tbuckley/cabot-search huggingface dataset:
The TRANSERI study: Effect of eribulin (E) on circulating TGFβ and TNFα in metastatic breast cancer (mBC) patients (pts)—Relationship with outcome.
Authors: Ornella Garrone, Cristiana Lo Nigro, Andrea Michelotti, Anna Maria Vandone, Andrea Abbona, Claudia De Angelis, Federica Tonissi, Paola Vanella, Nerina Denaro, Marco Carlo Merlano
Journal: Journal of Clinical Oncology (2018)

e24129 Background: E is approved for the treatment of mBC pts after previous exposure to antracyclines and taxanes. E interferes with microtubule leading to apoptosis and cell cycle arrest in G2/M. E reverses epithelial mesenchimal transition (EMT) in human cancer cell lines and in mice. Moreover, reduces metastatization in mice. TGFβ is an immunosuppressive cytokine, is a growth factor for cancer-associated fibroblasts (CAFs) and promotes EMT. TNFα synergizes with TGFβ to promote EMT. EMT permits cancer cells trafficking thus driving metastatization. Our study investigates the interference among E and TGFβ and TNFα levels in pts and the correlation with the outcome and the metastatic spread. Methods: Blood levels of TGFβ and TNFα were determined at baseline, before cycle (C) 3, 5 and at disease progression in mBC pts treated with E at 1.23 mg/m2, d 1–8 every 21 d. Results: We report data on 24 pts who completed 5 C or progressed before C 5. We did not observe changes of TNFα during treatment. The median (M) basal TGFβ value was higher in pts than in 4 healthy volunteers (M concentrations: 232 pg/ml vs 114 pg/ml respectively). We divided our population according to basal TGFβ levels upper or lower the M value. M PFS was similar in the two groups (112 vs 100 d). TGFβ increased in 9 pts from basal to C 5, and decreased in 15 pts. We observed a numerical difference in M PFS between the pts with decreased and increased values (107 vs 82 d respectively). In 8 pts TGFβ decreased at each subsequent point. M PFS in these pts was 167 vs 84 d in the remaining. Notwithstanding the continuous decline of TGFβ, 2 of these pts progressed at C 5 (both at CNS). In pts with continuous TGFβ decline the M value approaches healthy controls (160 pg/ml [range 303-90] vs 114 pg/ml [range 120-85] respectively). At C 5 9 pts did not progress: 3 PR and 6 SD (M PFS 175 d). TGFβ decreased in all but 2 pts (1PR+1SD). In these 2 pts PD occurred as early as 21 and 30 d respectively from C 5. The behaviour of pts with SD suggests that there is no correlation between tumor burden and TGFβ level. Conclusions: Basal TGFβ does not predict outcome. TGFβ changed during treatment with E regardless of tumor load. Our results suggest that TGFβ changes correlate with outcome.
Thyroid-related laboratory abnormalities to predict treatment-limiting adverse events in melanoma patients treated with immune checkpoint blockade.
Authors: Daniel Altman, Ryan Michael Weight, Mansi R. Shah, Marlana M. Orloff, Erin Sharpe-Mills, Michael J. Mastrangelo, Takami Sato
Journal: Journal of Clinical Oncology (2016)

e14536 Background: Checkpoint inhibitors have been shown to improve outcomes in patients with metastatic cutaneous melanoma. Thyroid-related laboratory abnormalities are one of the most common abnormalities seen with these treatments. We hypothesized that thyroid-related laboratory abnormalities predict future treatment-limiting immune-related adverse events (irAEs). Methods: An exploratory study was conducted in melanoma patients (n = 85) who have received anti-CTLA-4 antibody alone (n = 26), anti-PD-1 antibody alone (n = 26) or both (n = 23) at Thomas Jefferson University. Data were collected at baseline and at the time of individual treatments by a retrospective review of electronic medical records. irAEs were categorized into the following: hypophysitis, thyroid dysfunction, lipase elevation, pneumonitis, colitis, transaminitis, acute kidney injury, and diabetes. Results: Incidence and time-to-onset in days of irAEs is shown in table. Number of patients experiencing 0, 1, ≥ 2 irAEs was 35%, 26% and 39% respectively. It is of note that 85.7% (18/21) patients with thyroid-related laboratory abnormalities subsequently developed a serious irAE that required discontinuation of treatment (pneumonitis n = 1, colitis n = 4, hepatitis n = 7, AKI n = 1, DM n = 1, hypophysitis n = 2, thyroid disease n = 2) and this is much higher in incidence compared to those without thyroid-related laboratory abnormalities (P < 0.05). Conclusions: Incidence of individual irAEs was in line with previously published rates. Thyroid-related laboratory abnormalities had a statistically significant correlation (85.7%) with subsequent development of a treatment-limiting irAE. Hypophysitis Overt thy roid dysfunction Chemical thy roid dysfunction Lipase elevation Pneumonitis Colitis Transaminitis AKI DM CTLA- 4 % 12.2 12.3 50 4.1 8.2 22 59.2 12.2 0 Onset 62 87 63 107 79 43 75 63 N/A PD-1 % 5.1 10.3 22.2 7.6 12.7 18 66 22.6 2.6 Onset 109 69 122 38 105 66 58 49 98 Both % 8.7 26.1 30.4 8.7 17.4 26 69.6 0 4.3 Onset 196 118 51 181 175 137 131 N/A 172
The effect of a geriatric oncology (GO) evaluation on treatment (Tx) decisions for older patients (pts) with cancer in Mexico.
Authors: Haydee Cristina Verduzco-Aguirre, Ana Patricia Navarrete Reyes, Nora Ivonne Reyes Martinez, Jose de Jesus Ruiz Lopez, Odin Vazquez Valdez, Juan Cuadros Moreno, Juan Miguel Antonio Garcia Lara, Yanin Chavarri Guerra, Eucario Leon Rodriguez, Jose Alberto Avila Funes, Enrique Soto Perez De Celis
Journal: Journal of Clinical Oncology (2018)

10046 Background: GO evaluations may lead to improvements in the care of older adults with cancer, but their effect on Tx decisions in everyday clinical practice needs further research. Our goal was to describe the effect of GO evaluations on Tx decisions in the first GO clinic implemented in Mexico. Methods: The records of 173 pts aged ≥65 years (y) referred to our GO Clinic before active Tx initiation from 05/15 to 10/17 were reviewed. Pts were screened with a validated tool (G8; Soubeyran et al, 2011); those deemed vulnerable (score ≤14) underwent a full geriatric assessment; and Tx recommendations were sent to the treating oncologist. We measured the proportion of patients in which there was agreement between GO recommendations and final Tx decisions, and assessed whether agreement increased in cases in which the treating oncologist’s notes mentioned the GO evaluation. Results: Median age was 79 y (range 64-97). 37% of pts had genitourinary and 32% gastrointestinal malignancies; 42% were stage IV. Proposed Tx before GO evaluation included palliative chemotherapy (CT) (32%), curative surgery/radiotherapy (31%), and neo/adjuvant CT (19%). A recommendation to administer standard Tx was made in 47% of cases, less intensive Tx in 32%, and best supportive care (BSC) in 20%. The treating oncologist’s final Tx decision matched the GO recommendation for 81% of pts, and GO recommendations were mentioned in the treating oncologist’s notes in 62% of cases. Agreement between the treating oncologist & GO clinic was higher when BSC was recommended (94%), followed by standard Tx (77%), and less intensive Tx (75%). Agreement between the treating oncologist & GO clinic was 84% when the GO evaluation was mentioned, compared to 75% when it wasn't (p = 0.16). In pts for which less intensive Tx was recommended (n = 56), agreement was 84% when the GO evaluation was mentioned, compared with 56% when it wasn't (p = 0.04). Conclusions: Agreement between GO recommendations and final Tx decisions was high, especially for cases in which BSC was recommended. Including GO evaluations in everyday clinical practice may provide useful information to guide oncologists caring for older pts, particularly when considering less intensive therapy.
Hypofractionnated stereotactic radiotherapy and anti-PDL1 durvalumab combination in recurrent glioblastoma: Results of the phase I part of the phase I/II STERIMGLI trial.
Authors: Damien Pouessel, Augustin Mervoyer, Delphine Larrieu-Ciron, Bastien Cabarrou, Justine Attal, Marie Robert, Jean-Sebastien Frenel, Pascale Olivier, Muriel Poublanc, Muriel Mounier, Elizabeth Moyal
Journal: Journal of Clinical Oncology (2018)

2046 Background: Glioblastoma (GBM) is the most aggressive primary brain tumor with inevitable local relapse and no standard treatment. Hypofractionated stereotactic radiotherapy (hFSRT) has shown signs of efficacy with tolerable safety with PFS ranging from 3.4 to 5 months, but needs improvement. Radiotherapy (RT) causes immunogenic tumor cell death but also induces PDL1 and PD1 expression on tumors and immune cells, potentially evoking resistance to RT. Pre-clinical studies combining hFSRT with an anti-PD-1 antibody in GBM have shown increased efficacy of the combination. Clinical studies also show encouraging results when checkpoint inhibitors have been combined with high dose RT. We hypothesized that combining the anti PD-L1 Durvalumab (Durva) with hFSRT will be an effective regimen for patients with recurrent GBM. We designed a phase I and a phase II clinical trials studying the combination of hFSRT with Durva for recurrent GBM≤35 mm diameter. Results of the phase I are presented. Methods: A standard 3+3 dose escalation design was used. Patients were treated by hFSRT 24 Gy, 8 Gy/fraction at 80% isodose, every other day, combined with Durva infusion 1500mg first dose (Level 1) or 750 mg (Level -1) delivered on the last hFSRT, day followed by 1500 mg Durva infusion every four weeks until relapse and for a maximum of 12 months. The schema was defined as safe if one patient or less among 6 presents a dose limiting toxicity (DLT). DLT period started on the first Durva infusion with radiotherapy until 4 weeks. Brain MRI were performed before RT and then every 8 weeks until relapse. Results: Among the 6 patients (3 methylated MGMT, 3 unmethylated MGMT) included at the level 1, all completed the hFSRT course, only one had a DLT which was an immune related grade 3 vestibular neuritis. No DLT related to hFSRT or the Durva combination was reported. No other serious adverse event (SAE), immune-related AE or AE of special interest was reported. Conclusions: Combining three 8 Gy fractions of hFSRT with 1500 mg Durvalumab on the 3rd fraction hFSRT and every 4 weeks for recurrent GBM is well tolerated justifying exploration of its efficacy in the phase II component of the study. Clinical trial information: NCT02866747.
Utility and factors associated with imaging early-stage breast cancer: Are we choosing wisely?
Authors: Ana I. Velazquez Manana, Nina Nguyen, Carlos Rodriguez Bonilla, Theresa Shao
Journal: Journal of Clinical Oncology (2018)

52 Background: Breast cancer (BC) is the most common malignancy in women with estimated care costs of $20.50 billion/year by 2020. In 2012, ASCO released the Choosing Wisely Initiative which recommended against the use of routine imaging in patients with newly diagnosed early stage BC. We examined the adherence rate and factors associated with non-adherence in patients with early stage BC treated within a large health care system. Methods: We identified all women with stage I-II BC diagnosed between January 1, 2014 and December 31, 2015 from the Cancer Registry of Mount Sinai Health System. Demographic, clinical and treatment related factors were collected. Medical records were reviewed to identify patients who had routine staging scan. Data of initial and follow-up imaging over 1-year period were collected. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Results: Among 733 BC patients, the median age at diagnosis was 58 (range 26-98). One hundred thirty nine patients (19%) had routine imaging with a mean number of initial scans of 1.53 and 59 (42%) patients had at least 1 subsequent scan in the 1-year follow up (range 1-4 scans/year). PET/CT was the most frequent modality, followed by CT. Medical oncologist was the ordering provider in 52% of the cases and surgical oncologist in 44.6%. Routine scan identified no cases of metastatic disease. False-positive findings were identified in 43% and incidental findings in 8% of cases. Total cost of imaging in this group was $4480/patient. Young age ( &lt; 50), TN disease, tumor size &gt; 2cm and positive lymph node were associated with increased staging scan on univariate and multivariate analysis. Conclusions: Our study highlights the prevalence of unnecessary scan in up to 19% of patients with stage I-II BC. Routine imaging resulted in increased radiation exposure and additional cost of $4480/patient. The presence of T2 tumor, positive lymph node, TN disease and young age were associated with increased staging scan. Further educational efforts are needed to avoid unnecessary scans in patients with early stage BC. [Table: see text]
Primary and secondary gliosarcomas: A review of clinical features and pathological diagnosis.
Authors: Jinghui Liu, Liang Wang
Journal: Journal of Clinical Oncology (2018)

e14043 Background: Gliosarcoma (GSM) is a rare primary malignant brain tumor, accounting for approximately 4 % of all malignant gliomas. GSM can be further classified into primary tumors (PGS), and secondary gliosarcomas (SGS), which are identified in patients with prior glioblastoma (GBM). Clinical guidelines for GSM are poorly defined and the patients are usually treated in accordance with existing guidelines for glioblastoma. We conducted a single-institution retrospective review all of patients diagnosed with GSM over the past 5 years. Methods: We retrospectively reviewed and analyzed the clinical data of all patients treated at our institution with a histopathological diagnosis of GSM. Various characteristics were evaluated in univariate and multivariate models to examine their effects on overall survival. Results: A total of 43 patients were included in the study. 36 of the patients were primary GSM(83.7%). The median age was 52 years with a male preponderance (1.4:1). The locations, all supratentorial, included temporal in 55.8 %, midline in 35.9 %, frontal in 16.3 % and parietal in 11.3 %. Every patient underwent resection, and 60.5% underwent gross-total resection (GTR). Median overall survival (OS) for all patients who received adjuvant therapy was 9 months from the diagnosis of GSM, with a progression free survival (PFS) of 8 months. Comparing PGS with SGS, the median OS was 12 and 8.95 months, respectively (from the time of sarcomatous transformation in the case of SGS). The median OS in SGS patients from the initial diagnosis of GBM was 19 months, with a PFS of 13 months. On histopathology, all tumours showed biphasic pattern, glial component positive for glial fibrillary acidic protein and mesenchymal component positive for vimentin. The Cox proportional hazards regression model indicated that the adjuvant therapy (P = 0.001) was the significant prognostic factor. Conclusions: Despite an overall poor prognosis, adjuvant multi-modality therapy appears to be associated with better outcomes. Therefore, GSM can be treated according to glioblastoma guidelines, but further research into the clinical and molecular-genetic characteristics of GSM is required to better understand this malignant brain tumor.
Protease-activatable cell-penetrating peptides as prodrugs for delivery of cytotoxins into tumors.
Authors: Andrew J Gale, Marcel Miampamba, Junjie Liu, Jesus E Gonzalez
Journal: Journal of Clinical Oncology (2018)

e14538 Background: Highly potent cytotoxic drug payloads such as auristatins have vast promise for treating cancer. A key component of therapeutics utilizing such cytotoxic drugs is specific delivery of the drug into tumors and tumor cells while minimizing off-target delivery. We previously developed a peptidic ratiometric fluorescent cancer imaging agent (AVB-620), which is currently in clinical trial. AVB-620 is a protease-activatable cell penetrating peptide (ACPP) that is designed to be activated by proteases that are over-expressed in the tumor microenvironment. We have now designed ACPPs conjugated to cytotoxic drugs. These prodrugs release cell penetrating peptides (CPPs) conjugated to cytotoxins when cleaved by proteases in the tumor environment. The CPPs then deliver the cytotoxin into tumor cells. Methods: We generated ACPP conjugates with several protease cleavage sites targeting different proteases and several different linkers to connect Cy5 for imaging or MMAF for cytotoxicity. Cy5 conjugated versions were used to measure cellular uptake in flow cytometry and microscopy. MMAF conjugated versions were tested for cytotoxicity in cell culture and tumor inhibition in mouse cancer models. Results: Cellular uptake varied significantly depending on the ACPP protease substrate. This was observed by flow cytometry and microscopy. In addition, the linker connecting Cy5 to the CPP impacted uptake efficiency. Free MMAF has low cytotoxicity because it is not very cell permeable. CPP-conjugated MMAF had significantly better in vitro and in vivo efficacy than free MMAF. The ACPP substrate effect on Cy5 uptake correlated with substrate effect on MMAF cytotoxicity in a cell viability assay. Different ACPP substrates also had different efficacy and toxicity in mouse in vivo cancer models. Variations in the linkers connecting MMAF to the ACPP also impacted efficacy and toxicity in vivo. Conclusions: Activatable cell penetrating peptides have great potential for delivering non-specific toxins to malignant tumors that over-express proteases. ACPP conjugation improves the efficacy of MMAF with low toxicity. Optimization of the ACPP and drug linkers can further improve the therapeutic window of these prodrugs.
Association of Medical Scribes in Primary Care With Physician Workflow and Patient Experience
Authors: Pranita Mishra, Jacqueline C. Kiang, Richard W. Grant
Journal: JAMA Internal Medicine (2018)

Widespread adoption of electronic health records (EHRs) in medical care has resulted in increased physician documentation workload and decreased interaction with patients. Despite the increasing use of medical scribes for EHR documentation assistance, few methodologically rigorous studies have examined the use of medical scribes in primary care.To evaluate the association of use of medical scribes with primary care physician (PCP) workflow and patient experience.This 12-month crossover study with 2 sequences and 4 periods was conducted from July 1, 2016, to June 30, 2017, in 2 medical center facilities within an integrated health care system and included 18 of 24 eligible PCPs.The PCPs were randomly assigned to start the first 3-month period with or without scribes and then alternated exposure status every 3 months for 1 year, thereby serving as their own controls. The PCPs completed a 6-question survey at the end of each study period. Patients of participating PCPs were surveyed after scribed clinic visits.PCP-reported perceptions of documentation burden and visit interactions, objective measures of time spent on EHR activity and required for closing encounters, and patient-reported perceptions of visit quality.Of the 18 participating PCPs, 10 were women, 12 were internal medicine physicians, and 6 were family practice physicians. The PCPs graduated from medical school a mean (SD) of 13.7 (6.5) years before the study start date. Compared with nonscribed periods, scribed periods were associated with less self-reported after-hours EHR documentation (<1 hour daily during week: adjusted odds ratio [aOR], 18.0 [95% CI, 4.7-69.0]; <1 hour daily during weekend: aOR, 8.7; 95% CI, 2.7-28.7). Scribed periods were also associated with higher likelihood of PCP-reported spending more than 75% of the visit interacting with the patient (aOR, 295.0; 95% CI, 19.7 to >900) and less than 25% of the visit on a computer (aOR, 31.5; 95% CI, 7.3-136.4). Encounter documentation was more likely to be completed by the end of the next business day during scribed periods (aOR, 2.8; 95% CI, 1.2-7.1). A total of 450 of 735 patients (61.2%) reported that scribes had a positive bearing on their visits; only 2.4% reported a negative bearing.Medical scribes were associated with decreased physician EHR documentation burden, improved work efficiency, and improved visit interactions. Our results support the use of medical scribes as one strategy for improving physician workflow and visit quality in primary care.
Effect of donor type in patients with AML or MDS undergoing reduced intensity hematopoietic cell transplant.
Authors: Nahid Rashid, Nahid Rashid, Rizwan Romee
Journal: Journal of Clinical Oncology (2018)

7059 Background: Haploidentical (haplo) hematopoietic cell transplants (HCT) are a promising option for patients. Overall survival (OS) is comparable in patients receiving haplo vs matched unrelated donor (MUD) HCT. We are specifically interested in patients receiving peripheral blood (PB) HCT with a reduced intensity conditioning (RIC). Studies comparing AML/MDS patients who received only PB HCT and RIC are lacking. Based recent data, we hypothesized that enhanced graft-versus-leukemia effect may lead to lower relapse in RIC haplo verus MUDs. Methods: Our study included patients aged ≥ 18 undergoing MUD or haplo-HCT at Washington University between January 2010 and September 2017. Data was retrospectively collected via chart review. The primary outcome was OS, compared via the Kaplain-Meier method. Secondary outcomes included the cumulative incidence of relapse, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), neutrophil (NE) and platelet engraftment (PE), analyzed via the method of Fine and Gray. Results: Our study included patients aged ≥ 18 undergoing MUD or haplo-HCT at Washington University between January 2010 and September 2017. Data was retrospectively collected via chart review. The primary outcome was OS, compared via the Kaplan-Meier method. Secondary outcomes included the cumulative incidence of relapse, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), neutrophil (NE) and platelet engraftment (PE), analyzed via the method of Fine and Gray. Conclusions: There is no significant difference in OS, PFS, relapse, or TRM in haplo versus MUD between the two groups. This indicates that haplo are a reasonable alternative to MUD in patients receiving RIC. More data needs to be collected to determine if there is a significant difference in outcomes favoring haplo over MUD. Haplo MUD p value 1 year OS 49% (36 -61%) 42% (33 – 50%) 0.63 Relapse 38% (26 – 50%) 29% (21 – 36%) 0.14 TRM 22% (12 – 31%) 34% (26 – 42%) 0.08 Day + 30 NE 88% (81 – 95%) 94% (90 – 98%) < 0.001 Day +100 aGVHD (II-IV) 17% (8 – 26%) 10% (5 – 15%) 0.14 aGVHD (III-IV) 7% (1 – 13%) 6% (2 – 11%) 0.52 PE 75% (66 – 85%) 85% (79 – 91%) < 0.001