tbuckley/cabot-search huggingface dataset:
A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy (CN), metastasectomy (MS) or post-treatment biopsy (Bx).
Authors: Jianjun Gao, Jose A. Karam, Nizar M. Tannir, Rebecca Slack, Kamran Ahrar, Priya Rao, Chaan S. Ng, Eric Jonasch, Matthew T. Campbell, Surena F. Matin, Amado J. Zurita, Jennifer Wang, Jorge M Blando, Hao Zhao, Luis M Vence, Sreyashi Basu, Hong Chen, James Patrick Allison, Christopher G. Wood, Padmanee Sharma
Journal: Journal of Clinical Oncology (2018)

4520 Background: Since ipi and nivo use distinct mechanisms for T cell activation and bev promotes antigen presentation, we hypothesize that nivo+bev or nivo+ipi would safely lead to measurable immunologic changes and improved clinical activity in MRCC. Methods: In this open-label, randomized trial (NCT02210117), adults with MRCC w/o prior immune checkpoint therapy and anti-VEGF therapy were enrolled and randomized 2:3:2 to receive nivo, nivo+bev or nivo+ipi, followed by surgery (CN or MS), or Bx, and subsequent nivo maintenance therapy up to 2 years. Response was assessed at ≥12 weeks. Pre- and post-treatment blood and tumors were obtained for correlative studies. Results: One hundred patients have been accrued and 90 are evaluable for responses (table below, W = withdrawal; BOR = Best overall response; BRES = Best Response excluding surgical effect). Clinical trial information: NCT02210117. BOR was 50% complete response (CR) + partial response (PR) nivo, 48% CR+PR nivo+bev, 39% CR+PR nivo+ipi. For patients getting surgery, BOR was: 77% nivo, 93% nivo+bev, and 70% nivo+ipi. Grade 3 or 4 toxicities were 30% for nivo, 45% for nivo+bev (including 18% bev-specific hypertension), and 57% for nivo+ipi. We identified a number of immune signatures in relation to clinical responses. Conclusions: Patients able to stay on therapy and receive surgery had BOR ranging from 70%-93%. Combination therapy nivo ± [bev or ipi] plus cytoreductive surgery deserves to be tested in a larger phase 3 trial for MRCC. We will also report correlative biomarker data. Nivo (N = 26) Nivo+Bev (N = 38) Nivo+Ipi (N = 26) CR PR SD PD W CR PR SD PD W CR PR SD PD W All Patients BOR 1 (4%) 12 (46%) 5 (19%) 7 (27%) 1 (4%) 1 (3%) 17 (45%) 7 (18%) 11 (29%) 2 (5%) 1 (4%) 9 (35%) 2 (8%) 13 (50%) 1 (4%) BRES 0 10 (38%) 8 (31%) 7 (27%) 1 (4%) 0 14 (37%) 11 (29%) 11 (29%) 2 (5%) 0 7 (27%) 4 (15%) 14 (54%) 1 (4%) Patients with Surgery BOR 1 (8%) 9 (69%) 2 (15%) 1 (8%) 0 1 (8%) 11 (85%) 1 (8%) 0 0 1 (10%) 6 (60%) 2 (20%) 1 (10%) 0 BRES 0 7 (54%) 5 (38%) 1 (8%) 0 0 8 (62%) 5 (38%) 0 0 0 4 (40%) 4 (40%) 2 (20%) 0 Patients without Surgery BOR 0 3 (23%) 3 (23%) 6 (46%) 1 (8%) 0 6 (24%) 6 (24%) 11 (44%) 2 (8%) 0 3 (19%) 0 12 (75%) 1 (6%)
Final overall survival for CSLC 0501: Phase 3 study of adjuvant versus neoadjuvant chemotherapy with docetaxel combined carboplatin for resectable stageⅠB-ⅢA non-small cell lung cancer.
Authors: Xue-ning Yang, Wenzhao Zhong, Xiao-song Ben, Gui-bin Qiao, Qun Wang, Chang-li Wang, Hong-He Luo, Zheng Wang, Hong-Hong Yan, Si-yang Liu, Yi-Long Wu
Journal: Journal of Clinical Oncology (2018)

8508 Background: Adjuvant or neoadjuvant chemotherapy increased 5% survival compared with surgery alone for completely resected stage II-IIIa NSCLC. No significant difference in overall survival among adjuvant vs neoadjuvant vs surgery was found in NATCH study. Clinical issue is how to select adjuvant or neoadjuvant therapy for resectable NSCLC. Methods: Patients with stage IB-IIIA NSCLC were eligible. Adjuvant or neoadjuvant chemo regimen was designed as 3 cycles DC (Docetaxel: 75mg/m2, Carboplatin:AUC = 5 on day 1 every 3wks). The primary end point was 3yrs disease Free Survival (DFS) rate; secondary end points were 3yrs and 5yrs Overall Survival (OS) and Safety. The trial was closed early due to stage IB was not eligible since 2008 and slow accrual. The preliminary results were reported at 2013 ASCO & 2016 ESMO. Results: 214 patients were screened from 13 sites from March 2006 to May 2011, 198 patients were randomized. 97 were assigned to neoadjuvant (N) arm and 101 to the adjuvant (A) arm. Stage Ib, II and IIIa were 32.5%, 40.6% and 26.9%, respectively. 100% cases received neoadjuvant chemo and 85.1% completed the planned adjuvant chemotherapy. ORR was 34% and 12.4% patients developed PD in N arm. The 3yrs DFS rate was 53.4% (A) vs 40.2% (N) with HR 0.52 (95% CI 0.30–0.91), p = 0.033. 5yrs DFS rate was 47.9% vs 29.9%, HR 0.42 (0.24–0.75), p = 0.005. Median DFS 4.8 vs 2.1 yrs with HR 0.69 (0.48–0.98), p = 0.036. 5yrs OS was 57.8% vs 42.1%, HR 0.48 (0.27–0.85), P = 0.0143. Median OS 7.1 vs 4.2 yrs, HR 0.73 (0.50–1.07), p = 0.104. For stage II and IIIa subgroup 3yrs DFS rate was 49.3% vs 33.3% with p = 0.031, HR 0.43 (0.21–0.87), p = 0.031. 5yrs OS was 49.7% vs 40.7%, HR 0.60 (0.30–1.19), p = 0.142. Median OS 5.2 vs 3.6 yrs, HR 0.83 (0.53–1.30), p = 0.414. Recurrence model was similar between the two arms. 41.2% patients experienced grade 3-4 neutropenia. One chemotherapy related death in A arm.One patient died of perioperative pulmonary embolism in N arm. Conclusions: The 5-yrs DFS and OS of CSLC 0501 showed arm A was superior to arm N. Adjuvant chemotherapy or neoadjuvant with docetaxel plus carboplatin are feasible and safe in resectable clinical stage IB-IIIA NSCLC. Clinical trial information: NCT00321334.
Abstract 19365: A Gain-of-Function Mutation in CaV1.2 (Cacna1c) Promotes Progressive Aortic Valve Stenosis in Mouse
Authors: Maiko Matsui, Kushal Kadakia, Eric Wei, Daniel Sinden, Geoffrey Pitt
Journal: Circulation (2016)

Introduction: Calcific aortic valve stenosis (CAVS) is a life threatening disorder affecting approximately 2% of people > 65 yeas. Genome-wide association studies recently identified CACNA1C, encod...
Maternal prenatal depressive symptoms and risk for early-life psychopathology in offspring: genetic analyses in the Norwegian Mother and Child Birth Cohort Study
Authors: Laurie J Hannigan, Espen Moen Eilertsen, Line C Gjerde, Ted Reichborn-Kjennerud, Thalia C Eley, Fruhling V Rijsdijk, Eivind Ystrom, Tom A McAdams
Journal: The Lancet Psychiatry (2018)
Efficacy of sequencing of cytotoxic and endocrine therapies in veterans with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Nina Mosallaei Lamble, Julie Nicole Graff, Tomasz M. Beer
Journal: Journal of Clinical Oncology (2017)

e16501 Background: The optimal sequencing of therapies in the treatment of mCRPC has not been established. We examined the efficacy of one to two lines of endocrine therapy with chemotherapy sequencied before or in between endocrine therapies versus without chemotherapy. Methods: We prospectively enrolled 103 male veterans from 2013 to 2016 receiving abiraterone or enzalutamide for mCRPC therapy. Participants received usual care. Through chart review, for each line of therapy, we analyzed progression-free survival (PFS), defined as PSA increase 25% and 2ng/mL above nadir and confirmed by a second value, and PSA response rate, defined as a 50% PSA reduction from baseline at treatment initiation, for participants receiving various sequences of endocrine therapies with or without docetaxel chemotherapy. Results: We observed no statistically significant differences between the above measures except for an improvement in PFS when comparing those that received two lines of endocrine therapy without chemotherapy between treatments to those with who received chemotherapy between treatments ( p-value = 0.027, Log-rank test). Conclusions: There were no compelling clinically significant differences noted in PFS or PSA response rate amongst the various sequences of endocrine and cytotoxic therapies. Our results suggest that various sequences of therapy may yield similar results. Larger randomized studies analyzing sequencing of therapies will help determine if cross-resistance arises with use of multiple therapies. [Table: see text]
The preliminary study for safety of acrinol, as a novel dye, which can be used to visualize cancer nuclei of bladder urothelial carcinoma, for probe-based confocal laser endomicroscopy.
Authors: Yoshio Naya, Natsuki Takaha, Tsuneharu Miki, Osamu Ukimura
Journal: Journal of Clinical Oncology (2018)

e16510 Background: Recently, the utility of probe-based confocal laser endomicroscopy (pCLE) using fluorescein for detection of urothelial carcinoma (UC) was reported. Fluorescein revealed only tissue structures without imaging the cell nucleus. We previously reported the feasibility of acrinol for pCLE to observe the nuclei of the UC cells ex vivo. In order to confirm the safety of acrinol, we performed pCLE with acrinol and fluorescein during TURBT. This study was approved by the ethics committees of Meiji University of Integrative Medicine (approval number: 28-17) and registered as a part of ERB-C-525 (Kyoto prefectural University of Medicine) and UMIN 000021067. Methods: Six patients were undergone TURBT with pCLE. 50 ml of a 0.1% acrinol solution and 1 ml of 10% fluorescein in 99 ml of normal saline were injected into the bladder (5 minutes). After drainage of contrast agents from the bladder, pCLE was performed using a 2.7 mm cystoflex-UHD Cellvizio fiber and pCLE system (Mauna Kea Technologies, Paris, France), which was inserted using the working channel of the cystoscope. The laser probe was placed directly adjacent to the region of interest. After observation using pCLE, mucosal biopsy and TUR were performed. Adverse events were evaluated using common terminology criteria for adverse events version 4.0 (CTCAE v4.0) Results: In all 6 patients, pCLE detected the nuclei of cancer cells. In a patient with class V of urine cytology, standard cystoscopy could not detect any bladder tumor; however, pCLE could detect the abnormal nuclei of UC. There was no adverse event in all 6 patients. Conclusions: pCLE using acrinol as a novel dye can help visualize the cancerous nuclei of bladder UC, especially CIS that cannot be detected using conventional cystoscopy without severe adverse events. Clinical trial information: 000021067.
Immunotherapy releated cardiomyopathy.
Authors: Ozlem Sonmez, Ozlem Nuray Sever, Basak Oyan, Osman Gokhan Demir
Journal: Journal of Clinical Oncology (2017)

e14601 Background: Side effects of immunotherapies also differ from classical cytoxic chemotherapy agents such as effects. Cardiomyopathy is a relatively rare complication. Studies have shown that the risk of developing myocarditis is higher when the ipilimumab / nivolumab combination is used than when the single agent nivolumab is used. ImmunoCheckpoint inhibitors are associated with an increase in immunologic response and immunosuppressives such as corticosteroids, TNF-alpha antagonists and mycophenolate acetate are used in treatment.In this study, we aimed to report cardiac toxicity in patients who treated with immune checkpoint inhibitors. Methods: Forty patients who were treated with immunocheckpoint inhibitors were screened retrospectively at two centers in Turkey between August 2015 and January 2017 . Results: Twenty-eight of the patients were male (70%), 12 were female (30%); The median age was 61 (32-81) years. 23 (57.5%) patients received nivolumab and 16 (40 %) patients received pembrolizumab and 1(2.5%) patient received pembrolizumab/ipilimumab combination. Seven of the cases had immuno-related side effects (17.5%).In two of our patients, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. One week after the symptoms improved rapidly and control ejection fractions normalized. One of these patients was diagnosed with malignant melanoma and the other with RCC , they using pembrolizumab and nivolumab respectively. Conclusions: In conclusion, side effects that may occur may lead to fatal outcomes, while immunotherapy, which is increasingly used in oncology practice, may result in satisfactory success in treatment. Patients and their relatives should be adequately informed about side effects caused by these agents, complaints should be carefully evaluated and treatment should be started without spending time.
Trends in the geographic distribution of cancer clinical trials in the US: 2008-2015.
Authors: Caroline Savage Bennette, Wei-Jhih Wang, Scott David Ramsey, Jean A. McDougall
Journal: Journal of Clinical Oncology (2017)

6515 Background: Access to and patient enrollment in cancer clinical trials is likely strongly impacted by where trial enrollment sites are located. Our objective was to evaluate temporal trends in the geographic location of cancer clinical trials launched in the US. Methods: We obtained the recruiting location(s) of all public- and privately-funded phase II/ III cancer clinical trials launched in the US between 2008 and 2015 from the ClinicalTrials.gov database. We linked the recruiting location(s) of each trial to the relevant hospital service area (HSA), which are defined by ZIP codes as local health care markets for hospital care (n = 3436). We estimated the number of cancer clinical trial sites in each HSA each year between 2008 and 2015. We also calculated a statistical measure of inequality, the Gini coefficient. The Gini coefficient would be 0 if all hospital service areas launched the same number of cancer clinical trials, and would be 1 if all cancer clinical trials were launched in only a single hospital service area. Results: 62% of HSAs (n = 2133) did not launch a single cancer clinical trial between 2008 and 2015. There was a small and non-statistically significant decline in the overall number of cancer clinical trial sites in the United States between 2008 and 2015 (-1.6% per year [95% CI: -4.0, 0.9]). During this same period of time, however, inequality in the geographic distribution of cancer clinical trial sites considerably deepened. For example, in 2008-09, no trials were launched in 68% of HSAs while 19% of trial sites were in only 1% of HSAs. Trials launched in 2014-15 were even more concentrated: no new trials were launched in 74% of HSAs while 25% of trial sites were in the top 1% of HSAs. The Gini coefficient increased significantly from 0.683 (95% CI: 0.666, 0.700) for trials launched in 2008-09 to 0.726 (95% CI: 0.706, 0.746) for those launched in 2014-15. Conclusions: Our findings indicate increased inequality in the geographic distribution of cancer clinical trials launched in the United States since 2008. The underlying causes and consequences of such increasing concentration warrant further analysis given the importance in ensuring equitable geographic access to cancer clinical trials in the US.
New drug AIMPILA targeted to AFP receptor: Oral anticancer therapy and biodistribution in vivo.
Authors: Sergei Tsurkan, Janneta Tcherkassova, Vera Gorbunova, Helen Treshalina, Elena Yu. Grigorieva
Journal: Journal of Clinical Oncology (2018)

e24232 Background: Non-covalent AFP-complexes attract a great interest due to their targeting ability to selectively induce apoptosis in the tumor cells using AFP-receptor (AR) mediated mechanism of endocytosis. The objective was the evaluation in vivo the efficacy and the pharmacokinetic of the new oral atractyloside porcine AFP complex - AIMPILA (AMP). Methods: The efficacy was studied using oral daily doses 0,1–0,4 mg/kg for 5-10 days on s.c. human tumor xenografts featuring different expression of AR: SW620/AR+, HepG2/AR++ and T47D/AR+++. Also, we studied AMP’s efficacy using corresponding doses in rabbit (VX2, AR+) tumors in acid resistant capsules & the murine(P388) tumor (oral or iv). Biodistribution of 125I-AMP and 125I-AFP in the tumor, stomach and blood compared to normal mammary gland (MG) was studied using a direct radiometry within 24 h following oral drug administration. The radioactivity was measured using gamma counter. Results: AMP caused a significant tumor growth inhibition in vivo depending of AR expression in the tumors studied: T47D (Т/С = 22%) > HepG2 (Т/С = 51%) > SW620 (T/C = 70%) (criterion T/C≤42%). The effect of AMP for non-human tumor models didn’t match the criterion. A comparison of the tumor accumulation showed that the peak time of 125I-AMP was 6 times longer than of 125I -AFP (3 h vs 0.5 h).The maximum concentration of 125I-AMP in the tumor was accumulated faster than in the MG of the Balb/c nude+ mice with a peak time of 3h for T47D vs 6 h for the control MG. Maximum tumor/blood ratio was at 1 h for 125I-AMP vs 6 h for 125I –AFP (0.86 and 0.83, respectively). After 6 h both showed similar level of accumulation and the elimination rate in the tumor, i.e. ID/g = 3.14±0.19% for 125I-AMP and ID/g = 3.26±0.11% for 125I –AFP, respectively. The retention period was longer for the tumor as well (MRT = 12.3 h vs 9.5 h). By 24 h time period the radioactivity amount 125I-AMP in the tumor was higher than in the MG (ID/g = 0.87±0.08% vs ID/g = 0.18±0.09%, respectively with p = 0.002). Conclusions: High efficacy of low doses orally administrated AMP was achieved due to the AR targeting, receptor-mediated binding resulting in long retention of AMP in T47D. Oral administration of AMP showed intestinal absorption and sufficient bioavailability
Long-term prognosis of α-fetoprotein-producing gastric cancer defined as immunohistochemichal expression.
Authors: Yukio Maezawa, Yasushi Rino, Akihiro Suzuki, Junya Morita, Kazuki Kano, Shinya Amano, Sho Sawazaki, Masakatsu Numata, Toru Aoyama, Tsutomu Hayashi, Takanobu Yamada, Tsutomu Sato, Takashi Oshima, Norio Yukawa, Takaki Yoshikawa, Munetaka Masuda, Tetsuo Ushiku, Masashi Fukuyama, Shumpei Ishikawa, Hiroyuki Aburatani
Journal: Journal of Clinical Oncology (2018)

e16036 Background: Some of gastric cancers show hepatoid or fetal gut-like differentiation, and these cancers are previously reported as adenocarcinomas with primitive features morphology similar to the fetal gut epithelium or hepatocytes, according to oncofetal protein expression. Alpha-fetoprotein producing gastric cancer (AFP-GC) is one of these primitive cancers and reported as a distinct variant of gastric adenocarcinoma, which shows aggressive clinical behavior. Methods: We have analyzed 95 tumors and 22 normal gastric tissues by RNA sequencing. RNA clustering shows that AFP-GC is recognized as one subgroup and the prognosis of this group is worst. So we examined histological phenotype of tumors by evaluating immunohistochemichal expressions of AFP. AFP-GC was defined as immunohistochemichally high expression of AFP, GPC3, CLDN6, SALL4, or ALB. Results: The incidence of AFP-GC was 14.7% (14/95). The median preoperative serum AFP level (range) and tumor size were 5.4ng/mL (2.1-1070) and 75mm (45-130), respectively. Three of 14 patients had high level of preoperative serum AFP. The pathological T factor, N factor, and stage were pT2/T3/T4a: 1/4/9, pN0/N1/N2/N3a/N3b: 2/3/5/3/1, IIA/IIB/IIIA/IIIB/IIIC/IV: 2/1/3/4/1/3, respectively. The 1y, 3y and 5y overall survival were 72.2%, 43.3% and 43.3%, respectively. Ten patients relapsed, and 3 of 10 patients survived after the recurrence by multidisciplinary treatment. Conclusions: Evaluating immunohistochemical expressions demonstrated that AFP-GC represent a larger subgroup of gastric cancer than the previous report. The prognosis might not as poor as the previous report by multidisciplinary treatment even in patients after the recurrence.
Clinical relevance of circulating tumor cells in ovarian, fallopian tube and peritoneal cancer.
Authors: Gerhard Gebauer, Malgorzata Joanna Banys-Paluchowski, Hans Neubauer, Natalia Krawczyk, Anna Kaczerowski, Peter Paluchowski, Franziska Meier-Stiegen, Ahmed Abdel-Kawi, Tanja N. Fehm
Journal: Journal of Clinical Oncology (2017)

e17080 Background: Presence of circulating tumor cells (CTCs) in peripheral blood is associated with impaired clinical outcome in a variety of cancers. So far, limited data are available on the significance of CTCs in gynaecological malignancies. Aims of the present study were to evaluate the dynamics of CTCs in patients with ovarian, fallopian tube and peritoneal cancer during chemotherapy and to assess the clinical relevance of these changes. Methods: 38 patients with ovarian (n=31), fallopian tube (n=4) and peritoneal (n=3) cancer were included into the study. All patients received chemotherapy in the first-line setting (n=19) or tumor recurrence (n=19). CTC analysis was performed prior to systemic treatment, after three and six cycles of chemotherapy and analysed using CellSearch system (Veridex). A tumor cell was defined as EpCAM+, cytokeratin+, CD45-, and positive for the nuclear stain DAPI. CTC positivity was defined as detection of at least one CTC per 7.5 ml blood. Results: 11 out of 38 (29%) patients were CTC positive at baseline. Positivity rate was 20% in patients with first-line setting and 37% in those with tumor recurrence. 1of the 4 patients with fallopian tube cancer presented with CTCs in contrast to 1 out of 3 patients with peritoneal cancer and 10 out of 31 ovarian cancer patients. Presence of CTCs was not correlated with other prognostic factors, such as the FIGO stage, nodal status, or grading. CTC positivity declined to 8% after three cycles of cytotoxic therapy and no patient was CTC positive after 6 cycles of chemotherapy. 12 patients died during follow-up. Patients with CTCs at baseline had significantly shorter overall survival compared with CTC negative patients (p = 0.002; mean OS 5.8 [95%-CI 2.7-8.9] vs. 15.2 [10.5-19.8] months, median OS 3.0 [1.4-4.6] vs. not reached). In the subgroup of patients with primary cancer, CTC positivity was significantly associated with overall survival in the univariate analysis (p = 0.008). Conclusions: Hematogenous dissemination of single tumor cells is a common phenomenon in ovarian, fallopian tube and peritoneal cancer. Patients with CTCs in the peripheral blood at time of diagnosis are more likely to die than those who are CTC-negative at baseline.