tbuckley/cabot-search huggingface dataset:
Semaphorin 4D to suppress bone formation in multiple myeloma.
Authors: Konstantinos Lontos, Juraj Adamik, Peng Zhang, Quanhong Sun, David Roodman, Attaya Suvannasankha, Deborah Lynn Galson
Journal: Journal of Clinical Oncology (2017)

8039 Background: Myeloma bone disease is characterized by osteoclast activation and long-term osteoblast suppression. We investigated if Semaphorin 4D (Sema4D; CD100) plays a role in these processes. Sema4D has been shown to be a potent osteoblast inhibitor (Negishi-Koga T et al, Nat Med. 2011). A study recently identified that the breast cancer cell line MDA-MB-231 utilizes Sema4D to create osteolysis (Yang Y et al, PLOS One 2016). There have been previous data that Sema4D is increased in the serum of myeloma patients (Terpos et al, Blood 2012) and that co-culturing myeloma cell lines with osteocytes increases the expression of Sema4D mRNA in both (Suvannasankha et al, Blood 2016). We sought to investigate if myeloma cells are using Sema4D to suppress bone formation and if they affect the levels of Sema4D produced by osteoclasts. Methods: We used lentivirus carrying shRNA for Sema4D or control (Scr) to knock down the level of the protein in the 5TGM1 murine myeloma cell line. Knockdown was verified by qPCR and Western Blot. We subsequently co-cultured the 5TGM1 cells with the MC3T3-subclone M4 (MC4) murine stromal cell line for 2 days, removed the myeloma cells and then differentiated the MC4 cells using ascorbic acid and β-glycerolphosphate. At day 5, we analyzed the cells for Runx2 (a critical gene for the differentiation of stromal cells into osteoblasts) expression utilizing qPCR. Also, we performed qPCR in primary osteoclast (OCL) mouse cells differentiating into OCL with RANKL with or without pre-treatment with myeloma-conditioned media for 3 days before the addition of RANKL. Results: When 5TGM1-Scr were co-cultured with MC4 cells the expression of Runx2 on day 5 was decreased (p=0.02). Strikingly, the 5TGM1-shSema4D cells when co-cultured with MC4s did not have the same effect and allowed the upregulation of Runx2 expression on day 5 (p=0.01). Myeloma-conditioned media increased Sema4D expression by OCL throughout the 5 days of differentiation 2 to 3-fold (p=0.01 for day 5). Conclusions: The myeloma cells seem to be utilizing Sema4D both directly and indirectly to inhibit bone formation. Targeted therapy against Sema4D may improve outcomes and fracture-free survival for multiple myeloma patients.
Risk factors for febrile neutropenia in cancer patients treated with chemotherapy.
Authors: Leila Family, Yanli Li, Lie H. Chen, John Page, Zandra Karina Klippel, Chun Chao
Journal: Journal of Clinical Oncology (2016)

6559 Background: Several risk factors for febrile neutropenia (FN) have been identified in previous studies (eg, chemotherapy [chemo] dose intensity, advanced age, and comorbidities). The possible biological mechanisms underlying these risk factors include bone marrow suppression, impaired neutrophil function, and disturbances of barrier function and/or the microbiome. We assessed additional factors that might affect FN risk via these mechanisms, including select dermatologic, mucosal and open-wound conditions, recent surgery, recent/concurrent radiation, and recent antibiotic and corticosteroid use. Methods: We retrospectively evaluated medical records of members of Kaiser Permanente’s Southern California Health Plan who were diagnosed with non-Hodgkin’s lymphoma or lung, gastric, ovarian, colorectal, or female breast cancer between 2000 and 2009 and were treated with chemo. Patients who received prophylactic G-CSF or antibiotics were excluded. Multivariable Cox models were used to evaluate association between FN and potential risk factors in the first chemo cycle. Potential confounders (demographic/clinical/chemo) were adjusted using natural cubic spline functions of propensity scores as covariates. Results: Of the 16,956 patients included in this analysis, 68.4% were female, 61.8% were white, and mean age at cancer diagnosis was 60.4 years. In the first chemo cycle, 719 patients (4.2%) developed FN. Hazard ratios for association of FN risk with newly proposed risk factors are shown in the Table. Conclusions: Recent dermatologic conditions that might affect skin integrity and corticosteroid use increased FN risk and should be considered in managing patients treated with chemo. Association of FN risk with new risk factors. Risk Factor Hazard Ratio (95% CI) Recent dermatologic conditions (≤1 moa) 1.56 (1.033, 2.244) Recent corticosteroids (≤3 moa) 1.52 (1.219, 1.877) Concurrent radiation (≤5 db) 1.55 (0.776, 2.892) Recent mucosal conditions (≤1 moa) 1.36 (0.724, 2.312) Recent surgery (≤1 moa) 1.19 (0.996, 1.414) Recent open-wound (≤1 moa) 1.12 (0.442, 2.276) Recent antibiotics (≤3 moa) 1.04 (0.898, 1.211) Recent radiation (≤2 moa) 0.88 (0.612, 1.224) a Months before chemo start. b Days after chemo start.
Assessing the clinical feasibility of implementing a novel assessment of frailty: The electronic Rapid Fitness Assessment in diverse thoracic surgery clinics.
Authors: Robert J. Downey, Beatriz Korc-Grodzicki, Ryan Weber, Andrew J. Vickers, David Randolph Jones, Manjit S. Bains, Armin Shahrokni
Journal: Journal of Clinical Oncology (2017)

e21687 Background: The American College of Surgeons and American Geriatrics Society recommend a geriatric/frailty assessment (GA) in the preoperative evaluation. We previously reported the development and implementation of the electronic Rapid Fitness Assessment (eRFA) in geriatric clinics. The eRFA captures data on multiple GA domains, including functional activity, social support, emotional well-being, weight loss, polypharmacy, and cognitive function. We now report the feasibility of clinical implementation of the eRFA in diverse thoracic surgery outpatient settings. Methods: Over 5 months, the eRFA was implemented until used by 5 surgeons in 2 outpatient clinics. All patients presenting for initial consultation were to complete the self-reported components of the eRFA by themselves or with the help of caregivers using a tablet or desktop computer, before coming to the clinic or in the clinic. A nurse performed the timed “get up and go” test and MiniCog test. A summary report was prepared for the clinician by the time of the encounter, and the data were stored in a database and as part of the electronic medical record. Time to complete the eRFA was recorded. Results: Since initiation in 9/2016, 78% of patients (65/83; median age, 71 [range, 20-88]; 31F:34M) completed the eRFA at initial consultation with a thoracic surgeon. Median time to complete was 9 min (range, 2-50); 75% of surveys were completed by the patient alone, 23% with a caregiver, and 3% by a caregiver alone. A large number of geriatric syndromes were uncovered: 26% of patients (17/65) had abnormalities in word recall, clock drawing, and/or timed “get up and go”; 41% (27/65) needed assistance with activities of daily living; 9% needed a cane or other support to ambulate; and 26% had at least 1 fall in the last year. Conclusions: Administration of the eRFA, an electronic assessment of patient frailty, is feasible in the initial evaluation of thoracic surgery patients. Future steps include characterization of functional reserve of patients considered for surgery, creation of prognostic models, and development of clinical trials to assess means of improving outcomes in this population of patients at risk.
Measuring validity of response assessment in bone predominant metastatic breast cancer based on clinico-radiological evaluation: An Inter-observer study.
Authors: Gurdip Kaur Azad, Angela Swampillai, Ines Sandri, Paul Bassett, Hartmut Kristeleit, Mark Harries, Janine Mansi, Gary J. Cook
Journal: Journal of Clinical Oncology (2018)

e13055 Background: An accurate and reproducible reference standard for response assessment of bone metastases is prompted by the need to test novel diagnostic imaging methods and for response assessment in clinical trials of novel therapeutics but is lacking. We hypothesized that clinical response assessment, based on standard imaging {bone scans, computed tomography (CT)}, pain scores and blood tests is reproducible between oncologists. We aimed to measure inter-observer variation of treatment response assessment between oncologists at 8,12 and 24 weeks following treatment for bone-predominant metastatic breast cancer and determine optimal timing for assessment. Methods: Seventeen patients starting endocrine treatment for de-novo or progressive bone metastases in a prospective trial were included. A questionnaire, with blood biochemistry, tumor markers (ALP, CA15-3), imaging and clinical symptoms at baseline, 8,12 and 24 weeks was given to 4 oncologists. At each timepoint, patients were scored as progressive disease (PD), stable disease (SD) or partial response (PR). Non-PD (PR+SD) was analysed separately. Agreement between oncologists was evaluated using kappa (κ) statistic {poor agreement(κ < 0.20), fair(κ = 0.21-0.40), moderate(κ = 0.41-0.60), good(κ = 0.61-0.80), very good(κ = 0.81-1.0)}. Results: 47/51 responses were received for each oncologist. Similar proportions of patients were categorized as PD (5,13,5,9/47) and non-PD (42,34,42,38/47) by all oncologists. Greater variation was observed between SD (34,15,29,31/47) and PR (8,19,13,7/47). Analyzing 3 timepoints separately, fair agreement was observed at 8,12 and 24 weeks {κ = 0.31(0.17-0.46); κ = 0.31(0.16-0.45); κ = 0.36(0.20-0.53) respectively}. When classified as PD and non-PD, strength of agreement was highest at 24 weeks, κ = 0.87(0.64-1.0) compared to 8 and 12 weeks {κ = 0.40(0.20-0.59); κ = 0.30(0.10-0.49), respectively}. Conclusions: Using the clinically relevant binary classification of PD vs non-PD, 24 weeks is subject to least variation between clinicians and is the best timepoint when measuring clinical reference standard.
Risk factors, clinical outcomes, and natural history of uveal melanoma: A single institution analysis.
Authors: Glenda Maria Delgado Ramos, Fridtjof Thomas, Ari M. Vanderwalde, Matthew W. Wilson, Arnel M. Pallera
Journal: Journal of Clinical Oncology (2018)

e21631 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with an incidence of 6 cases per million in the US. We sought to describe the characteristics of our UM patients and explore associations and predictors of outcomes. Methods: We retrospectively analyzed patients with UM treated at West Cancer Center, Memphis, TN, from 07/2006 to 08/2017. Clinical characteristics and outcomes (death and metastasis) were explored. The relative importance of variables with respect to outcome was studied by time-to-event analysis using Cox proportional hazards model. Results: There were 244 patients with a median follow-up of 34 months, IQR (12, 62) (Table 1). Four patients (1.6%), all < 55 years, had metastasis at presentation, while 19.3% subsequently developed metastasis. Death occurred in 46 patients (19.2%) (mortality rate of 4.6/1,000 patient-years), of which 32 (70%) were diagnosed with metastasis, with 24 (75%) dying < 1 year from metastatic diagnosis. There was no difference in treatment modality in patients who died (p = 0.75) or developed metastasis (p = 0.41), compared to those who did not. Symptoms were present in 184 patients (75%) prior to diagnosis, with change in vision the most common (83%). Age (HR = 1.1/year, 1.02-1.08), tumor size (T4, HR = 9.8, 1.2-81) and family history (FHx) of nonmelanoma skin cancer (HR = 4.4, 1.8-11) were significant covariates for mortality; likewise for metastasis. Metastasis was the strongest predictor of death (HR = 29.1, 14.5-58.6). Younger patients had higher alcohol use (p = 0.04). Conclusions: One in 5 patients developed metastasis which was the most influential factor on mortality. Predictors of mortality and metastasis were age, tumor size and FHx of skin cancer. Most patients had preceding symptoms highlighting an opportunity for earlier recognition in primary care and primary ophthalmologic specialties. The possible association with skin cancers merits further research. Table 1. Patients' characteristics, N = 244; [n, (%)] Median age, y (range) 59 (16-89) Female 123 (50) Caucasian 235 (96) Tumor size T1 = 41 (17); T2 = 57 (23); T3 = 52 (21); T4 = 25 (10) Brachytherapy 212 (87) Choroid involvement 225 (92) Alcohol use 90 (36) Tobacco use 109 (45)
The importance of evaluation and taking care of the patient and caregiver in the oncological disease experience: A multicentre study.
Authors: Maria monica Ratti, Alessandra Portaluppi, Federica Bertin, Eleonora Franchini, Claudio Verusio
Journal: Journal of Clinical Oncology (2017)

e21551 Background: Caregiver and patient are a dyad in which the hardship of one inevitably results in a worsening of the other’s condition. Supporting caregivers so they can deal with their relatives’ cancerous condition is useful to improve both patient care and collaboration with medical teams (Zavagli et al., 2012). Burden of caregivers has psychological and physical negative impact on patients (Gritti et al., 2011). This research matches the effects of the oncological disease on the patients and the caregivers, to find similarities and differences in order to better understand their specific needs and optimizing the support provided to them in hospital setting. Methods: Two different sets of tests are composed of a particular registry paper, SF-36, MAC, BDI-II, STAI-Y, addressed to patients, and SF-36, ZBI, COPE, addressed to caregivers. The samples are made up of 250 patients (M = 107; W = 143) and 143 caregivers (M = 54; W = 89). 34% of the sample had changes in job life due the illness process (C1), while 69% of caregivers had changes in their social, working or familiar life due taking care patients (CC1). 40% of patients in sample of caregivers had received the diagnosis since less than 3 months (CD3), 23% from 3 to 6 months (CD3-6), 14% from 6 to 12 months (CD6-12) and 22% over 12 months (CD12). Results:C1 reported worse levels of “Mental Health Index” (t = 2,016; p = ,045), depression (t = -3,949; p = ,000) and anxiety (t = -3,363; p = ,001) than patients had not changes in job. CC1 had worse levels of “Mental Health Index” (t = 4,276; p = ,045) and burden (t = -6,402; p = ,000) than caregivers without changes in life. Patients who received the diagnosis since less than 3 months reported less “Fighting Spirit” coping style (F(210;8) = 2,76; p = ,006) and worse levels of “Role Limitations due to Emotional Problems” (F(211;8) = 2,346; p = ,020) than in other periods. CD12 reported worse levels of burden than CD3, CD3-6 and CD6-12 (F(136;3) = 3,67; p = ,014). Conclusions:The results suggest that patients and caregivers share a similar suffering related to life changes, but underscore a difference in the adaptation to the disease condition with increasing time from diagnosis.
Selecting patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of MGMT.
Authors: Sarit Schwartz, Fabiola Cecchi, Yuan Tian, Kerry Scott, Maria Di Bartolomeo, Federica Morano, Giovanni Fucà, Antonia Martinetti, Filippo G. De Braud, Francesca Dominoni, Massimo Milione, Maria Alessandra Calegari, Armando Orlandi, Carlo Barone, Filippo Pietrantonio, Todd A. Hembrough
Journal: Journal of Clinical Oncology (2017)

11601 Background: Temozolomide (TMZ) is a standard treatment for melanoma and glioblastoma and it has shown limited but encouraging activity in patients with metastatic colorectal cancer (mCRC). In multiple cancer types, the DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) is a resistance marker for TMZ; MGMT promoter methylation is associated with loss of MGMT expression and response to TMZ. We hypothesized that mCRC patients whose tumors expressed quantities of MGMT protein below a pre-defined cutoff would have better outcomes on TMZ than patients with MGMT expression above the cutoff. To test our hypothesis, we assessed MGMT by mass spectrometry in the tumor samples of patients with refractory mCRC and MGMT promoter methylation receiving TMZ. Methods: Archived formalin-fixed, paraffin-embedded tissue sections were obtained from 24 patients from two phase 2 trials. A pathologist marked the tumor areas, which were microdissected and solubilized. In each tumor sample, multiple protein biomarkers including MGMT were quantified with selected reaction monitoring mass spectrometry. An MGMT cutoff of 200 amol/ug was based on the limit of quantitation from a concentration curve. The Mantel-Cox log-rank and the Fisher’s exact tests were used for survival comparisons. Results: MGMT protein was detected in 13 of 24 (54.2%) colorectal tumor samples (range: 229.3-784.8 amol/µg). The overall response rate was 29%. Patients with MGMT protein levels below a cutoff of 200 amol/ug (n = 11) had a notably higher response rate than patients with MGMT levels above the cutoff (64% vs. 0%; p = 0.001 Fisher’s test). Also a longer progression-free survival was observed (4.3 vs. 1.6 months, HR = 0.36, 95% CI = 0.13-1.10, p = 0.054). Results for overall survival were consistent but not statistically significant (8.9 vs 6.9 months, HR = 0.55, p = 0.221). Conclusions: Patients with mCRC whose tumors expressed low or undetectable levels of MGMT protein had a better outcomes following TMZ treatment than their counterparts. Quantitative proteomic analysis of MGMT could potentially be used to select CRC patients for TMZ treatment. The results of validation studies are forthcoming.
Perioperative and 90-day complication rates in patients with localized prostate cancer treated with high intensity focused ultrasound (HIFU): A prospective case series study.
Authors: Claudio Bovolenta Murta, Jose Pontes Jr, Vitor Lazarini, Davi Constantin, José Ricardo Silvino, Eugenio Borges, Renato Almeida, Anderson Queiroz Rocha, Fabio Galucci, Deyvid Mattei, Joaquim Francisco de Almeida Claro
Journal: Journal of Clinical Oncology (2018)

e17083 Background: Localized prostate cancer (PC) has been treated with radical prostatectomy, radiotherapy, or active surveillance. Recently, focal treatment was introduced as an alternative option and HIFU showed promising results. However, reports on complication rate are scarce. Our aim was to evaluate the early complication rates in a prospectively cohort of patients treated with HIFU. Methods: Between April/17 and July/17, 50 patients with low or intermediate-risk localized PC were treated with Focal OneR. The following data were prospectively collected: age, BMI, ASA, PSA, ISUP, Qmax, prostate volume, treated prostate volume, Foley catheter time. We evaluated complication rate according to Clavien classification. At 3 months we assessed the incidence of any complication, PSA serum level, the IPSS score, urinary incontinence (≥ 1 pad) and erectile dysfunction by comparing pre and post-IIEF5 score. Results: Mean age was 65.6 years and all patients were followed-up at least 3 months. 25 patients were previously submitted to TURP and the mean resected tissue weight was 17.4g. The tumors were ISUP grade 1 in 62%, 2 in 34% and 3 in 4% of cases. The hemi-ablation was the treatment adopted in 70% of cases. The mean pre and post-PSA was 7.52 and 1.74. ng/mL (p < 0,001). We observed perioperative complications in 5 patients. Clavien I (40%) and IIIa (60%). At 3 months, we found complications in 52% of patients of whom 13 (26%) were urinary retention treated only with indwelling catheter. Only age and prior TURP was significantly correlated with the occurrence of any complication (p = 0.048, p = 0.002, respectively). No patient submitted to previous TURP had urinary retention. The mean pre and post-HIFU IPSS and IIEF-5 scores were 11.4 and 8.5 (p = 0.065), and 16.1 and 12.4 (p < 0,001), respectively. Only age was significantly correlated with a decrease of IIEF-5 score to less than 12 (p = 0,038). At 3 months, 7 patients were using pads (6 use only 1 pad). Conclusions: The main perioperative and 90-d complications were urinary retention which can be avoided by a previous TURP. The incidence of urinary incontinence is low and mild, but we observed a decrease of IIEF-5 score.
Phase I study of trametinib with neoadjuvant chemoradiation (CRT) in patients with locally advanced rectal cancers (LARC).
Authors: Christina Sing-Ying Wu, Terence Marques Williams, Lai Wei, Hamida Umar, Sameh Mikhail, Kristen Keon Ciombor, Emily Chan, Anne M. Noonan, Sameek Roychowdhury, Samer S El-Dika, Somashekar Krishna, Sean T McCarthy, Mark Arnold, Alan Harzman, Sherif Abdel-Misih, William Cirocco, Amber Traugott, Tanios S. Bekaii-Saab, Evan John Wuthrick
Journal: Journal of Clinical Oncology (2017)

3612 Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m 2 /day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]