tbuckley/cabot-search huggingface dataset:
Combined chemotherapy (CT) and erlotinib (E) as a first-line treatment of EGFR-mutated (EGFR M) NSCLC.
Authors: Elizabeth Dudnik, Jean Lopategui, Myriam Chevarie-Davis, Ronald B. Natale
Journal: Journal of Clinical Oncology (2014)

e19076 Background: EGFR-TKI's and CT induce apoptosis in EGFR M NSCLC by different mechanisms that may result in synergistic effects when used concurrently rather than sequentially. We reviewed the efficacy and toxicity of concurrent treatment with E + CT in 41 consecutive patients with EGFR M NSCLC. Methods: Medical records of 41 consecutive patients (pts) with advanced EGFR M NSCLC treated at CSMC between 2006 and 2013 with first line E were reviewed. 37 pts achieved >30% tumor regression within 4 weeks of the start of E and immediately received concurrent CT. 4 pts were non-responders and were switched to CT alone. Outcomes in all 41 pts were analysed. Results: Pt baseline characteristics were as follows: median age 70y (range, 40-79y); females 54%; Caucasians 80%; never smokers 54%; M1a-M1b-recurrent disease 22%-54%-24%; brain metastasis 27%; ECOG 0-1=88%, ≥2=12%; histology: adenocarcinoma 78%, NSCLC NOS 15%, other 7%; EGFR M type: del 19 37%, L858R 34%, other 12%, unspecified 17%. E starting dose was: 150mg/d 37%, 100mg/d 58%, other 5%. CT regimens used were: platinum/pemetrexed +/- bevacizumab 71%, other 29%. Median treatment duration was: E 15.1 mos (range, 0.8-91.9); CT 2.9 mos (range, 0.7-23.4). 29% of patients received maintenance treatment other than E. Median duration of follow-up was 25.5 mos (range, 0.9-94.7); 68% of patients have progressed and 44% have died. Median PFS was 18.9 mos (95% CI, 14.4-25.9) and % survival at 1y and 2y was 90% and 75%, respectively. Median OS has not been reached and currently projects to 48.9 mos (95% CI, 30.6-62). No unexpected adverse effects were observed. CT and/or E dose reduction was required in 67% of patients. There were no cases of pneumonitis or treatment-related death. Conclusions: In this uncontrolled study, the addition of CT within the first 4 weeks of induction treatment with E appears to result in PFS and OS outcomes (18.9 mos and 48.9 mos, respectively) greater than have been reported with their sequential use (7 randomized trials of EGFR-TKI versus CT, median PFS and OS range 8.4-13.1 mos and 21.6-30.9 mos, respectively, in the arm with EGFR-TKI followed sequentially by CT). This observation merits follow-up in a properly designed randomized clinical trial.
Molecular surgery using a novel biological agent, OBP-301, for lymph node micrometastasis in human colorectal cancer.
Authors: Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara
Journal: Journal of Clinical Oncology (2014)

e14027 Background: Endoscopic submucosal dissection (ESD) for early-stage colo-rectal cancer (CRC) is not yet effective for lymph node (LN) metastasis. We previously constructed a telomerase-dependent oncolytic adenoviral agent (OBP-301), which was evaluated in a Phase 1 clinical trial in the United States in 2008. The current study determined whether OBP-301 could inhibit LN metastasis in a rectal tumor mouse model. Methods: Human colon cancer HCT-116 and Colo-205 cells, both expressing green fluorescent protein (GFP), were orthotopically implanted into the submucosal layer of nude mouse rectum with resultant submucosal invasive rectal cancer and LN metastasis. Whether resection of the SM invasive rectal tumor with prior peritumoral OBP-301 injection could sterilize LN metastasis in the mouse model was assessed. Results: Seven days after cancer cell implantation, the LN metastatic rate for mice implanted with HCT-116-GFP was 78.5%. At that time, OBP-301 was injected to the peritumoral submucosal layer and the primary tumor was resected. Seven days after tumor resection, OBP-301 was observed to have significantly inhibited LN metastasis compared to the untreated group. Moreover, LN metastatic recurrence was not detected in the OBP-301-treated group even 4 weeks after tumor excision. Similar results were also observed with another human colon cancer cell line, Colo-205, implanted in the submucosal layer of the mouse rectum. Conclusions: These results demonstrate that OBP-301 inhibits LN metastasis and should be of use in conjunction with ESD. Based on these promising preclinical results, multicenter clinical traials are warranted.
<i>TP53</i>-mutation status by gene-expression signature (<i>TP53</i> signature) and prediction of efficacy of neoadjuvant chemotherapy (NAC) and recurrence after surgery in breast cancer.
Authors: Shin Takahashi, Takafumi Fukui, Nobuhisa Gondo, Takanori Ishida, Noriaki Ouchi, Tadashi Nomizu, Yoichiro Kakugawa, Chikashi Ishioka
Journal: Journal of Clinical Oncology (2014)

11069 Background: TP53 mutation is an independent poor prognostic factor in breast cancer. We have reported that status of the TP53 mutation is predictable by expression profile of 33 genes (‘TP53 signature’) in breast cancer and that the TP53 signature can predict overall survival and recurrent free survival of early breast cancer (Cancer Sci. 99: 324-32, 2008). The aim of this study is to determine whether the TP53 signature can also predict both the efficacy of NAC and the recurrence after surgery in breast cancer. Methods: An open-access data of the NAC cohort (E-GEOD-25066) that contains 508 patients with HER2 negative breast cancer is used. Among the genes previously used TP53 signature, 20 up-regulated and 5 down-regulated genes in breast cancer with TP53 mutation were selected and the TP53 status was determined by the ratio of the sum of expression values of 20 up-regulated genes to that of the 5 down-regulated genes. If the ratio (5 down-regulated genes / 20 up-regulated genes) was less than 0.325, the tumor was determined as aTP53 mutant. If it was greater than or equal to 0.325, the tumor was determined aTP53 wild-type. Results: Fifty percent (255 of 508) of tumors was determined as a TP53 mutant. The pathological CR (pCR) rate is significantly higher in TP53 mutant tumor than in TP53 wild-type tumor (34.7% vs 5.4%). In Stage I and II patients (n=280), recurrence free survival (RFS) was significantly better in patients leading to pCR than in patients not leading to pCR (P=0.047), supporting the previous reports. Patients with TP53 wild-type tumor showed better RFS than patients with TP53 mutant tumor (P=0.0018). Patients with TP53mutant tumor not leading to pCR showed significantly worse RFS than the other patients (P<0.001). Conclusions: TP53 signature has the ability to predict the efficacy of NAC and recurrence after surgery in breast cancer. The TP53 signature was especially useful to predict the recurrence in combination with pCR status. Our data suggests that patients with TP53 mutant tumor not leading to pCR after NAC may need adjuvant chemotherapy after surgery to improve prognosis of these patients.
Influence of histopathologic features and other risk factors on the outcomes of uveal melanoma patients submitted to ocular enucleation.
Authors: Diego de Araujo Toloi, Mariana Scaranti, Natalia Moreno Perez Fraile, Iuri Amorim De Santana, Ana Cristina Malacarne Mencarini, Rodrigo Ramella Munhoz, Veridiana Pires De Camargo, Vera Regina Cardoso Castanheira, Olavo Feher, Roger Chammas, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2014)

e20028 Background: Uveal Melanoma (UM) diagnosis is mostly based on clinical and complementary exams. Given its low incidence and the lack of tumor specimens of primary lesions, clinical and histopathological data are scarce. We analyzed the outcomes and prognostic factors of UM patients (pts) submitted to upfront ocular enucleation. Methods: Single center retrospective study of 65 UM consecutive pts treated at the Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo between 2002 and 2013. Results: Median age was 56 years; 56 (86.2%) pts had choroidal involvement and 61.5% had retinal detachment. The median largest tumor diameter (LTD) was 15mm; extraocular extension (EE) was present in only 2 cases and cilliary body involvement (CBI) in 8. Among 18 pts who developed metastases, all had liver involvement. Sixty-seven percent received first-line systemic treatment. Other initial treatments included chemoembolization, metastasectomy and radiation therapy. Pts with LTD < 15mm had higher 3y-PFS (HR: 0.03; CI 95%: 0.01-0.36; p<0.01) and 3 y-OS rates (HR: 0.04; CI 95%: 0.01-0.45; p=0.01). In univariate analysis, LTD (OR 1.225 CI 95% 1.044 – 1.438 p 0.013) and thickness (OR 1.431 CI 95% 1.119 – 1.831 p 0.004) were prognostic factors for survival. EE, CBI, liver function tests and lactate dehydrogenase levels were not statistically significant. Conclusions: Since ocular enucleation is not usually indicated for localized UM, there are few data on the prognostic impact of clinical-pathologic features. Our data suggest that LTD and thickness are prognostic factors. However, further investigation of different risk factors and the role molecular profiling is warranted.
Preliminary testing of a patient-reported outcome measure for recurrent or metastatic head and neck cancer.
Authors: Leanne Kolnick Jackson, Jie Deng, Sheila H. Ridner, Mary S. Dietrich, Barbara A. Murphy
Journal: Journal of Clinical Oncology (2014)

6050 Background: There are no patient reported outcome measures developed and tested in patients with recurrent-metastatic head and neck cancer (RMHNC). Symptom (sx) burden in RMHNC is poorly described. Available tools focus on acute and late effects of primary therapy and are hypothesized to lack content specific to RMHNC. We undertook development of the Vanderbilt Head and Neck Symptom Survey - Recurrent/Metastatic (VHNSS-RM) to assess tumor related sx, residual toxicity from prior therapy and side effects from current therapy. The tool contains 35 physical sx and 12 psychosocial issues scored on a 0 (none) to 10 (severe) scale (ASTRO abstract 46, 2014). We now report preliminary testing of the tool. Methods: A pilot trial with 39 patients was completed 6/2013 - 1/2014. Inclusion criteria: non-curable recurrent or metastatic HNC. The tool was administered online to all patients during clinic. Results: No barriers to completion of the tool via computer interface were noted. Patients found the tool acceptable, with high feasibility and readability. Completion time was ≤15 minutes for 92.4% of patients. A full range of scores was noted for 46 of 47 questions. VHNSS-RM includes 12 novel sx questions and 7 novel psychosocial issues. Novel sx include: diet change due to mouth swelling; tongue movement affecting speech/swallowing; swelling of face/neck; cramping in neck/jaw; bad breath; drooling; wound complications: drainage/pain/odor; nasal congestion/drainage; eyes watering; numbness of face/tongue/ear/scalp; headaches and confusion. Psychosocial issues include: perception of burden to family/friends; lost independence; fear; embarrassment; mood swings; stress and boredom. Overall, sx burden was high with moderate to severe symptoms (VHNSS-RM ≥5) identified in >30% of patients for 33/47 questions (70.2%), of those 48.5% had severe sx (VHNSS-RM ≥7). Conclusions: The VHNSS-RM is feasible and can be completed in a timely manner. Sx experienced by patients with RMHNC are often different than at initial presentation and during primary treatment. The 19 novel questions could aid in improved palliation to these patients. There are plans to validate the VHNSS-RM and analyze its role in assessment of treatment response and impact on overall sx burden.
Functional renal parenchyma volume as an indicator for partial nephrectomy in RCC.
Authors: Oleksandr Stakhovskyi, Iuriy Vitruk, Oleg Voylenko, Volodymyr Kotov, Eduard Stakhovsky
Journal: Journal of Clinical Oncology (2014)

e15594 Background: Evolution of surgical technique in kidney cancer pushes the limits of partial nephrectomy (PN) over the range of 7cm nowadays. Additional tools needed to help surgeon to verify right indications for an organ-sparing approach. Our objective was to develop a tool that will ease surgeons to proceed with PN in patients with RCC, taking into account functional renal parenchyma volume (FRPV). Methods: 240 patients with T1 stage RCC treated from January 2012 till December 2013 were included in analisys. 210(87.5%) PN and 30(12.5%) radical nephrectomies (RN) were performed. Mean patients age was 55.0 ± 11.3 years and mean tumor size was 42.5 ± 14.4 mm. CT imaging was used to calculate FRPV. New nephrometry system with regard to FRPV was developed and validated to assess additional indications for organ-sparing surgery. Results: Mean FRPV of the study group was 71.6 ± 9.5 %. In all cases of polar or laterally located tumours with FRPV more than 55% on effected side PN was performed. There was no significant correlation between (g = 0.21 ) FRPV and surgery type in segment near kidney pelvis (Nearness), but tumor size was found to be important predictor. All tumors less than 4cm in size were removed, but in tumors more than 4cm the rate of nephrectomies performed was 60%. Conclusions: New nephrometry system taking into account RFPS optimizes and eases surgeons choice for PN. RFPV more than 55% in polar or lateral locations is an indication for PN disregard tumors size. In central location of the tumor the choice of surgical strategy is dependent on tumor size. Results of the study should be validated in other series.
Efficacy of daikenchuto for the intestinal hypomotility after open abdominal surgery: A pooled analysis of three randomized controlled trials.
Authors: Toru Kono, Mitsuo Shimada, Masaaki Nishi, Yuji Morine, Kozo Yoshikawa, Hidetoshi Katsuno, Koutarou Maeda, Keisuke Koeda, Satoshi Morita, Masahiko Watanabe, Mitsuo Kusano, Junichi Sakamoto, Shigetoyo Saji, Hiroki Sokuoka, Yuya Ohtake, Yasuto Sato, Takashi Kanematsu, Masaki Kitajima
Journal: Journal of Clinical Oncology (2018)

801 Background: Postoperative intestinal hypomotility (IH) is very common after open abdominal (OAS) surgery. Although several advances have been made in medical therapy, very few recognized treatment or prevention methods are currently available. Daikenchuto (DKT), a traditional Japanese prescribed medicine, peripherally stimulates the neurogenic pathway, attempted to reduce postoperative IH in three exploratory randomized controlled trials (RCT). For further analysis of whether DKT accelerates IH recovery after scheduled OAS we conducted a pooled analysis of three RCTs. Methods: A pooled retrospective subset analysis of OAS patients with colon, liver, or gastric cancer in DKT RCTs was performed; RCTs were supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC). Among all patients enrolled and randomized in the three RCTs (JFMC project numbers 39-0902, 40-1001, and 42-1002), 740 patients who were eligible were included for the efficacy analysis. The modified intent-to-treat population was 410 patients, who did not have their bowel movement before the first meal; these patients were randomized to receive either 5 g DKT (n = 214) or placebo (n = 196) orally, three times a day for up to 12 days. The primary end point of each trial was the time from the end of the surgery (extubation) to the first bowel movement; this was assessed using survival analysis. Results: Compared with the placebo group, the time from the end of the surgery to the first bowel movement was accelerated in the DKT group (p = 0.004, hazard ratio;1.337 (95% CI 1.096-1.631)), with a difference of median 14.8 h. The tolerability profiles were similar in both the groups. Conclusions: Compared with the placebo, DKT was well tolerated, and it significantly accelerated IH recovery in patients who underwent OAS. Clinical trial information: UMIN000026292.
Updated phase I data of AFM13: A bispecific tandem antibody (TandAb) in relapsed/refractory (R/R) Hodgkin lymphoma (HL).
Authors: Achim Rothe, Max S. Topp, Dennis A. Eichenauer, Bastian von Tresckow, Horst-Dieter Hummel, Miroslav Ravic, Jens-Peter Marschner, Andreas Engert
Journal: Journal of Clinical Oncology (2014)

3025^ Background: AFM13 is a bispecific anti-CD30, anti-CD16A antibody construct which recruits NK cells for targeted lysis of CD30+ tumor cells. HL cells are characterized by CD30 positivity and represent a promising target for AFM13. 30-40% of HL patients (pts.) relapse after standard chemotherapy ± radiation. 2nd line therapies induce durable remission in only 50% of the patients. Hence, there is a high medical need in R/R HL. Methods: This was a dose escalation trial in heavily pre-treated R/R HL pts. AFM13 was infused weekly (0.01-7.0 mg/kg) or twice weekly (4.5 mg/kg) over 4 weeks. The primary objectives were safety and tolerability, secondary objectives were pharmacokinetics (PK), pharmacodynamics (PD), and efficacy measured using Cheson criteria. Results: 28 pts. were recruited, 26 were eligible for efficacy. 4 pts. were treated twice weekly. AFM13 was well tolerated with mainly mild to moderate adverse events (AEs). The maximum tolerated dose was not reached. Only one relevant, possibly treatment-related toxicity was observed in the 0.5 mg/kg cohort: hemolytic anemia CTCAE Grade 4. The most common AEs were pyrexia (53.6%) and chills (39.3%). 8 pts. (26.8%) experienced serious AEs. PK data revealed that a weekly dose regimen is suboptimal, the half-life was 10-22 hours. PD data showed a dose dependent activation of NK cells (CD69+). Clinical activity was observed over all dose levels but was more pronounced at dose levels ≥1.5 mg/kg (n=13). In this cohort 3 PR (23%), 7 SD (54%), 3 PD (23%) were observed with a disease control rate of 77%. Pts. were not followed-up for duration of response. The time to next treatment (TTNT) was assessed retrospectively for pts. with PR and SD. Mean TTNT was 5.14 months (1.5 – 9.0). 6/7 patients refractory to most recent brentuximab vedotin (BV) therapy achieved SD under AFM13. Mean time between end of BV and start of AFM13 treatment was 1.86 months (1 – 3). Conclusions: AFM13 was well tolerated and demonstrated clinical activity also in pts. refractory to BV. The dose regimens investigated seem to have been suboptimal to demonstrate the full clinical potency of AFM13. A phase II study with a modified dose regimen is in preparation. Clinical trial information: NCT01221571.
THU0041 The effects of abatacept on human b cell activities
Authors: M.-H. Chen, C.-T. Ssu, C.-Y. Tsai, C.-M. Leu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Abatacept is a cytotoxic T lymphocyte antigen-4 (CTLA-4) fusion protein approved for rheumatoid arthritis (RA) treatment worldwide. Abatacept mimics the natural CTLA-4 and competes with CD28 for binding the CD80/CD86 on antigen presenting cells to prevent T cell activation. However, the impacts of CTLA-4-Ig through its interaction with CD80/CD86 on B cells are not fully understood. <h3>Objectives</h3> The aim of this study was to test whether CTLA-4 regulates human B cell functions <h3>Methods</h3> We assayed the effect of abatacept on human B cells in both <i>in vitro</i> and <i>in vivo</i> conditions. Blood was taken from 20 patients with RA before and after abatacept treatment and the expression of surface proteins on B cells was detected using immunofluorescent staining. Serum level of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) was measured by ELISA. Purified human B cells from healthy donors were stimulated in the presence of abatacept and cell proliferation, cytokine production, plasma cell differentiation, and antibody production were measured. <h3>Results</h3> In RA patients, abatacept treatment transiently reduced the level of CD80/CD86 on peripheral blood memory B cells and increased the naïve to memory B cell ratio. Also, abatacept reduced IgM-RF level in 10 out of 12 patients, which correlates with patients' disease activity, but it had no significant effects on serum levels of anti-citrullinated protein antibody or anti-tetanus toxoid antibodies during the 6 months of abatacept treatment. In the <i>in vitro</i> assays, we observed that the CD80 and CD86 induced by T-independent (TI) but not T-dependent (TD) stimulation was significantly downregulated by abatacept at both the mRNA level and protein level. Some TI-induced cytokine production by B cells from healthy donors was also reduced by abatacept. Neither TI nor TD- stimulated B cell proliferation was reduced by abatacept in <sup>3</sup>H-thymidine incorporation assay. Abatacept had no significant effect on CD38<sup>high</sup> CD27<sup>high</sup> plasma cell differentiation. Finally, abatacept inhibited Daudi-B cell induced allogeneic T cell proliferation, indicating a significant blockade of T-B interaction by abatacept. <h3>Conclusions</h3> In RA patients, abatacept may decrease RF level by interfering the interaction of CD28 with CD80/CD86, therefore preventing B cells from T cells' help for differentiation into plasma cells. Our results also indicate that abatacept binding CD80/CD86 may provoke a negative reverse signal to B cells to further regulate B cells activation. <h3>Disclosure of Interest</h3> M.-H. Chen Grant/research support from: BMS, C.-T. Ssu: None declared, C.-Y. Tsai: None declared, C.-M. Leu Grant/research support from: BMS
Reduction rate of the maximal value of the baseline standardized uptake value on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography to predict response of breast cancer to neoadjuvant chemotherapy.
Authors: Takayuki Kadoya, Etsushi Akimoto, Ai Amioka, Keiko Kajitani, Akiko Emi, Hideo Shigematsu, Kazuo Matsuura, Norio Masumoto, Morihito Okada
Journal: Journal of Clinical Oncology (2014)

11121 Background: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is potentially useful to predict response of breast cancer to neoadjuvant chemotherapy. Methods: 114 breast cancer patients (mean age: 53.7±11.0) with clinical Stage I~III between January 2006 and December 2011, were prospectively evaluated. Patients underwent a whole-body FDG PET/CT before and after neoadjuvant chemotherapy. The reduction rate of maximal value of the baseline standardized uptake values (ΔmaxSUV) before and after neoadjuvant chemotherapy with sequential regimen of anthracyclines and taxanes were assessed for predicting pathological complete response (pCR). For the evaluation of relationship between ΔmaxSUV and prognostic factors, statistical analyses were performed using Student t test and log-rank test, and p values of less than 0.05 were considered to indicate statistically significant differences. Results: Clinical stage included were I (n =10), II (n=81) and III (n=23). Tumors with estrogen receptor (ER) positive and HER2 positive were 79 (69.3%) and 30 (26.3%), respectively. Patients were divided into two groups according to cut-off ΔmaxSUV established on the basis of receiver operating characteristic analysis (>80.4% vs 80.4% ≤, AUC=0.676). There was a significant difference in pCR between two groups (p=0.006) and, ER, progesterone receptor, HER2, clinical T factor were found strong relation to ΔmaxSUV. ER, HER2, tumor size and ΔmaxSUV were predictive factors with multivariable analysis using cox proportional hazard regression model (p<0.01, p<0.01, p=0.02 and p=0.04, respectively). Conclusions: The reduction rate of maxSUV on FDG PET/CT before and after neoadjuvant chemotherapy has a predictive value for pCR in operable breast cancer. Factors Favorable Unfavorable Hazard ratio (95%CI) p value Clinical T factor T1 T2, T3, T4 0.200 (0.050-0.797) 0.02 Clinical N factor N0 N1,N2,N3 1.103 (0.319-3.818) 0.88 ΔmaxSUV > 80.4% 80.4%≤ 3.816 (1.059-13.745) 0.04 ER (+) (-) 0.068 (0.018-0.258) <0.01 HER2 (-) (+) 12.625 (3.295-48.375) <0.01