chung, Barbara Ann Millar, Catherine Maurice, Kim Edelstein
Journal: Journal of Clinical Oncology (2015)

TPS9637 Background: Quality of life is increasingly recognized as important to comprehensive cancer care. Individuals with brain tumors face the particular challenge of cognitive impairment from their disease and/or treatment effects. Prevalent deficits in processing speed, memory, attention and executive functions interfere with patients' interpersonal relationships, occupational activities and functional independence. Standard medical care typically provides minimal education or intervention for cognitive symptoms. Cognitive rehabilitation is a relatively new field, with very few well-controlled studies in cancer patients. As a result, oncology and supportive care teams lack accessible, reliable tools to address cognitive dysfunction. Methods: Building on research in other cognitively-impaired populations, we designed two behavioural interventions for brain tumor patients. Each offers a structured yet client-centered program through 8 weekly individual treatment sessions and between-session exercises. Goal Management Training (GMT) is a neuroscience-based intervention combining mindfulness practice and strategy training. The Brain Health Workshop (BHW) is a supportive psycho-educational program about the brain, cognition, and living with effects of a brain tumor. Using a prospective randomized controlled design, 54 brain tumor patients (with chronic cognitive dysfunction, ≥ 3 months post-radiation or surgery) are being enrolled in one of three study arms: GMT, BHW, or standard care (wait-list control). Patients complete a battery of tests assessing cognitive functioning, daily functioning, and quality of life (1) prior to intervention, (2) after the 8-week behavioural intervention (or wait-list) period, and (3) after an additional 4 months to evaluate longer-term outcomes. Analyses of variance will examine treatment effects, with regression analyses to explore moderating effects of participant demographics, severity of baseline cognitive impairment, and tumor and treatment factors (e.g., tumor location, radiation dose and distribution). Results of this trial will lay the groundwork for implementation of evidence-based cognitive interventions for brain tumor and cancer patients across other disease sites.