tbuckley/cabot-search huggingface dataset:
Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration
Authors: Robyn H. Guymer, Zhichao Wu, Lauren A.B. Hodgson, Emily Caruso, Kate H. Brassington, Nicole Tindill, Khin Zaw Aung, Myra B. McGuinness, Erica L. Fletcher, Fred K. Chen, Usha Chakravarthy, Jennifer J. Arnold, Wilson J. Heriot, Shane R. Durkin, Jia Jia Lek, Colin A. Harper, Sanjeewa S. Wickremasinghe, Sukhpal S. Sandhu, Elizabeth K. Baglin, Pyrawy Sharangan, Sabine Braat, Chi D. Luu
Journal: Ophthalmology (2018)

There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD.The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial.Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy.Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals.The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events.Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant.In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.
Virtual consults: A paradigm shift for second opinions in oncology care.
Authors: Stephanie A. Velis, Nicholas J Dreyer, Neil Andersen, Erica L. Mayer, Matthew Steven Davids, Thomas Adam Abrams, Toni K. Choueiri, Jeffrey A. Meyerhardt, David Christopher Fisher, Christopher S. Lathan, Susana M. Campos, Susan Lane, Philip T. Glynn
Journal: Journal of Clinical Oncology (2016)

e18049 Background: Lack of access to specialized oncology care is increasing. The underprivileged and underserved are at a great disadvantage, as time and financial expenses can create barriers to receiving a full range of care. A secure telemedicine platform was used to bring patient and specialists together for a virtual second opinion. Methods: Mercy Hospital, Mercy Oncology Services (MOS) contracted with Partners Connected Health (PCH) to pilot a virtual second opinion program. Consult request was initiated and reimbursed by MOS through PCH. All patient data were processed through PCH. The patient and family, MOS oncologist, and regional medical oncology specialist all participated in the consult. A post consult satisfaction survey was constructed by MOS and PCH data analysts for increased validity. Patients completed the survey evaluating their experience on a 1-5 scale(1 strongly disagree, 5 strongly agree). The MOS physician completed a 15 question form evaluating the patient's status.Data obtained was recorded for analysis. Results: From July 2015 to January 2016,16 patients (8 female and 8 male, median age: 61 years) and 9 specialists participated in the pilot. Patient pathology included both epithelial and hematologic malignancy. Average consult duration was 25.4 minutes (minimum: 12 minutes, maximum: 40 minutes). After analyzing all patient questionnaires, 14 out of 16 patients
Preliminary report of a multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: An NF Clinical Trials Consortium study.
Authors: Scott Randall Plotkin, James H. Tonsgard, Nicole J. Ullrich, Jeffrey C. Allen, Tena L. Rosser, Jian Li Campian, David Wade Clapp, Michael J. Fisher, Gary R. Cutter, Bruce R. Korf, Roger Packer, Coretta Thomas, Matthias A. Karajannis, Jaishri O'Neill Blakeley
Journal: Journal of Clinical Oncology (2018)

2056 Background: Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. However, the optimal treatment dose and schedule are unknown. Methods: This multicenter, phase II, open-label study evaluated subjects (≥6 years old) with NF2 and progressive VS. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as ≥20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. Results: We enrolled 22 subjects (median age = 23 years). The overall hearing and radiographic response rates were 41% (9/22) and 23% (5/22), respectively. In an unplanned post-hoc analysis, the hearing and radiographic response rates were 14% (1/7) and 0% in pediatric subjects ≤21 years, as compared with 53% (8/15) and 33% (5/15) in adult subjects. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 women with elevated FSH underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Conclusions: Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates comparable to previous studies using lower doses. Pediatric subjects appear to benefit less than adults during bevacizumab treatment. Clinical trial information: NCT01767792.
Phase I study of intermittent high-dose lapatinib alternating with capecitabine for HER2-positive breast cancer with central nervous system metastases.
Authors: Aki Morikawa, Elena Pentsova, Margaret Kemeny, Sujata Patil, Bob T. Li, Kendrick Tang, Martin Fleisher, Catherine H. Van Poznak, Larry Norton, Andrew David Seidman
Journal: Journal of Clinical Oncology (2018)

e14016 Background: Central nervous system (CNS) metastasis is an unmet clinical challenge. While lapatinib (L) and capecitabine (C) have modest efficacy in the treatment of brain metastases (BM) from HER2+ breast cancer (HER2+BC), intratumoral penetration of L in human HER2+ BM is suboptimal (Morikawa A et al. Neuro-Oncol 2015), and L+C has overlapping toxicity. High dose L improves efficacy in preclinical models (Vivanco I et al. Cancer Disc 2012, Morikawa A et al. SABCS 2016). Methods: This multi-center phase I trial of intermittent high dose (IHD) L alternating with C in HER2+BC patients (pts) with CNS metastasis was designed based on Norton-Simon modeling and our preclinical data. An accelerated titration was used. The primary objective was to determine the maximum tolerated dose (MTD) of IHD L given twice a day (BID) 3 days on/11 days off, sequentially with fixed dose C at 1500mg BID given 7 days on/7 days off. The exploratory objectives included evaluation of clinical efficacy and circulating tumor cells (CTC). 4 dose levels were planned for IHD L: 1000mg BID, 1500mg BID, 2000mg BID, and 2500mg BID. Proactive use of anti-diarrheal medications was employed. Key eligibility criteria included HER2+BC with progression of disease in the brain, LM, or spinal cord (SC). There were no limits on prior therapy including standard dose L, intrathecal therapy (IT), and radiotherapy (RT) to the CNS and C was allowed if exposure was > 6 months prior. Results: The study enrolled 11 pts: 4 BM only, 5 LM, and 2 SC pts. 9/11 pts had prior RT. 3/5 LM pts had prior IT. 2 DLTs were G3 vomiting and G3 nausea (despite supportive measures per protocol);the MTD was L at 1500mg BID. The most frequent treatment emergent toxicities (>20%) were G2 vomiting, G1-2 diarrhea, G1 abdominal pain, G1-2 fatigue, G1 headache, G1-2nausea, and G1 palmar-plantar erythrodysesthesia. 3 pts with BM and/or LM remained on therapy for > 6 months with an exceptional responder currently on treatment > 1.5 yrs. CTCs in cerebrospinal fluid were detected in 3/3 pts examined, and changes paralleled the clinical course. Conclusions: IHD L alternating with C is a tolerable regimen for HER2+ CNS metastasis with potential clinical benefit. Clinical trial information: NCT02650752.
A phase 1/2 study of relacorilant + nab-paclitaxel (nab-pac) in patients (pts) with solid tumors: The dose-finding phase.
Authors: Pamela N. Munster, Jasgit C. Sachdev, Gini F. Fleming, Thaddeus S. Block, Stacie Peacock Shepherd
Journal: Journal of Clinical Oncology (2018)

2554 Background: Glucocorticoid receptor (GR) expression has been linked with chemotherapy resistance. Nonclinical and clinical studies have suggested that a GR antagonist (GRA) can enhance the efficacy of chemotherapy. Relacorilant (formerly CORT125134), a potent selective GRA, is being evaluated in solid tumors in combination with nab-pac. Methods: This ongoing phase 1/2 study is evaluating the tolerability, anticancer activity, and Phase 2 dose of relacorilant + nab-pac. Nab-pac is administered weekly for 3 of 4 weeks of a 28-day cycle. The study includes assessment of 2 relacorilant dosing schedules: continuous (CON) daily dosing and intermittent (INT) dosing (the day before, of, and after nab-pac). Pts ≥18 y old with advanced solid tumors, up to 3 prior lines of therapy in the advanced setting, ECOG status 0-1, and adequate renal, hepatic, and marrow function are included. Prior treatment with nab-pac is allowed. Results: As of Jan 1, 2018, 25 pts were enrolled; 17 had prior taxane. In CON dosing, 16 pts received 100 mg relacorilant/80 mg/m2 nab-pac and 1 received 100 mg relacorilant/60 mg/m2 nab-pac. In INT dosing, 4 pts received 200 mg relacorilant/150 mg/m2 nab-pac and 4 received 150 mg relacorilant/100 mg/m2 nab-pac. Grade ≥3 AEs included neutropenia (40%), anemia (12%), pneumonia (8%), mucosal inflammation (8%), and leukopenia (8%). Dose-limiting toxicity included neutropenia; GCSF support was added to regimens subsequently. Among pts treated to date, 1 unconfirmed CR (ovarian CA), 2 confirmed PRs (pancreatic CA, vulvar CA), and 5 SDs (2 ovarian CA, 2 pancreatic CA, 1 carcinoid) were observed. Pancreatic CA pt with confirmed PR has remained on study 48 weeks, despite having progressed within 14 weeks on earlier gemcitabine/nab-pac. For the 6 pts with available tissue, all had GR IHC results with ≥50% staining (range 50%-100%); 4/6 pts were responders; all 4 had ≥60% GR staining. Conclusions: An efficacy signal has been observed in pts with pancreatic and gynecologic CA previously treated with taxane. Neutropenia is manageable with GCSF support and dose modification. Expansions are planned, including pancreatic and ovarian CA cohorts. Clinical trial information: NCT02762981.
Surviving cancer between demoralization and hope: A cross-sectional assessment and clinical implications.
Authors: Mario Airoldi, Rossana Botto, Andrea Bovero, Riccardo Torta, Valentina Ieraci
Journal: Journal of Clinical Oncology (2018)

e22071 Background: Cancer deeply impacts on psychological and existential well-being. In this regard, demoralization is a common response to the perceived sense of loss elicited by cancer. Vice versa, hope represents a crucial resource for cancer patients. This cross-sectional study aimed to explore demoralization and hope in cancer survivors, examining their relationship with other psychological and physical variables such as distress, quality of life, pain, physical problems and symptoms intensity. Methods: Participants completed a set of rating scales, i.e. Demoralization Scale (DS), Hope Herth Index (HHI), 36-Item Short Form Health Survey (SF-36, V1, standard), Distress Thermometer (DT), Visual Analogue Scale for Pain (VAS), and SIDE. Results: Sample had 92 cancer survivors with histories of heterogeneous cancers. On average, participants presented a moderate level of demoralization (36.82 ± 35.01) and a high level of hope (35.31 ± 36.02). Demoralization and hope negatively correlated with each other (r = -.694; p < .0025) and were differently associated with the other considered variables. Hope, “Mental health” SF-36 subscale, physical problems, and distress had a significant predictive ability on demoralization, while “Disheartenment” and “Sense of failure” DS subscales were the hope significant predictors. Conclusions: Returning to “normal” daily life can be challenging for cancer survivors. In this regard, demoralization can affect them, while hope can represent a useful resource for survivors and an effective tool to use in the clinical practice. Therefore, the surveillance of patients during the survivorship seems to be clinically relevant. Meaning-focused interventions can support survivors in coping with demoralization and existential distress.
Population pharmacokinetics of PQR309, a dual PI3K/mTOR inhibitor in adult patients with advanced solid tumors.
Authors: Matthias Machacek, Lionel Renaud, Sasa Dimitrijevic, Debora Schmitz, Elena Ivanova, Karin Jorga
Journal: Journal of Clinical Oncology (2016)

e14101 Background: PQR309 is an orally bioavailable, pan-PI3K, mTORC1 and mTORC2 inhibitor, in clinical development for the therapy of solid tumors and hematologic malignancies. The aim of this work was to develop a population pharmacokinetics (PK) model for PQR309 and to identify patient factors (covariates) that impact exposure to PQR309. Methods: Data from the escalation phases of two open phase 1 clinical trials of continuous once daily PQR309 were used to evaluate safety, PK and pharmacodynamics in patients with advanced solid tumors (n = 41). Non linear mixed effects modeling with Monolix was used for the analysis. Results: PQR309 PK was best described with a two compartmental model with first order absorption with a time lag and with linear clearance from the central compartment. For the typical 70 kg patient the absorption rate was 2.1 h-1 (CV 111%), the absorption time lag 0.4 h (CV 36%), the clearance 4.2 L/h (CV 61%), the central volume 84.4 L (CV 91%) and the peripheral volume 211.9 L (CV 41%). The exchange coefficient between the two compartments was 65.1 L/h. The terminal half life was 51 h. Usage of acid-reducing agents (ARA) was identified as covariate on the absorption rate (kaARA = 0.67 h-1). ARA in combination with GI surgery lowered the bioavailability by 47%. Bodyweight had an effect on the central and peripheral volumes (bV1 = 2.8, bV2 = 1.2). Using the estimated individual PK parameters for simulation, the mean cmax at steady state for the 80 mg and 100 mg dose groups were found to be 0.96 μg/mL and 1.46 μg/mL, respectively, and the mean AUC24h at steady state 16.28 μg h mL-1and 23 μg h mL-1, respectively. Comparing the effect of bodyweight, ARA use and GI surgery on the steady state AUC24h , it was found that none of the covariates were relevant except ARA with GI surgery which reduced the AUC24h by 47% compared to the typical patient. Compared to the typical 70 kg patient, the cmax at steady state was 27% higher for a 50 kg patient, 20% lower for a 100 kg patient, 16% lower for ARA and 55% lower for ARA with GI surgery. Conclusions: While bodyweight, ARA use and ARA use in combination with GI surgery had an effect on steady state cmax it was only ARA use in combination with GI surgery that had a relevant effect on steady state AUC24h . Clinical trial information: NCT01940133 NCT02483858.
A phase II study of palbociclib (P) for previously treated cell cycle gene alteration positive patients (pts) with stage IV squamous cell lung cancer (SCC): Lung-MAP sub-study SWOG S1400C.
Authors: Martin J. Edelman, Mary Weber Redman, Kathy S. Albain, Eric C. McGary, Norman Rafique, Daniel P. Petro, Saiama Naheed Waqar, Jieling Miao, Katie Griffin, Vassiliki Papadimitrakopoulou, Karen Kelly, David R. Gandara, Roy S. Herbst
Journal: Journal of Clinical Oncology (2017)

9056 Background: S1400 is a master platform trial designed to assess targeted therapies in SCC. Study C evaluated the response rate (RR) to P, a CDK 4/6 inhibitor, in pts with cell cycle gene abnormalities. Methods: Pts with SCC, PS 0-2, normal organ function, who had progressed after at least one prior platinum-based chemotherapy for any NSCLC indication were eligible. Tumor specimens were required and evaluated for gene alterations (Foundation Medicine, Foundation One NGS assay). Pts with CDK 4 or CCND1/2/ 3 amplifications were eligible. The study was originally designed as a phase II/III trial comparing P to docetaxel (D), but was modified to a 2-stage phase II trial with primary endpoint of response rate. If &gt; 3 responses (R) of the first 20 pts were seen the study would continue to 40 pts, with 10 R for the 40 pts considered a positive study. Results: 89 pts (14% of pts screened) were assigned to S1400C, 53 pts enrolled (including 17 to D). One pt assigned to D re-registered to P. Frequency of cell cycle gene alterations for the enrolled pts: CCND1 amplification (n = 44, 83%); CCND2 amplification (n = 7, 13%); CCND3 amplification (n = 5, 9%); and CDK4 amplification (n = 3, 6%). (Note: some pts with multiple alterations.) Of the 37pts enrolled to P: 5 were ineligible (4 inadequate baseline labs, 1 did not progress on prior therapy). 1 not determinable for response. For the 32 eligible pts the median age was 67 (53-81), 21M/11F. Response: 2 PR (6% RR, 95% CI: 2%, 20%), 12 SD (38%, 95% CI: 21%, 54%) for a disease control rate (DCR) of 44% (95% CI: 27%, 61%). Median PFS was 1.7 mo (95% CI 1.6-2.9 mo). Of the 2 PR, one has progressed (duration of response, DOR, 7.7 mo), one still responding (DOR, 4 mo). Both responders had CCND1 amplification. 32 pts have been assessed for adverse events (AE). 4 experienced Grade 4 AE including lymphopenia (3), and thrombocytopenia (1). 13 others experienced Grade 3 treatment-related AE. Conclusions: 1. P failed to demonstrate the pre-specified RR to justify advancement to phase III. 2. P was well tolerated in this population. 3. Further analysis of those who derived benefit (e.g. response or prolonged SD) is underway. Clinical trial information: NCT02785939.
Unusual disease characteristics of multiple myeloma in eastern North Carolina.
Authors: Srikala Addepalli, Denise Brigham, Darla K. Liles
Journal: Journal of Clinical Oncology (2017)

e19512 Background:Multiple Myeloma (MM) is a relatively common malignancy in Eastern NC, especially in African American population. There have been several advances in treatment of MM but it is unclear how well current therapies are being utilized and what barriers prevent this. Our goal was to identify any unique clinical and epidemiological features of this disease in our patient population as this may help us to improve outcomes. Methods: Demographics, clinical features, FISH/ Cytogenetic features, clinical outcomes of the patients enrolled on MMRF CoMMpass study at our institution were reviewed and analyzed to identify any unusual features in our dataset. Results:The median age at diagnosis of MM is 69 years. There was a higher proportion of younger patients in our dataset, 40% of our patients were &lt; 60 years and 11% of patients were &lt; 40 years which may point to environmental and genetic factors in this population and needs to be studied further. About 20% of patients with MM are reported to have Light Chain Myeloma (LCM) while 30% patients had LCM in our dataset. More patients had a higher stage of disease, ISS stage III at diagnosis, 72%.The benefits of Autologous Stem Cell Transplant (ASCT) in management of Multiple Myeloma is well established but only 22% of the patients had ASCT as part of their management. This appears to be secondary to multiple factors including comorbidities, socioeconomic factors such as financial concerns, difficulty with access to treatment and availability of care givers Conclusions:There is a disproportionately high proportion of younger patients with Multiple Myeloma in Eastern NC, especially with LCM. The environmental and genetic factors responsible for this need to be studied further. Many patients have a high tumor burden at diagnosis. Improvement in access to care, enhancement of provider education, collaboration with regional oncologists and study of novel drug combinations to achieve deeper and more durable responses may help improve outcomes for this treatable malignancy. "These data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives (https://research.themmrf.org and www.themmrf.org)”.
Pharmacological and therapeutic relevance of BRCA1 and BRCA2 variants in solid tumors.
Authors: Istvan Petak, Julia Deri, Eszter Kanta, Agnes Maczak-Gyongy, Csilla Hegedus, Edit Varkondi, Dora Mathiasz, Richard Schwab, Istvan T. Valyi-Nagy
Journal: Journal of Clinical Oncology (2018)

e24300 Background: Relevance of hereditary BRCA mutations is well-known in breast and ovarian cancer and is also emerging in other solid tumors. Most databases provide BRCA classification on a genetic basis considering clinical relevance of germline mutations. Somatic/germline BRCA mutations might predict sensitivity to PARP inhibitors. However, BRCA classification criteria might differ according to genetic and pharmacological aspects, challenging molecular and clinical interpretation of BRCA variants. We present an algorithm for variant interpretation that aggregates and ranks all relevant evidence and incorporates clinical experience. Methods: In 2015-17, we sequenced BRCA1/2 using tumor tissue samples of ~400 patients. Variants were uploaded in the Precision Medicine Calculator, our in-house developed decision support software. Evidence linking tumors-drivers-targets-compounds were uploaded. Variants were classified with our proprietary algorithm using aggregated evidence levels calculated from tumor, molecular profile and evidence input. Therapeutic strategies were designed by the joint opinion of our Molecular Tumor Board and local medical teams. Results: We classified many of the detected pathogenic variants as drivers, and many of the polymorphisms as non-drivers. However, we found non-pathogenic mutations where the decision support system predicted response based on pharmacogenetic properties, and we also identified pathogenic variants which we predicted to be negatively associated with Olaparib. BRCA2-I2627F (unknown clinical significance) was detected in a patient with cervix neuroendocrine carcinoma. Based on preclinical data this variant is deleterious. The patient responded to Olaparib in a clinical trial. In an ovarian cancer patient, BRCA1-C61G, a founder mutation was detected. It is a hypomorphic variant causing partial loss of function. Mice harboring BRCA1-C61G showed poor response to Olaparib. The patient was not recommended to receive PARP inhibitor and is currently on chemotherapy. Conclusions: Our standardized algorithm that aggregates and ranks all relevant evidence was highly useful for defining the potential therapeutic relevance of BRCA variants.