tbuckley/cabot-search huggingface dataset:
Inflammation and depression in allogeneic stem cell transplant recipients.
Authors: Alexandra A. Erdmann, Mark Juckett, Christopher L. Coe, Paul J. Rathouz, Walter L. Longo, Ashley M. Nelson, Peiman Hematti, Erin S. Costanzo
Journal: Journal of Clinical Oncology (2014)

7037 Background: Depressed mood is a prevalent concern for individuals undergoing allogeneic stem cell transplantation (allo-SCT). Recent research suggests that proinflammatory cytokines can activate central nervous system pathways, eliciting adverse behavioral responses such as depressed mood. We hypothesized that inflammation may contribute to depression in allo-SCT patients. We also examined the extent to which cytokines were associated with neurovegetative (NV) versus cognitive/affective (CA) depression symptoms. Methods: Adults with hematologic malignancies undergoing allo-SCT (N = 66) participated in this longitudinal observational study. Participants completed the Inventory of Depression and Anxiety Symptoms pre-transplant and at 1, 3, and 6 months post-transplant. Proinflammatory (IL-6, TNFα) and regulatory (IL-10) cytokines were assessed by ELISA in peripheral blood at the same time points. Mixed-effects and subject-level fixed effects regression models were employed to examine relationships between plasma cytokine levels and depression symptoms. Results: Participants with elevated IL-6 (z = 3.16, p = .002) and TNFα (z = 2.23, p = .026) reported more severe depressive symptoms compared to those with low/normal levels. Follow-up analyses clarified that these relationships were seen for NV (z = 2.14-3.26, all p values <.05) but not for CA symptoms (p values >.05). All models adjusted for time since transplant, conditioning regimen, graft-versus-host-disease, and recipient’s age. Similarly, within-subjects analyses revealed that among individuals, changes in cytokine levels across the assessments were associated with corresponding changes in depressed mood, with patients reporting greater overall and NV depression symptoms when IL-6 (z = 3.05, p = .003; z = 3.34, p = .001) and TNFα levels were elevated (z = 2.11, p = .037; z = 2.73; p = .007). Conclusions: Results provide evidence for a novel biobehavioral pathway by which inflammation from conditioning therapy or transplant-related complications can evoke depressive symptoms among allo-SCT patients, specifically NV symptoms. This potential treatment-related cause of depression could be targeted to improve the quality of life for allo-SCT recipients.
Angiomotin to regulate prostate cancer cell proliferation by signaling through Hippo-YAP pathway.
Authors: Pengfei Shen, Hao Zeng, Angelica Ortiz, Chien-Jui Cheng, Yu-Chen Lee, Guoyu Yu, Song-Chang Lin, Li-Yuan Yu-Lee, Sue-Hwa Lin
Journal: Journal of Clinical Oncology (2017)

e559 Background: Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. Methods: Purified GST-AMOTp80 was used as immunogen for antibody generation. Real-time PCR, western blot and immunohistochemistry were used to identify the expression of AMOT. To study the function of AMOT, retroviral vector were constructed, also shRNA was used to knockdown AMOT in cells. Cell migration and invasion assays were performed by using transwell chambers. Nuclear and cytoplasmic protein fractions were prepared by using NE-PER reagents (Pierce). The SPSS 19.0 software was used for statistical analysis. Chi-square test and t test were used for the comparisons between groups. Results: AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80 functioned as a tumor promoter by enhancing PCa cell proliferation while AMOTp130 did not. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting the nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Conclusions: Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.
Complete remission (CR) during treatment for metastatic renal cell carcinoma (mRCC) with tyrosine kinase inhibitors (TKIs).
Authors: Daniele Santini, Matteo Santoni, Alessandro Conti, Giuseppe Procopio, Elena Verzoni, Luca Galli, Giuseppe di Lorenzo, Ugo De Giorgi, Delia De Lisi, Maurizio Nicodemo, Marco Maruzzo, Francesco Massari, Sebastiano Buti, Elisa Biasco, Riccardo Ricotta, Camillo Porta, Bruno Vincenzi, Paolo Marchetti, Stefano Cascinu, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2015)

e15594 Background: Data about complete remission in patient with metastatic mRCC in TKIs era are extremely limited. We performed a multicenter, retrospective analysis of patients who obtained CR during treatment with TKIs, either alone or with local treatment. Methods: 63 patients who achieve complete clinical remissions (absence of clinically or radiologically identifiable signs of the disease) after at least one line treatment with targeted therapies, obtained with or without adjuvant loco-regional treatment of the metastases, were retrospectively collected in 13 Italian centers. Overall and disease-free survival (OS and DFS respectively) of the whole population and by subgroups were investigated by means of Kaplan-Meier method; univariate comparison between groups was performed with the Mantel-Haenszel log-rank test. Results: We included patients with good (40 pts) or intermediate (23 pts) prognosis, according to Motzer modified criteria.Metastatic sites before tki: lung (43%)and lymph-nodes (30%), bone (14%), the contralateral kidney (16%), adrenal gland (14%), liver (13%), pancreas (11%) and brain (13%). CR obtained with tki alone: 23(37%); with tki plus locoregional therapy: 40 (63%). Tki achieving CR: sunitinib 51(81%); pazopanib 9 (15%); others 3 (4%). Second line therapy in patients recurring after CR: same tki 15 (56%); switch to different tki (7 (26%); m-TOR inhibitor 5 (19%).Median OS from first line was 52 months (95% CI 42 -71). Median DFS from RC was 52 months (34-71). DFS was not significant different if CR was obtained with or without local therapy [34 months (18.2-NA) vs 53 month (47-NA) p = 0.141].No differences according to type of tki (p = 0.656), neither according to who stopped or not tki at the moment of CR [47 months (49 – 71) vs 53 months (42 - NA) p = 0.113]. Median time to recurrence from CR was significantly lower for peritoneal [17 (15-NA) vs 52 (42-NA), p = 0.039]and cerebral metastases [16 (15-NA) vs 53 (47-74), p < 0.001]. No differences in DFS were found according to the number of sites at presentation and to Motzer risk group (p = 0.150). Conclusions: The prognostic value of CR depends from the site where was obtained. Cessation of tki can be an option in selected CR patients.
A prospective international randomized phase II study evaluating the food effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC).
Authors: Russell Zelig Szmulewitz, Abiola Falilat Ibraheem, Cody J. Peer, William Douglas Figg, Bradley Curtis Carthon, Mark Kozloff, Donald Harvey, Paul A. S. Fishkin, Wei Peng Yong, Edmund Chiong, Chadi Nabhan, Peter H. O'Donnell, Walter Michael Stadler, Mark J. Ratain
Journal: Journal of Clinical Oncology (2017)

176 Background: AA is a standard of care for the treatment of metastatic CRPC, with an approximate retail cost of $8000/month. Despite a large food effect (~17-fold increase in C Max with a high-fat meal), AA was administered under fasting conditions in its pivotal trials. There are no randomized continuous dosing studies examining prandial state dosing on AA PK/PD. We sought to test the hypothesis that LOW (250mg w/food) would have similar PK/PD and safety to standard (STD, 1000mg fasting) in patients with progressive CRPC. Methods: Patients (n = 72) with progressive CRPC from seven institutions in the US and Singapore were randomized to treatment with STD or LOW (with low-fat breakfast). Both arms received prednisone 5mg twice daily. PSA was assessed monthly, and testosterone, DHEA/DHEAS were assessed every 12 weeks along with standard disease burden assessments. PK samples were collected at day 1, 8 and months 2, 3, 4. Log change in PSA response rate from baseline to week 12 was examined as the primary endpoint, with a non-inferiority design based on a non-inferiority margin of 15%. This margin corresponds to a 0.51 standard deviation (SD) difference in the mean log changes between the groups. Results: Accrual was completed with n = 36 on STD and n = 36 on LOW. Median (range) age was 74 (52-89) and baseline PSA was 39.2(range 0.6-1789). Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). The 95% confidence for the difference (STD-LOW) ranged from -0.40 to 1.19, with lower limit corresponding to -0.24SD. Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms (p = 0.53). Preliminary analysis of PK showed no difference in C Max beyond the first cycle with lower PK variability in the LOW arm. Conclusions: Low-dose (250mg/day) abiraterone acetate with a low-fat breakfast is non-inferior to standard dosing in a fasted state with respect to PSA and PK metrics. Although PSA response and progression are not clinically validated surrogates, given the pharmacoeconomic implications, these data warrant consideration by prescribers and payors. Clinical trial information: NCT01543776.
Atypical vascular neoplasms and risk of development of angiosarcoma.
Authors: Vinod Ravi, Rohan Gupta, Elizabeth G Demicco, Dejka M. Araujo, Joseph A. Ludwig, Robert S. Benjamin, Wei-Lien Wang, Shreyaskumar Patel
Journal: Journal of Clinical Oncology (2012)

10071 Background: Atypical vascular neoplasms are rare cutaneous lesions that develop following radiation therapy to the breast that have evidence of atypia but do not meet all criteria for a diagnosis of angiosarcoma. They typically have a benign course and are managed by surgical resection. Histopathological changes consistent with atypical vascular neoplasm are commonly found adjacent to angiosarcoma and have lead some investigators to believe that these may be precursor lesions to development of angiosarcoma. Methods: We performed a retrospective review of all patients with a diagnosis of atypical vascular neoplasm from 2002 to 2012. Patient with a prior/concurrent history of angiosarcoma were excluded from the analysis. Primary objective of the study was to determine the percentage of patients with atypical vascular neoplasms that progressed to angiosarcoma on long-term follow-up. Results: 37 patients were identified in the tumor registry at MD Anderson cancer center with a diagnosis of atypical vascular neoplasm between 2002 and 2012 with a median follow-up of 24 months. The median age of the study population was 53. Females represented 89% of the study population. Atypical vascular neoplasms occurred most frequently in the breast/chest (70%) and 68% of patients had a prior history of breast cancer. 54% of patients had prior radiation therapy. The median time to development of atypical vascular neoplasms from radiation therapy was 52 months. Among patients who underwent surgical resection with negative margins, there were no recurrences. We failed to observe any progression to angiosarcoma in the study population. Conclusions: Patients with atypical vascular neoplasms may not progress to angiosarcoma and are best managed with surgical resection.
Maintenance treatment with capecitabine plus cetuximab after first-line standard fluorouracil-based chemotherapy plus cetuximab for patients with RAS wild-type advanced colorectal cancer.
Authors: Xianglin Yuan, Ben Zhao, Hong Qiu, Mingsheng Zhang, Yanmei Zou
Journal: Journal of Clinical Oncology (2017)

806 Background: The optimum duration of first-line treatment with chemotherapy in combination with cetuximab (CET) in patients with RAS wild-type (wt) advanced colorectal cancer (ACRC) is unknown. The current study was designed to evaluate the efficacy and safety of maintenance treatment (MT) with capecitabine (CAP) plus CET in ACRC. Methods: The trial was conducted at Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, China. We included patients with previously untreated RAS wt ACRC, with stable disease or better after induction treatment with 4-6 months of standard fluorouracil-based chemotherapy plus CET, WHO performance status of 0 or 1. The selected patients were assigned to MT-CAP (1250mg/m 2 orally twice daily on day 1-14 every 3 weeks), and CET (400 mg/m 2 on day 1 of the first week, then 250 mg/m 2 on day 1 every week). We assessed disease status every 6 weeks. The primary endpoint of the study was disease progression or unacceptable toxicity, defined as progression-free survival (PFS). All endpoints were calculated from the time of inclusion. Analyses were done by intention to treat. Results: From Jan. 1, 2014 to May 1, 2016, we assigned 13 patients to MT-CAP plus CET. Median follow-up time was 22 months. Median PFS was 16.7 months, and the PFS of MT was 12.1 months. MT was well tolerated, and none of the 13 patients discontinued treatment due to toxic effects. The general quality of life did not deteriorate during MT. Conclusions: MT-CAP plus CET after 4-6 months of standard chemotherapy and CET in ACRC patients was effective and did not compromise life quality. Based on these results, we launched a single arm, open-label, multi-center, Phase 2 clinical trial to investigate the efficacy and safety of MT-CAP plus CET after first-line standard fluorouracil-based chemotherapy plus CET for patients with RAS wt ACRC. The trial was registered with ClinicalTrials.gov, number NCT02717923, and approved by the Institutional Review Board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Clinical trial information: NCT02717923.
Thirty-Two-Year-Old Woman With Corrected Tetralogy of Fallot
Authors: D. Brian Newman, William R. Miranda, Heidi M. Connolly
Journal: JAMA Cardiology (2017)

An asymptomatic woman in her 30s with history of tetralogy of Fallot presented for evaluation of her congenital heart disease; on examination, venous pressure was visualized 4 cm above the clavicle at 45° with a prominent a wave. What would you do next?
Phase II trial of oxaliplatin and 5-FU in patients (pts) with platinum-resistant recurrent (PRR) ovarian carcinoma (OVCA).
Authors: Joseph N. Kerger, Fabienne Lebrun, Thierry Gil, Andrea Gombos, Amina Ridoine, Fanny Bustin, Veronique D'hondt
Journal: Journal of Clinical Oncology (2014)

5580 Background: Based on clinical data and the partially non-cross-resistance of oxaliplatin with other platinum compounds, this phase II trial evaluated the safety and efficacy of a modified FOLFOX6 regimen in pts with PRR OVCA with a platinum-free interval of less than 6 months after any previous platinum-containing line of therapy. Methods: From 10/2008 till 08/2013, a total of 43 eligible pts with measurable (RECIST) and/or evaluable (CA125) disease were included in this study and received a median number of 8 courses (range: 1-14) of a modified FOLFOX6 regimen consisting in oxaliplatin 85 mg/m² d1, L-leucovorin 200 mg/m² d1 followed by a continuous iv infusion of 5-FU 2600 mg/m²/48hrs every 2 weeks until disease progression or unacceptable toxicity. Pt characteristics: median age 57 years (range: 37-81), median PS 1 (0-2), serous histological subtype 60%, median number of previous lines 3 (1-12), prior exposure to carboplatin 100%, paclitaxel 98%, pegylated liposomal doxorubicin 63%, gemcitabine 23%, topotecan 23%, cyclophosphamide 14%, bevacizumab 9%. Results: Antitumor activity was seen in 35 cases with measurable disease: 1 CR + 15 PR, for an objective response rate of 46% (95%CI: 29-63%) and a median duration of response of 7.0 months (95%CI: 5.5-8.4 months); 13 SD (37%); 6 PD (17%). A clinical benefit rate (CR + PR + SD > 6 months) was observed in 21/43 (49%) pts (95% CI: 34-64%). Overall, the median time to progression was 5.8 months (95%CI: 4.9-6.5). Most side effects were moderate (G1&2): anemia in 88%, thrombocytopenia 67%, leucopenia 56%, neurological 81%, fatigue 72%, liver 51%, mucositis 41%, diarrhea 30%, renal 18%, hand-foot syndrome 9% of the pts. G3 toxicities included febrile neutropenia in 9%, neurological 9%, diarrhea 7%, mucosal 2% and liver toxicity 2% of the pts, leading to dose reductions in 13 pts (30%). Two hypersensitivity reactions to oxaliplatin also occurred. Conclusions: In this heavily pretreated patient population with PRR OVCA, this modified FOLFOX6 regimen exhibited a promising activity with an expected, but acceptable safety profile and might deserve further exploration, maybe in combination with biological or targeted agents. Clinical trial information: NCT01481701.
Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors
Authors: Takayuki Kosaka, Junko Tanizaki, Raymond M. Paranal, Hideki Endoh, Christine Lydon, Marzia Capelletti, Claire E. Repellin, Jihyun Choi, Atsuko Ogino, Antonio Calles, Dalia Ercan, Amanda J. Redig, Magda Bahcall, Geoffrey R. Oxnard, Michael J. Eck, Pasi A. Jänne
Journal: Cancer Research (2017)

Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712-21. ©2017 AACR.
Comprehensive genomic characterization of upper tract urothelial carcinoma (UTUC).
Authors: Tyler J. Moss, Yuan Qi, Liu Xi, Bo Peng, Maribel E Mosqueda, Charles Guo, Michael Ittman, David A. Wheeler, Seth P. Lerner, Surena F. Matin
Journal: Journal of Clinical Oncology (2017)

375 Background: Integrated analysis of UTUC was performed to characterize the genomic landscape of UTUC and provide insights into biology. Methods: 31 untreated samples underwent WES, RNAseq, and RPPA. Consensus mutation calls from independent pipelines of 2 centers identified gene expression clusters using unsupervised consensus hierarchical clustering (UCHC). Results: Clinical data are shown in the Table. WES identified mutations in FGFR3 (74.1%; 92% low grade, 60% high grade), KMT2D (44.4%), PIK3CA (25.9%), TP53 (22.2%). APOBEC and CpG signatures were identified. Expressed marker genes from bladder TCGA were not associated with molecular subtypes in this study. UCHC of RNAseq segregated samples into 4 molecular subtypes. Cluster 1: no PIK3CA mutations; enriched for nonsmokers, high grade non-muscle invasive tumors, high recurrence rates and favorable survival. Cluster 2: 100% FGFR3 mutations; enriched for low grade, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations; high tobacco use and bladder recurrence (62.5%); tumors all non-muscle invasive. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations; enriched for high grade, muscle-invasive disease, tobacco use, CIS, reduced survival; novel fusion of SH3KBP1-CNTNAP5 was identified, with high expression levels in the sample. Conclusions: We show mutations in UTUC occurring at differing frequencies and subtypes than bladder cancer. Novel fusion SH3KBP1 regulates RTK signaling and acts to recycle TGFβ receptors. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. [Table: see text]
Is immediate repeat biopsy necessary for men with atypical small acinar proliferation?
Authors: Christi Butler, Katherine Rotker, Andrew Leone, Ali Amin, Stephen Frank Schiff, Gyan Pareek, Dragan Golijanin, Joseph F. Renzulli
Journal: Journal of Clinical Oncology (2014)

e16049 Background: Atypical small acinar proliferation (ASAP) is a diagnosis that occurs in about 1-2% of prostate biopsies. Approximately, 30-40% of patients with ASAP may develop prostate cancer. Current guidelines recommend a repeat biopsy within 3-6 months after the initial diagnosis. The adoption of active surveillance for low risk prostate cancer has reduced overtreatment by recommending repeat biopsy after one year of surveillance. Our objective was to determine if there is an association between ASAP and low risk prostate cancer, with no significant occurrence of skip lesions to high grade disease and thus, challenge the need for immediate repeat biopsy. We hypothesize that ASAP patients who develop low risk prostate cancer may be managed on active surveillance, with no increased risk of disease progression. Methods: We performed a retrospective chart review that identified 108 patients who underwent prostate biopsy from 2000 to 2013 and obtained a diagnosis of ASAP. Patients underwent biopsies either for elevated PSAs or prostatic nodules found on digital rectal exam. These patients were followed with repeat biopsies and PSA evaluations. Prostate cancer detection, stage, and Gleason score were documented. Results: Of the 96 patients with ASAP on initial diagnosis, 56 had a repeat biopsy, but only 45 were within 3-6 months. The remaining 12 were within 2.5 years. 21 patients went on to develop prostate cancer. Of those 21 patients, 17 had Gleason 3+3 disease and only 4 had Gleason 3+4 disease. Prostatectomy was performed on 9 patients, while 2 received radiation. One patient was upgraded from 3+3 to 3+4 on final pathology. No patients had a Gleason score of 4+3 or higher. Conclusions: Our results demonstrate that a limited number of patients (37.5%) with an initial diagnosis of ASAP went on to develop prostate cancer if they had a repeat biopsy within 2.5 years. Of the 37.5% who progressed, 76.3% developed low risk prostate cancer defined by D’amico criteria. Significantly, no patients developed high risk disease following an initial diagnosis of ASAP. Based on this information we recommend that an ASAP diagnosis be managed with active surveillance. This would include PSA and DRE at 4-6 month intervals followed by a repeat biopsy at one year.