tbuckley/cabot-search huggingface dataset:
Cardiac safety of afatinib: Review of clinical trial data.
Authors: Michael S. Ewer, Kalpesh P. Patel, Dennis OBrien, Robert M Lorence
Journal: Journal of Clinical Oncology (2014)

e19037 Background: Afatinib, an oral irreversible ErbB family blocker, is approved for treating non-small cell lung cancer (NSCLC) with common EGFR mutations (DEL19/L858R). As anti-HER2 therapies have been associated with cardiac dysfunction, we report cardiac events from 2 phase 3 trials of afatinib and a pooled analysis of additional trials. Methods: Cardiac data were analyzed from trials of afatinib 40 mg in previously untreated patients (pts) with EGFR mutation-positive NSCLC (LUX-Lung 3 [LL3]; n = 229 afatinib, n = 111 chemotherapy [CTX]) and 50 mg in EGFR TKI-pretreated pts with NSCLC (LUX-Lung 1 [LL1]; n = 390 afatinib, n = 195 placebo [PBO]). Additional data from 49 trials (pooled; n = 3,865 afatinib) is reported. When feasible, left ventricular ejection fraction (LVEF) was assessed at baseline, every 12 weeks, and end of treatment. Cardiac failure adverse events (CF-AEs) including cardiac failure and depressed LVEF per MUGA scan or ECHO were analyzed (Table). Time at risk adjusted CF-AE rates were used to compare treatment arms in LL1 and LL3 due to large differences in treatment exposure. Clinically significant LVEF reductions were examined using established criteria: LVEF <50% and ≥10% decrease from baseline or LVEF ≥50% and ≥15% decrease from baseline. Results: Time at risk adjusted CF-AE rates (events/100 pt-years [yrs]) were similar for afatinib vs PBO in LL1 (2.40 vs 2.23) and vs CTX in LL3 (2.28 vs 2.92); the pooled afatinib CF-AE rate (2.88) was consistent with that for LL1 and LL3. The frequency of clinically significant LVEF reductions was higher for CTX in LL3 (CTX 2/15 [13.3%], afatinib 13/208 [6.3%]) and similar to PBO in LL1 (PBO 5/122 [4.1%], afatinib 14/304 [4.6%]). No pts in LL3 discontinued due to a CF-AE; 1 afatinib pt and no PBO pts discontinued due to a CF-AE in LL1. Conclusions: Afatinib was not associated with cardiac failure or reductions in LVEF in pts in this clinical trial program. CF-AEs LL3 Afatinib CTX Time at risk (mo) 11.5 3.7 Time at risk adjusted AE rate (events/100 pt-yrs) 2.28 2.92 HR (95% CI) 1.18 (0.12, 11.39; P = 0.8870) LL1 Afatinib PBO Time at risk (mo) 5.1 2.8 Time at risk adjusted AE rate (events/100 pt-yrs) 2.40 2.23 HR (95% CI) 1.32 (0.14, 12.50; P = 0.8086) Pooled Afatinib Time at risk (mo) 5.7 Time at risk adjusted AE rate (events/100 pt-yrs) 2.88
Tumor antigen specific T cell expansion is greatly facilitated by in vivo priming.
Authors: Yushe Dang, Keith L. Knutson, Corazon Dela Rosa, Vivian Goodell, Doreen Higgins, Jennifer Childs, Mary L. Disis
Journal: Cancer Research (2006)

5566  Adoptive T cell immunotherapy has the potential to induce a clinical response in patients with established cancers and infectious diseases. Polyclonal antigen specific CD4 T cell therapy holds promise as a treatment modality as CD4 T cells are critical in eliciting and maintaining both CD8 and B cell immunity. Expansion of antigen specific CD4 T cells, however, has been limited by a lack of ex vivo priming and expansion techniques. We evaluated the feasibility of expanding tumor-specific T cells ex vivo following in vivo priming with HER-2/neu (HER2) peptides. First, using a well characterized CMV model, we expanded CMV specific T cells from 10 healthy donors who have been previously infected with CMV (CMV+). PBMC from 5 CMV seronegative donors (CMV−) were used as controls. During expansion, PBMC were stimulated with CMV lysate on Day 0 and then expanded with Xcyte CD3/CD28 beads on Day 12. IL-2 was added into culture every 2 to 3 days after the bead stimulation for a period of 12 days. At the end of expansion, the total number of T cells increased 22-fold in CMV+ subjects as compared with 11-fold in CMV− donors. Although there was no difference in the phenotype of expanded cells, the frequencies of CMV-specific T cells generated from CMV+ donors were more than 11-fold higher than those from CMV− donors (p=0.00037). Moreover, the expanded CMV specific T cells responded at 103 to 104 lower concentrations of CMV lysate in CMV+ donors than that in CMV− donors. These results demonstrate that highly functional anti-CMV T cells can be expanded following endogenous priming by virus. Using the same expansion procedure, we stimulated PBMC from 11 patients who had been vaccinated with a HER2 peptide vaccine with 3 neu helper peptides. The cells from 7 breast cancer patients without previous vaccination were used as controls. At the end of expansion, the total number of T cells increased 21-fold in primed patients as compared with 7-fold in naive patients. Although the phenotype of the expanded cells was similar, the frequencies of neu-specific CD4 cells generated from primed patients were more than 17-fold higher than those from naive patients (p=0.01). The expanded anti-tumor T cells from vaccinated patients responded to a 102 –103 times lower concentration of peptides than naive samples, similar to the CMV+ donors. Expansion of HER2 specific CD8 cells was also observed in primed patients. Moreover, the growth of HER2 specific T cells over the expansion period correlated with the maximal T cell response to HER2 peptides during active immunization (p=0.008). Thus, anti-tumor specific T cells can be largely expanded ex vivo following previous priming in vivo with a vaccine. This approach provides an effective method to generate tumor specific polyclonal T cells ex vivo for therapeutic use.
Conditional survival in melanoma and thyroid cancer patients.
Authors: Megan Rist Haymart, Mousumi Banerjee, Daniel G Muenz, Francis P. Worden, Sandra L. Wong
Journal: Journal of Clinical Oncology (2014)

6599 Background: Melanoma and thyroid cancer are two increasingly common malignancies. Although likelihood of survival from both cancers can vary by disease severity, it isn't known how patients' life expectancy changes the further they are from time of diagnosis. Methods: Using Surveillance, Epidemiology, End Results (SEER) data we selected patients diagnosed with melanoma (N=95,041) or well-differentiated thyroid cancer (N=43,392) between 1998 - 2005. Patients were followed for up to 12 years. Cox regression provided estimates of disease-specific survival by SEER stage and age, which we then transformed to estimate conditional five year survival. Results: Patients with localized melanoma and thyroid cancer have an excellent five year survival at time of diagnosis and for subsequent years. For both regional melanoma and thyroid cancer there is an age gradient with improved conditional survival in melanoma patients over time. For distant melanoma, the initial five year survival is poor but improves rapidly whereas the improvement is gradual with distant thyroid cancer. There is an age effect for disease-specific survival for both cancers, but it persists across all stages for thyroid cancer: for local disease [hazard ratio for age 70-79 versus <30 is 26.6 (95% confidence interval is 8.08-164)], for regional disease [59.4 (30.1-140)], and for distant disease [54.5 (20.7-221)]. For melanoma, the age effect is smaller and only present for local disease [3.79 (3.01-4.84)] and regional disease [2.36 (1.93-2.91)]. Conclusions: The likelihood of continued survival in a patient with melanoma or thyroid cancer differs based on age and how long the patient has already survived. Understanding the five year conditional survival of these cancers can help patients and physicians with their treatment plans.
Preliminary evaluation of quality of psychosocial care indicators: Results from the Quality Oncology Practice Initiative (QOPI)
Authors: P. B. Jacobsen, P. Kadlubek, M. N. Neuss
Journal: Journal of Clinical Oncology (2009)

6534 Background: To gauge the opportunity for improvements in psychosocial care, ASCO's QOPI program tested two new quality indicators in 2008. Similar to other QOPI indicators, these were presented as questions to be answered (yes/no) based on review of patient records: 1) was current emotional well-being assessed within one month of a first visit with a medical oncologist; and 2) was action taken for a patient identified as having a problem with emotional well-being. In addition to examining variability on these indicators, performance of assessments of pain (another QOPI indicator) and emotional well-being were directly compared. Methods: Practices participating in the Spring 2008 QOPI data collection round were included if they reported results for psychosocial care indicators with at least 40 patients. This criterion was met by 96 practices, which provided information on 9,045 patient records. Results: Across practices, rates of assessment of emotional well-being ranged from 0–100% (Mdn = 78%), with 27% of practices achieving rates &lt; 50%. In contrast, rates of assessment of pain ranged from 12–100% (Mdn = 88%), with 9% of practices achieving rates &lt; 50%. Mean rates of assessment of pain (83%) and emotional well-being (70%) differed significantly across practices (t = 4.61, p &lt; 0.001). Problems in emotional well-being were documented in 10% of records. Among these records, rates of documentation of action taken ranged from 0–100% (Mdn = 73%, M = 72%), with 26% of practices achieving rates &lt; 50%. Conclusions: Wide variability in the documentation of psychosocial care was evident among the practices surveyed, with at least 26% showing substantial opportunity for improvement (i.e., performance &lt; 50%). Additional findings suggest that, to date, efforts to promote routine symptom assessment have been more successful for pain than for emotional well being. No significant financial relationships to disclose.
Cytotoxic effect of euphol from <i>Euphorbia tirucalli</i> on a large panel of human cancer cell lines.
Authors: Rui Manuel Reis, Viviane Aline Oliveira Silva, Marcela Nunes Rosa, Aline Tansini, Joao Paulo Da S.N. Lima, Chris Jones, Luiz Francisco Pianowski
Journal: Journal of Clinical Oncology (2013)

e13557 Background: The tetracyclic triterpene alcohol euphol is the main constituent found in the sap of Euphorbia tirucalli. In Brazil its latex is used as anticancer and other diseaseas folk treatment, yet, little is known about its anticancer proprieties. We aimed to study the antitumor effect of euphol on a large panel of human cancer cell lines. Methods: Anti-tumor effects of euphol in vitro were assessed using MTS assays on 77 human cancer lines from13 solid tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Euphol exhibited dose and time-dependent cytotoxic effects on all cancer cell lines analyzed. Among each tumor type, the distinct cell line exhibited a heterogeneous profile of response to euphol. Esophageal squamous cell carcinoma and pancreatic carcinomas showed the most sensitive profile. In comparison with temozolomide, euphol showed a median of 30 fold higher efficacy, range 5-167 fold, in the glioma cell lines analyzed (Table). Conclusions: Euphol demonstrated potent anti-tumor activity on the majority of cancer cell lines evaluated. Our findings may provide insight into the tailoring designing of euphol-based therapies for cancer patients. [Table: see text]
Multiplatform biomarker analysis on non-sun exposed mucosal melanoma.
Authors: Alan H. Bryce, David Arguello, Sherri Z. Millis, Ryan Bender, Sandeep K. Reddy, Zoran Gatalica, Rene Gonzalez
Journal: Journal of Clinical Oncology (2015)

9042 Background: Mucosal melanoma is a rare malignancy, notoriously resistant to conventional chemotherapy, with few treatment options. Because of their origin, they do not receive screening and, hence, are detected in advanced stages where prognosis and curative rates are poor. The purpose of this study is to identify novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: In total, 93 mucosal melanoma specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and/or gene amplification (CISH or FISH). Conjunctival melanoma was excluded. Results: Notable protein overexpression rates included co-expression of PD-1 and PD-L1 (71.4%, 5/7) and cKIT (42.4%, 14/33). Percent agreement between c-KIT by IHC and sequencing was 62% (16/26). Overall, sequencing revealed the highest mutation rates in TP53 (17%, 4/23), cKIT (18.2%, 14/77), BRAF (12.0%, 10/83), and NRAS (10.0%, 4/40). A sub-analysis of BRAF, cKIT, and NRAS (BRAF/cKIT/NRAS) based on the anatomic location of the melanoma revealed the following: sinonasal (5.3%, 0.0%, 27.0%), vulvovaginal (21.2%, 27.3%, 7.1%), and anorectal (5.0%, 18.0%, 0.0%). Details on the TP53-mutated specimens (n=4) are shown in the table below. Conclusions: Multiplatform tumor profiling identified multiple, potentially actionable targets. Given the high rate of PD-1 and PD-L1 co-expression, new immunotherapies should be strongly considered in advanced stages of this disease. In addition, mutations detected may provide further guidance in this rare malignancy. The highest rates of NRAS mutations occurred in the sinonasal melanomas. Meanwhile, cKIT mutations were highest in vulvovaginal and anorectal mucosal melanomas. This variability in mutation rates of BRAF, cKIT, and NRAS based on the primary site's location should be further elucidated in larger studies for potential diagnostic and theranostic purposes. Specimen Primary Site TP53 Mutation(s) Sinonasal H179R (c.536A>G) Nasopharyngeal V272L (c.814G>T), R248W (c.742C>T) Vaginal R337C (c.1009C>T), R273C (c.817C>T) Rectal N268fs
Management of cutaneous adverse effects during treatment with ZD1839 in advanced non-small cell lung cancer (NSCLC): Surprising efficacy of early local treatment
Authors: E. Cortesi, A. De Pasquale Ceratti, G. D'Auria, F. Nelli, M. L. Evangelista, M. Mazzoli, C. Di Fonzo, N. Pizzardi, V. Picone, A. Lugini
Journal: Journal of Clinical Oncology (2004)

7100 Background: The incidence of cutaneous adverse effect during therapy with ZD1839, usually dose-dependent, is reported from 48% to 65% with the dose of 250 mg/day. Despite neither dose reduction nor treatment discontinuation are suggested in case of grade 1–2 adverse events, however the extension of abnormalities to face and extremities, and some cutaneous reaction patterns, such as acneiform eruptions, dry skin, or itching, might have a worsening effect on patient's quality of life and compliance to treatment. Patients and Methods: From 01/2002 to 10/2003 47 patients with advanced NSCLC received ZD1839 250 mg/day as third (91%) or fourth (9%) line therapy. PS at ZD1839 starting was mainly 0–1 (57%) and 2 (28%).19 (40%) and 10 (21%) patients developed grade 1 (erythematous papules) and grade 2 (purulent fulliculitis) cutaneous adverse events, respectively, with an overall incidence of 61%. The lesions were mainly distributed over chest (34%), neck (28%), and back (25%). The cutaneous reactions started 5–12 days after initiation of treatment, and were accompanied by moderate to severe dry skin and itching in 32% and 36% of cases, respectively. Local treatment started soon after the eruption and consisted of twice daily application of alpha-hydroxyacids 0.025% cream in case of erythematous lesion, with the addition of three times a day gentamicin 0.166% and betametazone 0.122% cream in case of grade 2 toxicity. Results: Complete disappearence of grade 1 erythematous lesions was observed within 7 days in 17 (89%) cases. In case of fulliculitis, we obtained a complete resolution of all lesions in 5 cases (50%), whereas in 4 (40%) patients a decrease to grade 1 level was observed. Dose reduction or treatment discontinuation were not required. Conclusions: Our preliminary data show that the early treatment of ZD1839-induced mild and moderate cutaneous adverse events with local antiacneic drugs may be useful in order to prevent worsening of skin lesions and to maintain patient's compliance to the treatment. A specific analysis on impact of cutaneous side effects on quality of life is still ongoing. No significant financial relationships to disclose.
Difference in risk factors associated with biochemical recurrence after salvage RT compared to post-prostatectomy patients with negative margins.
Authors: Austin B Hopper, Ajay Pal Sandhu, John Paul Einck
Journal: Journal of Clinical Oncology (2017)

39 Background: Previous research has also shown that higher pathologic stage, higher Gleason score (GS) and positive margins are associated with increased rates of disease recurrence after prostatectomy and may be indicators for early intervention with adjuvant or salvage radiotherapy (SRT). Conversely, a negative surgical margin is a negative prognostic factor for the success of SRT. We sought to investigate the relative significance of prognostic factors in patients grouped by margin status and differences in their response to treatment. Methods: 227 patients were treated with SRT at our institution between Jan 2005 and Dec 2013. Patients with positive lymph nodes at surgery, those treated with adjuvant radiation and patients with metastases prior to SRT were excluded, leaving 196 for analysis. Biochemical recurrence (BCR) was defined as post-SRT PSA nadir + 0.2 ng/mL. Median follow-up was 48 mo. Covariates evaluated were factors found to be significant in previous studies on SRT (pre-SRT PSA, pathologic stage, GS) as well as treatment to the pelvis vs fossa. Patients were grouped by margins and evaluated using Kaplan-Meier and multivariate Cox regression. Results: In univariate analysis of patients with positive margins significant factors for increased rates of recurrence were pre-SRT PSA (p = 0.016), GS (p &lt; 0.001), and pathologic stage (p &lt; 0.001). Treatment to the pelvis was not significant. Conversely, in patients with negative margins, pre-SRT PSA and GS no longer significantly affected BCR and pathologic stage only approached significance (p = 0.061). In these patients treatment to the pelvis was significantly associated with decreased BCR (p = 0.005). On multivariate analysis these trends in significance were maintained. Conclusions: In post-prostatectomy patients with negative margins treatment to the pelvis is associated with improved bPFS, while traditional factors associated with recurrence such as pathologic stage, GS and pre-treatment PSA were not significant. Patients with negative margins and PSA recurrence after prostatectomy should be considered for treatment to the pelvic nodes, even in the absence of nodal involvement on imaging.
Updated results of the FOLL05 phase III trial from the Fondazione Italiana Linfomi comparing R-CVP, R-CHOP, and R-FM in patients with advanced follicular lymphoma.
Authors: Stefano Luminari, Alessandra Dondi, Luigi Marcheselli, Giuseppe Rossi, Carola Boccomini, Annalisa Chiarenza, Luigi Rigacci, Francesco Merli, Giovanni Bertoldero, Alessandro Levis, Andres J. Ferreri, Daniele Vallisa, Maria Christina Cox, Monica Balzarotti, Massimiliano Salati, Massimo Federico
Journal: Journal of Clinical Oncology (2014)

8530 Background: The final results of FOLL05 for the initial therapy of advanced stage follicular lymphoma (FL) were recently reported with a median follow–up of 34 months. This trial showed that R–CHOP and R–FM were superior to R–CVP in terms of 3–year time to treatment failure (TTF), the primary study endpoint, and that R–CHOP had a better risk/benefit ratio compared with R–FM. Here, we present the 5–year follow–up analysis of progression free survival (PFS) of the 504 patients included in the study. Methods: Patients were 18–75 year old, with untreated stage II–IV FL, ECOG performance status of 0–2, and active disease according to the Italian Society of Hematology guidelines. They were randomly assigned to receive 8 doses of rituximab associated to 8 cycles of CVP, or 6 cycles of CHOP or FM. Maintenance was not admitted. Results: The median follow–up was 56 months (range 1–90). The overall 5–year TTF was 52% (95%CI, 47–56%). R–CHOP and R–FM had a better TTF compared to R–CVP (56% and 56% vs 43% at 5–years; p= 0.007 and p=0.017, respectively). Regarding PFS a total of 215 events were recorded, thus determining a 5–year PFS of 56% (95%CI, 52-61%). Compared to initial report 31 additional events for PFS were observed and were mainly represented by lymphoma relapses (80%). Better PFS rates were observed for R–CHOP and R–FM compared to R–CVP (62% and 60% vs 47% at 5–years). After adjustment by FLIPI, and using R–CVP as reference, HRs for PFS were 0.66 for R–CHOP (95%CI, 0.47–0.92; p=0.013), and 0.71 for R–FM (95%CI, 0.52–0.98; p=0.035); the HR between R–FM and R–CHOP was 1.08 (95%CI, 0.76–1.52; p=0.677). Considering additional events reported during the follow–up, 27 second malignancies were recorded in all treatment arms: four in R–CVP, 9 in R–CHOP and 14 in R–FM (p=0.062; R–CVP vs R–CHOP, p=0.169; R–CVP vs R–FM, p=0.018). Finally with 47 recorded deaths the 5–year overall survival rate was 91% (95%CI, 87–93%). Conclusions: The 5–year update of the FOLL05 study, with mature data on PFS, confirms that R–CHOP has the best efficacy profile compared to R–CVP and R–FM for the initial treatment of patients with advanced FL. Clinical trial information: NCT00774826.
Fluoropyrimidine-based adjuvant chemotherapy in patients with resected biliary tract cancers.
Authors: Se-Il Go, Jung Hun Kang, Chi-Young Jeong, Gyeong-won Lee, Hoon-Gu Kim, Myoung-Hee Kang, Haa-na Song
Journal: Journal of Clinical Oncology (2014)

e15108 Background: The role of adjuvant therapy is controversial in patients with resected biliary tract cancers(BTC). There are few data regarding the benefit of adjuvant chemotherapy in BTC. Methods: We retrospectively reviewed patients who had curative intent surgery for BTC from March 1999 to December 2013 in a single institute. Patients were eligible if they did not die from surgical complications within 3 months, and followed by either fluoropyrimidine-based adjuvant chemotherapy(FAC) or best supportive care(BSC). The following patients were excluded:1) R2 resection 2) Gemcitabine-based adjuvant chemotherapy 3) radiotherapy or chemoradiotherapy. Results: Of total 184 enrolled patients, 100 patients received FAC and 84 patients had BSC. Gallbladder (43.5%) and intrahepatic bile duct (32.1%) cancer were most common subtypes. FAC significantly improved the overall survival(OS) of stage II and III BTC patients (stage II; median 89.6 vs 18.0 months; p = 0.010, stage III; median 24.7 vs 6.6 months; p < 0.001). The benefit of FAC was consistent to stage II and III patients group in relapse free survival(RFS). However, there was no difference in OS and RFS of stage I and stage IV group patients (stage I; median OS 68.0 vs 50.7 months; p = 0.340, stage IV; median OS 13.8 months vs not reached; p = 0.451). In multivariate analysis, R0 resection, lower preoperative serum CA19-9 level and FAC were independent good prognostic factors for OS in stage II and III patients. Conclusions: The results showed the benefit of FAC in stage II and III BTC patients. Further studies are warranted.