tbuckley/cabot-search huggingface dataset:
Rociletinib-associated cataracts in EGFR-mutant NSCLC.
Authors: Zofia Piotrowska, Erica Liu, Jennifer Logan, Jessica Chow, Fasika A Woreta, Alona Muzikansky, Lisa Stober, Alexandra Carly Wanat, Kelly Goodwin, Christopher G. Azzoli, Jennifer S. Temel, Rebecca Suk Heist, Alice Tsang Shaw, Jeffrey A. Engelman, Kamden Kopani, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2016)

9042 Background: Rociletinib (roci) is a T790M-selective EGFR TKI. We observed unexpectedly frequent sudden-onset cataracts (cats) among pts treated with roci on the phase I/II TIGER-X study at MGH. We retrospectively assessed the incidence and characteristics of cats among our pts. Methods: To identify pts at risk of roci-associated cats, we excluded pts with pre-existing cat/prior cat surgery, pts treated with sub-therapeutic roci doses ( < 900 mg BID free base (FB) capsules,) and those who lived < 120 days from roci initiation. We requested all living pts undergo eye exams. A study ophthalmologist reviewed all records. Associations between cat surg and age, gender, starting roci dose, time on roci and markers of hyperglycemia (c-peptide, HgbA1c) were analyzed with univariate logistic regression models. Results: Of 67 pts treated with roci at MGH, 40 were at risk of cats, including 25 women and 15 men. The median age was 55 yrs (range, 37-75). The median duration of roci exposure was 8 mos (range, 1-20). Pts received starting BID roci doses of 900 mg FB (4 pts), 500 (11), 625 (8), 750 (15) and 1000 (2.) Median follow up was 14.8 mos. 21 (53%) pts developed cats during or after roci treatment; 17 (43%) required surgical repair. The median time from initial roci exposure to first cat surg was 15 mos (95% CI, 14-17); 11/17 had discontinued roci at the time of surg. Roci-associated cats frequently progressed to hypermature, surgical cats within weeks to months. Surgery was often more complex than typical senile cats, with increased risk of high intralenticular pressure and need for specialized intraop techniques, but ultimately successful in all documented cases. Variables associated with an increased risk of cat surg included male sex (HR 3.4, 95% CI 1.7-10.1; p = 0.03) and roci monthly exposure (HR 1.15, 95% CI 1.05-1.26; p = 0.003). Conclusions: Roci is associated with a high risk (53%) of late-onset cataracts in our limited cohort, with a median latency of 15 mos from initial drug exposure to surgery. With every month of roci exposure patients increased their risk of requiring cat surgery by 15%. The age of onset was younger and the course more rapid than typical senile cats. Delayed surgical removal may result in increased risk of intraop complications; roci-treated pts should be screened. Clinical trial information: NCT01526928.
Diagnostic dilemma: Overlapping clinical and radiologic features of osteoradionecrosis and recurrent head and neck squamous cell carcinoma.
Authors: Andrea M Tufano, Ryan Sugarman, Sewit Teckie, Maged Ghaly, Jed Michael Pollack, Douglas K. Frank, Dev Kamdar, Lucio Pereira, Priscila Hermont Goncalves, John Fantasia, Michael Lessin, Gerardo Romeo, Jian Yi Li, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2018)

e18072 Background: Definitive chemoradiotherapy (CRT) is the standard of care treatment for locally advanced head and neck squamous cell carcinoma (SCC) but carries the risk of osteoradionecrosis (ORN), a debilitating complication in bone healing. ORN and recurrent SCC share many clinical and radiologic features, making these conditions difficult to differentiate. However, it is crucial to distinguish between ORN, a benign condition that is managed conservatively, and recurrent SCC, which carries a poor prognosis even with treatment. Methods: We performed a single center retrospective chart review of 13 patients with head and neck SCC treated with CRT who subsequently had clinical suspicion of ORN. Patient demographics, history and physical findings, imaging results and final diagnosis were collected. Results: 6 patients were male, and 7 were female. Median age was 66 years (range 22-90). 7 had a final diagnosis of ORN and 6 had recurrent SCC. Findings on history, physical exam, and imaging are compared in Table 1. The average time interval between completion of CRT and clinical suspicion of ORN was longer in patients with a final diagnosis of ORN than recurrent SCC (21.6 vs. 5.2 months). Mean radiation dose and radiation technique used were not predictive of either outcome. Mean SUV on PET scan was similar for ORN and recurrent SCC (8.1 vs 7.2). Several patients with a final diagnosis of SCC had biopsies that were initially negative for malignancy, but tested positive on repeat biopsy. All 7 patients with ORN are alive but 5 of 6 patients with recurrent cancer have expired. Conclusions: ORN and recurrent SCC share common clinical and radiologic features. Our data suggests that suspicion for ORN within 6 months of CRT is concerning for disease recurrence. A negative biopsy does not rule out SCC recurrence. Repeat biopsy, ideally with direct visualization or via image guidance, should be considered if ORN symptoms progress despite supportive care. Findings Final dx ORN (# of patients) Final dx SCC (# of patients) Trismus 4 4 Oral pain 3 5 Exposed bone 4 5 Soft tissue enhancement on CT 6 6 Bone sclerosis on CT 3 3
Association of inflammatory cytokines with obesity and prevention with ASA or DHA/EPA supplementation.
Authors: Aleksandra Gruslova, Duan Quach, Lucy Lengfleder, Stefano Tiziani, Alessia Lodi, Kenneth Kist, Virginia G. Kaklamani, Linda A deGraffenried, Andrew Jacob Brenner
Journal: Journal of Clinical Oncology (2017)

e14619 Background: Obesity is associated with poor breast cancer outcomes. Our prior data suggested a positive feedback loop whereby circulating factors associated with obesity induce the COX-2 enzyme, resulting in increased pro-inflammatory cytokine prostaglandin E2 (PGE2), which can then increase aromatase levels. In order to establish a better understanding of baseline PGE2 levels, as well as select the proper COX2 inhibitor for prospective study, we performed a randomized study of aspirin (ASA), fish oil (DHA/EPA), and the combination in postmenopausal women of varying body habitus and assessed changes in cytokines. Methods: Women were recruited and randomly assigned into 3 interventions: ASA 81mg, docosahexaenoic acid (DHA, 1500mg) with eicosapentaenoic acid (EPA, 2500mg), or combination ASA and DHA/EPA (DUAL). Blood was collected before and after 28 days of supplementation, and 27 cytokines were assessed by Luminex array (Millipore); PGE2 was measured by ELISA. Investigators were blinded until analysis was complete. Statistical analyses were performed in R. Results: 110 patients were included: 90% participants white; of which 50% Hispanic; average BMI 31.5±0.67; and age: 60.1±0.58. Cytokines were not correlated with demographic variables. At baseline inflammatory cytokines IL-6 and Eotaxin were correlated with BMI ((p &gt; 0.029 and p &gt; 0.017, respectively). After 28 days of DHA/EPA BMI was correlated with Eotaxin, Il-2, IL-7 and GM-CSF (p &lt; 0.05), in ASA group correlation was significant only with IL-2 (cor.coef= 0.58). Two sample t-test showed significant difference between DUAL and ASA or DHA/EPA for IL-6 (p = 0.008 and p = 0.034, respectively), and for IL-2 only between DUAL and ASA (p = 0.039). Furthermore, impact on PGE2 was observed with ASA with 81% obtaining a decrease from baseline (median change -28%); by comparison 55.1% (-1%) and 65.6% (-22%) of subjects showed decrease in the DUAL and DHA/EPA groups respectively. Level of macrophage inflammatory proteins (MIP-1b) were lower in the DUAL group compare to ASA (p &lt; 0.014). Conclusions: Chronic inflammatory cytokines are correlated with obesity, and may be modified by use of ASA and DHE/EPA. This strategy may be useful in the secondary prevention setting. Clinical trial information: NCT02062255.
Intratumoral heterogeneity and chemo-resistance in nonseminomatous germ cell tumor of the testis.
Authors: Mehmet Asim Bilen, Kenneth R. Hess, Matthew T. Campbell, Jennifer Wang, Russell Broaddus, Jose A. Karam, John Francis Ward, Christopher G. Wood, Priya Rao, Miao Zhang, Rosale General, Diana H. Cauley, Sue-Hwa Lin, Louis L. Pisters, Shi-Ming Tu
Journal: Journal of Clinical Oncology (2016)

e16055 Background: Intratumoral heterogeneity contributes to the emergence of chemo-resistance and plays a role in the development of refractory disease in certain subtypes of nonseminomatous germ cell tumor of the testis (NSGCT). Methods: In this retrospective study, we evaluated consecutive patients (pts) who had been diagnosed with the three most common histological phenotypes of NSGCT, i.e., pure embryonal carcinoma (pure E), embryonal carcinoma with yolk sac tumor and teratoma (EYT), or embryonal carcinoma with yolk sac tumor, seminoma, and teratoma (EYST). Chemo-resistance was determined by the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor and in those pts who developed progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 pts to identify any actionable genetic mutations. Results: Between January 2000 and December 2010, 275 pts whose primary tumor showed pure embryonal carcinoma (pure E), embryonal carcinoma, yolk sac tumor, and teratoma (EYT), or embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST), were included for the study. Pts with EYST had the highest cancer-specific mortality rate (P= .009). They tended to undergo somatic transformation (P= .0007). For pts with stage I disease, the recurrence rate was 29% (23/78 pts) on surveillance and 4% (2/49 pts) with adjuvant chemo therapy. Certain pts with clinical stage I NSGCT who developed recurrence on active surveillance appeared to be at increased risk of dying from disease [i.e., E: 0/5 = 0%, EYT: 2/15 (13%), EYST: 2/5 (40%)]. This result needs further confirmation and additional investigation. Two (25%) of 8 pts with advanced EYST harbored a KIT somatic mutation. Conclusions: Our data suggest that chemo-resistance of NSGCT is related to the tumor subtypes. Pts with clinical stage I NSGCT who develop recurrence on active surveillance with histologically EYST subtype may be at increased risk of dying from disease. Understanding the role of intratumoral heterogeneity in the development of refractory disease may improve treatment strategies and the clinical outcome of pts with NSGCT.
Abstract 361: Regulation of Activity of Apoptosis Inducing Factor by SUMO Conjugation
Authors: Eun Y KIim, Yi Zhang, Abha Grover, Wei Yu, Jun Wang
Journal: Circulation Research (2017)

Apoptosis inducing factor (AIF), a mitochondrial oxidoreductase, is primarily involved in maintaining mitochondrial function. However, in response to apoptotic insults, AIF is released from mitochondria via cleavage and relocates to the nucleus, where it binds chromatin, subsequently causing its condensation and cell death. Thus, AIF plays an important role in both cell survival and death. The regulatory pathways/signaling events that govern the key step of AIF translocation and activity in cell death are not completely deciphered. SUMO conjugation, a highly conserved posttranslational modification, plays an important role in cardiac homeostasis. Herein, we report AIF as a novel SUMO substrate, and SENP5, a SUMO deconjugation enzyme, increased cardiomyocyte death once overexpressed in the mouse hearts, which coincided with an increase level of truncated AIF in cytosol. In line with the above findings, adenoviral mediated transduction of SENP5 wild type (wt), but not the C713L mutant, the latter of which lacks de-sumoylation activity, triggered cell death and AIF nuclear occupancy. Also, the SENP5-wt, but not the catalytically inactive mutant, de-sumoylated AIF. We further identified lysine residue 89 (K89) on AIF as one of the major SUMO attachment sites, and mutation of K89 to arginine (K89R) promoted AIF nuclear translocation in AC16, a cardiac cell line, and necrosis in L929 cells induced by TNFα/Z-vad-fmk. Our findings provide a novel mechanism by which SUMO conjugation is involved in mediating the function of AIF, which is important for cardiomyocyte survival and death.
A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan
Authors: Fouad T. Chebib, Ronald D. Perrone, Arlene B. Chapman, Neera K. Dahl, Peter C. Harris, Michal Mrug, Reem A. Mustafa, Anjay Rastogi, Terry Watnick, Alan S.L. Yu, Vicente E. Torres
Journal: Journal of the American Society of Nephrology (2018)

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.
Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids.
Authors: Mirjana Ziemer, Eleni Koukoulioti, Jan-Christoph Simon, Thomas Berg
Journal: Journal of Clinical Oncology (2017)

3073 Background: The CTLA4-antibody ipilimumab, and PD-1-antibodies pembrolizumab as well as nivolumab have revolutionized antineoplastic therapies. Induction of autoimmune-like drug-induced liver injury (DILI) is within the spectrum of adverse reactions of these new drugs and has been observed in about 1-5 % of patients, developing predominantly within the first 6 to 12 weeks after start of treatment. Immediate application of systemic steroids and a permanent discontinuation of immune checkpoint-inhibition therapy are recommended for any alanine aminotransferase increase ≥ WHO grade 3. In severe autoimmune-like DILI the permanent discontinuation of the immune checkpoint inhibitor is recommended, as drug re-exposure might be associated with a significant risk of a fulminant DILI. Methods: We report six patients with severe grade 3 autoimmune-like DILI (according to Common Terminology Criteria for Adverse Events 4.3) treated with long-term application of budesonide, a liver-directed topical steroid. Results: Immune checkpoint inhibitors were stopped and methylprednisolone was applied initially with a dose of 1 mg/kg body weight and tapered thereafter. To reduce systemic steroids and to minimize the exposure time to systemic steroids, the topical steroid budesonide 3 mg three times per day was additionally given in combination with N-acetylcysteine and ursodeoxycholic acid. Under this multimodal approach transaminases normalized and the respective immune-checkpoint inhibitor could be re-started without re-manifestation of DILI under the continuous treatment with budesonide. Conclusions: Budesonide - a liver-directed topical steroid - might be an interesting approach to target liver related autoimmune adverse reactions induced by immune checkpoint inhibitors without compromising their anti-cancer effect. We were able to safely and effectively re-introduce and continue immune checkpoint inhibitors under the continuous application of the topical steroid without showing any further liver toxicity.
Safety, dose tolerance, pharmacokinetics and pharmacodynamics study of CPX-POM in patients with advanced solid tumors.
Authors: Scott James Weir, Robyn Wood, Tammy Ham, Rashida Challenger, Prabhu Ramamoorthy, Greg Reed, Michael Jay Baltezor, Roy A. Jensen, John Arthur Taylor, Shrikant Anant, Michael Dalton, Michael J McKenna, Valentina Zhukova-Harrill, William McCulloch, Howard A. Burris
Journal: Journal of Clinical Oncology (2018)

TPS2618 Background: Ciclopirox (CPX) is an antifungal agent contained in a number of FDA-approved topical drug products. CPX possesses anticancer activity in a number of in vitro and in vivo preclinical models, however, it’s clinical utility is limited due to low oral bioavailabilty, gastrointestinal toxicity, and poor water solubility. Ciclopirox Prodrug (CPX-POM) selectively delivers its active metabolite, CPX, to the entire urinary tract following systemic administration. In a chemical carcinogen mouse model of bladder cancer, CPX-POM treatment resulted in significant decreases in bladder weight, a clear migration to lower stage tumors, dose-dependent reductions in Ki67 and PCNA staining, and inhibition of Notch 1 and Wnt signaling pathways. Methods: Study CPX-POM-001 (NCT03348514) is an ongoing US multicenter, Phase I, open-label, dose escalation study to evaluate dose-limiting toxicities (DLTs), define the maximum tolerated dose (MTD), and to determine the recommended Phase II dose of IV CPX-POM. Approximately 24 patients with any histologically- or cytologically-confirmed solid tumor type refractory to standard therapy, and also meet other standard Phase I eligibility criteria, will be enrolled in dose escalation cohorts. The MTD will be defined as the dose BELOW that dose which causes DLTs in ≥33% of patients. Safety and tolerability will be based on an assessment of adverse events, physical examinations, vital signs, electrocardiogram, clinical laboratory tests, ophthalmologic assessments, and concomitant medications. Single dose and steady-state pharmacokinetics of CPX-POM, CPX and ciclopirox glucuronide are being characterized in both plasma and urine. Urine ß-glucuronidase activity is also being determined. Single and multiple dose pharmacodynamics of CPX-POM are being characterized by measuring circulating biomarkers of Wnt and Notch cell signaling pathways. Enrollment began in January 2018 at a starting IV CPX-POM dose of 30 mg/m2. Doses are currently being escalated in 100% increments until a ≥Grade 2 is encountered, at which point that cohort and all subsequent cohorts will follow a classical “3 + 3” dose escalation design. Clinical trial information: NCT03348514.
Molecular testing during AML treatment for early prediction of clinical response.
Authors: Hong Yuen Wong, Anthony Derek Sung, Katherine E Lindblad, Sheenu Sheela, Gregory W Roloff, Kristi Romero, Meghali Goswami, Matthew P Mulé, Christin B Destefano, David Rizzieri, Laura W Dillon, Catherine Lai, Christopher Simon Hourigan
Journal: Journal of Clinical Oncology (2018)

7047 Background: Early prediction of response in acute myeloid leukemia (AML) patients undergoing cytotoxic chemotherapy may have clinical utility. Currently, measurable residual disease (MRD) testing after initial chemotherapy treatment can predict relapse and survival in AML. However, it has not been established if repeat molecular or genetic testing during chemotherapy can offer information regarding the chemotherapy sensitivity of the leukemic clone. Methods: Blood from 45 adult AML patients at day 1 and 4 of induction (n = 35) or salvage (n = 10) cytotoxic chemotherapy was collected for next generation sequencing ( > 500x) of 49 gene regions recurrently mutated in MDS/AML (Raindance Thunderbolts™ Myeloid Panel) and quantitative real-time PCR (qPCR) assessment (WT1) on IRB approved protocols. Results: The average age was 58 (23-78); 42% achieved a complete response. A median of 4 non-synonymous coding mutations (range 0-7) were detected in 45 patients by NGS in blood from day 1 (median VAF: 28%). Only 1 patient had no such mutations detectable. White blood cell (WBC) count decreased 75% on average from 10K/ul (range 0.3-60) on day 1 to 2.3K/ul (range 0.2-26) by day 4 of chemotherapy. All mutations found on day 1 remained detectable in blood on day 4 of therapy. Remarkably, the ratio of mutated to wild-type sequence was often maintained despite three days of intensive therapy, a phenomenon not limited to DNMT3A, TET2 and ASXL1. This surprising finding did not hold for NPM1 (present only in responders, n = 5, mean decrease -44%, range -2% to -98%) or TP53 (present only in non-responders, n = 9, mean increase 34%, range -38% to 94%). WT1 was overexpressed on day 1 in 31 of 34 patients tested. In evaluable patients 7 of 12 responders had a 4-fold reduction in WT1/Abl1 expression by day 4 compared with 7 of 19 non-responders. Conclusions: Molecular testing on day 4 of AML chemotherapy is not predictive of clinical response. The stability of NGS detectable mutations in blood suggests that cytotoxic therapy may have a limited therapeutic specificity for clones containing these mutations. WT1 qPCR was uninformative for very early MRD assessment. Further validation is required to confirm the utility of NPM1 and TP53 monitoring in blood during cytotoxic therapy. Clinical trial information: NCT02527447.
Contralateral prophylactic mastectomy, social economics, and informed medical decision making.
Authors: Hadeel Assad, Bianca Barbat, Maria Markosyan, Arushi Hukku, Archana Balakrishnan, Jeffrey Flynn, Robert Eric Bloom
Journal: Journal of Clinical Oncology (2018)

e12622 Background: The rate of contralateral prophylactic mastectomy (CPM) in the United States has more than tripled in the past decade. The majority of women who undergo CPM have no major genetic or familial risk factors for contralateral disease. In patients of standard risk, CPM has not been shown to decrease breast cancer mortality. We hypothesized that women who undergo CPM have a higher sense of loss aversion which may distort the risk-benefit ratio of CPM at a time when they are vulnerable because of fear and sense of loss of control. Methods: We conducted a survey of 38 patients who underwent CPM and 28 patients who had unilateral breast surgery for mammary carcinoma, along with 40 control women with no history of cancer. Participants were excluded if they were carriers of deleterious gene mutations or had bilateral breast cancer. The groups were matched for age and cancer stage. Data was analyzed using Fisher’s exact, Chi Square and Mann Whitney U tests; p < 0.05 was considered statistically significant. Results: Women who underwent CPM were twice as likely to undergo genetic testing than women who did not (61% vs. 32%, p = 0.07). Most women (75%) who had CPM had breast reconstruction, compared to none of the unilateral surgery women (although 5 had total mastectomy). Two-thirds of physicians discussed the risks and benefits of CPM with their patients, of which 12% and 53% recommended against it in CPM and unilateral surgery groups, respectively. Most women (92%) who underwent CPM felt that decrease in anxiety alone was a valid reason to have the procedure compared to 71% of women who had unilateral surgery (p = 0.04) and 66% of women with no history of cancer (p = 0.02). Participants who underwent CPM were less likely to bid in a theoretical office lottery compared to women without a history of cancer (p = 0.04). Conclusions: We were not able to demonstrate that women who chose to undergo CPM have a higher sense of loss aversion, however our study confirms that anxiety is a major factor resulting in cognitive biases that could affect informed medical decisions. Further studies need to investigate factors that influence women’s decision to undergo CPM so that educational efforts can be redirected in a way that might be more effective.