tbuckley/cabot-search huggingface dataset:
Adverse effects of topical photodynamic therapy: a consensus review and approach to management
Authors: S.H. Ibbotson, T.H. Wong, C.A. Morton, N.J. Collier, A. Haylett, K.E. McKenna, R. Mallipeddi, H. Moseley, L.E. Rhodes, D.C. Seukeran, K.A. Ward, M.F. Mohd Mustapa, L.S. Exton
Journal: British Journal of Dermatology (2018)

Topical photodynamic therapy (PDT) is widely used to treat superficial nonmelanoma skin cancer and dysplasia, and is generally well tolerated. However, as with all treatments, adverse effects may occur and awareness may facilitate approaches to prevention and management. To review the available evidence relating to the adverse effects of topical PDT, to help inform recommendations in updated clinical guidelines produced by the British Association of Dermatologists and British Photodermatology Group, and the efficacy of preventative and therapeutic approaches. This review summarizes the published evidence related to the adverse effects of topical PDT and attempts to interpret this evidence in the context of patient risk and management. Pain and discomfort during PDT are acute adverse effects, which can be minimized through the use of modified and low‐irradiance PDT regimens and do not therefore usually limit successful treatment delivery. Other adverse effects include the risk of contact allergy to photosensitizer prodrugs, although this is rare but should be kept in mind, particularly for patients who have received multiple PDT treatments to larger areas. There are no other significant documented longer‐term risks and, to date, no evidence of cumulative toxicity or photocarcinogenic risk. Topical PDT is usually well tolerated, reinforcing the utility of this important therapeutic option in dermatology practice. The main acute adverse effect of pain can typically be minimized through preventative approaches of modified PDT regimens. Other adverse effects are uncommon and generally do not limit treatment delivery.
Veliparib in combination with nivolumab and platinum doublet chemotherapy (CT) in metastatic/advanced NSCLC.
Authors: Jeffrey Melson Clarke, Jyoti D. Patel, Francisco Robert, Ebenezer A. Kio, Eddie Thara, Brage Garofalo, Marcia Barnes, Tian Tian, Qin Q. Qin, Martin Dunbar, Silpa Nuthalapati, Giovanni Selvaggi, Mark D. McKee, Minh Dinh, D. Ross Camidge
Journal: Journal of Clinical Oncology (2018)

3061 Background: Veliparib (V), a PARP inhibitor, combined with platinum (Pt) doublet CT has shown promise in a Phase 2 study of NSCLC. Nivolumab (N), a PD-1 inhibitor, has demonstrated single-agent activity in relapsed NSCLC. This is the first study evaluating dose and safety of V combined with N + Pt-doublet CT. Methods: This Phase 1, dose-escalation study (NCT 02944396) enrolled adult patients (pts) with metastatic or advanced NSCLC, ECOG 0-1, and no prior cytotoxic CT, anti-PD-1 or PARPi. Primary objective was to establish the recommended Phase 2 dose (RP2D) of oral V BID combined with N (360 mg) and carboplatin (C, AUC 6)/paclitaxel (Pac, 200 mg/m2) or C (AUC 6)/pemetrexed (Pem, 500 mg/m2). Combined with N, dose cohorts were 120 mg V + C/Pac or 80-200 mg V + C/Pem for 6 cycles (cycle = 21 d), or until unacceptable toxicity or disease progression, followed by N + Pem maintenance as indicated. DLTs incl. hematologic and non-hematologic AEs delaying treatment (tx), requiring dose modifications, and attributed to V. Safety, PK, and anti-tumor activity by RECIST 1.1 were assessed. Results: As of December 15, 2017, 17 pts (median age 61) with Stage IV NSCLC were enrolled (11 non-squamous for V + N + C/Pem; 1 non-squamous and 5 squamous for V + N + C/Pac). Median drug exposure was 105 d (range 3-284). Primary discontinuation of V occurred in 41% due to AE (2), PD (1), physician decision (1), pt withdrawal (1), death (1), or other (1). No DLTs were reported. Tx-emergent AEs incl. fatigue (47%), nausea (35%), anemia (35%), neutropenia (29%) and thrombocytopenia (29%). Grade 3/4 AEs additionally incl. febrile neutropenia, increased lipase, pneumonitis, and rash (6% each). SAEs additionally incl. sinus arrhythmia, acute kidney injury, pleural effusion, pulmonary embolism, and sudden death (6% each). ORR was 27% [95% CI 6, 61] for V + N + C/Pem and 17% [0, 64] for V + N + C/Pac. For V + N + C/Pem, best response was PR (50%) or SD (50%). For V + N + C/Pac, best response was PR (50%). PK data will be presented. Conclusions: RP2D is 120 mg for V + N + C/Pac, and has not been determined for V + N + C/Pem (to date, highest tolerated dose is 200 mg). V combined with N + Pt-doublet CT showed anticipated safety signals, with no additional toxicity of V when added to these regimens. Clinical trial information: NCT 02944396.
Abstract 19517: Left Atrial Strain - A Novel Index of Diastolic Dysfunction
Authors: Swethika Sundaravel, Robert Chait, Elie Donath
Journal: Circulation (2017)

Introduction: Left atrial strain is an emerging concept to measure LA hemodynamics which also correlates indirectly with LVEDP. It has been well studied in atrial fibrillation and HFrEF. Its use in...
A phase 3, randomized, open-label study to compare the efficacy of tislelizumab (BGB-A317) versus chemotherapy as second-line therapy for advanced unresectable/metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Lin Shen, Jaffer A. Ajani, Sung-Bae Kim, Eric Van Cutsem, Baohong Guo, James Song, Virginia Paton, Ken Kato
Journal: Journal of Clinical Oncology (2018)

TPS3111 Background: Approximately 40% of patients (pts) with esophageal cancer are diagnosed with advanced unresectable or metastatic disease; the 5-year survival rate for advanced disease is < 5%. Inhibition of programmed cell death protein-1 (PD-1) has demonstrated promising antitumor activity and manageable safety in pts with advanced unresectable or metastatic ESCC. Tislelizumab (also known as BGB-A317), a humanized IgG4 monoclonal antibody, has high affinity and specificity for PD-1. Tislelizumab was specifically engineered to minimize FcgR binding on macrophages, thus abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance. A first-in-human study (NCT02407990) demonstrated that single-agent tislelizumab was generally well tolerated and had preliminary antitumor effects in pts with solid tumors, including ESCC. A recommended phase 2 dose of 200 mg administered IV every 3 weeks (Q3W) has been established for tislelizumab. Methods: This phase 3, randomized study (NCT03430843) was designed to evaluate the efficacy, safety, and tolerability of tislelizumab compared with chemotherapy for second-line treatment of advanced unresectable/metastatic ESCC. Adult pts, aged ≥18 years, with histologically or cytologically confirmed ESCC that has progressed with first-line therapy, have ≥1 measurable/evaluable lesion, and have an Eastern Cooperative Oncology score ≤1 will be enrolled. Approximately 450 pts will be randomized (1:1) to receive either tislelizumab 200 mg IV Q3W or investigator-chosen chemotherapy (paclitaxel 135–175 mg/m2 IV Q3W or 100 mg/m2 IV weekly for 6 weeks with 1 week of rest [Japan only], docetaxel 75 mg/m2 or 70 mg/m2 IV Q3W, or irinotecan 125 mg/m2 IV Q3W). Overall survival is the primary endpoint; secondary endpoints include objective response rate, progression free survival, duration of response, and health-related quality-of-life outcomes. Safety/tolerability will be assessed by monitoring adverse events (AEs), including immune-related AEs, as well as physical examinations, vital signs, and electrocardiograms. Clinical trial information: NCT03430843.
Post-cross-over activity of regorafenib (RE) in soft tissue sarcoma: Analysis from the REGOSARC trial.
Authors: Nuria Kotecki, Thomas Brodowicz, Axel Le Cesne, Marie-Cecile Le Deley, Jennifer Wallet, Antoine Italiano, Jean-Yves Blay, Francois Bertucci, Christine Chevreau, Sophie Piperno-Neumann, Emmanuelle Bompas, S Bastien Salas, Christophe Perrin, Corinne Delcambre, Bernadette Lieg-Atzwanger, Maud Toulmonde, Isabelle Laure Ray-Coquard, Julien Thery, Olivier Mir, Nicolas Penel
Journal: Journal of Clinical Oncology (2017)

11052 Background: Based on the placebo (PBO) controlled phase 2 trial (Mir, Lancet Oncol 2016), RE has shown to be an active drug in patients (pts) with leiomyosarcoma (LMS), synovial sarcoma (SS) and other non-adipocytic sarcoma (OTH), but not in liposarcoma. Pts initially allocated to PBO were allowed to cross-over to RE after progression. We here report the activity of RE after cross-over. Methods: From July 2013 to Dec 2014, 138 pts were enrolled in the non-adipocytic sarcoma cohorts (LMS, SS &amp; OTH). After update in Dec 2016, median follow-up was 32 mo (vs 17 mo in the initial publication). Benefit of RE vs PBO in terms of progression-free survival (PFS) and overall survival (OS) from randomization was estimated by hazard ratio (HR) in Cox models. In the PBO arm, intra-patient benefit of RE after cross-over was evaluated by the growth modulation index (GMI), where PFS1=PFS with PBO before cross-over, and PFS2=PFS with RE after cross-over. The impact of timing of RE allocation (delayed after cross-over, vs early at study entry) was evaluated by comparing PFS after cross-over in PBO arm to PFS after randomization in RE arm. Results: As detailed in the table, major PFS benefit of RE vs PBO allocated by randomization was confirmed with long follow-up (HR=0.50 [95%CI 0.35-0.71] p&lt;.0001). However, this translates into a smaller and non-significant OS benefit (HR=0.78 [0.54-1.12] p=.18). This finding may partially be explained by the fact that 55 of the 68 pts who progressed in the PBO arm (81%) could receive RE after progression and benefit from RE: 56% of them had a GMI greater than 1.3. Delayed start of RE was associated with a non-significantly shorter PFS compared to earlier treatment (HR=1.21, [0.84-1.73] p=.30). Conclusions: Efficacy of RE vs PBO is confirmed with longer follow-up in non-adipocytic sarcoma. PFS of pts receiving RE after cross-over is not significantly shorter than that of pts initially randomized to receive RE. Clinical trial information: NCT01900743. [Table: see text]
Association between cocaine use and hematological malignancies.
Authors: Amandeep Singh Aujla, Sung Ho Lee
Journal: Journal of Clinical Oncology (2016)

e19072 Background: Cocaine is the fifth most-commonly abused drug in United States. Studies have shown some co-relation of cocaine abuse with Non-Hodgkin lymphoma (NHL). Further literature review reveals genomic toxicity and mutagenic potential of cocaine as well as potential to phosphorylate ‘bcl-2’ gene leading to deregulation of cellular apoptosis pathway. It is also shown to enhance transcription of human immunodeficiency virus-1 (HIV-1) in infected human embryonic kidney cells. Hence we have designed a study to evaluate the association between cocaine use and hematologic malignancies, stratified between HIV positive and HIV negative population. Methods: It is a retrospective cohort study including all patients (N = 136) with documented diagnosis of NHL, Hodgkin’s Lymphoma (HL) and leukemia at the infusion center in our institution. Data was extracted from electronic medical records (EMR) search. Those with incomplete medical records (N = 24) were excluded. Cocaine use was determined by positive urine toxicology or documentation in EMR as reported by patient. Patients were divided into four cohort groups – cohort A (cocaine positive and HIV positive); cohort B (cocaine positive and HIV negative); cohort C (cocaine negative and HIV positive); cohort D (cocaine negative and HIV negative). Statistical analysis was done by calculating odds ratio using Mantel-Haenszel method. Results: Cohorts population consisted mainly of Hispanic (55.4%) and African-American (26.8%) origin. 55.4% were males and 44.6% were females. Median age at diagnosis was 55 years. Pathologic diagnosis was NHL in 75.9% followed by HL in 18.7 % and Leukemia in 5.4%. Odds ratio for association among cocaine users in HIV negative population compared to HIV positive population was 0.09 (95% CI of 0.02 - 0.35; p < 0.0001). However, odds ratio for association among cocaine users in HIV positive population compared to non-users was 10.93 (95% CI of 3.27 - 36.53; p < 0.0001). Conclusions: This study suggests that cocaine use in association with HIV infection would significantly increase the likelihood of hematological malignancies. But, it was unable to show similar correlation in the absence of HIV infection. Further prospective study needs to be done to verify its cause effect.
OS3.5 Dynamic insights into the cellular heterogeneity of malignant gliomas
Authors: R Xie, T Kessler, J Grosch, L Huang, G Solecki, W Wick, F Winkler
Journal: Neuro-Oncology (2018)

gery in 18 cases (23.1%), radiotherapy in 10 cases (10.4%), and palliative care in 13 cases (16.7%) -we miss information about 4 patients.).Factors positively associated with PFS and OS in univariate analysis were younger age, absence of contrast enhancement, and gross total resection.Age and extent of surgery retained a statistically significant importance in multivariate analysis.CONCLUSION: WHO grade II IDH-wild type gliomas have a worse outcome as compared with IDH-mutant tumours.This is the first study that details clinical and radiological presentation of this rare subgroup of tumours and suggests that gross total resection is critical in improving survival.
Thymic carcinomas are all the same disease? A monocentric experience.
Authors: Giovannella Palmieri, Margaret Ottaviano, Mirella Marino, Alfredo Di Giovanni, Elide Matano, Vincenzo Damiano
Journal: Journal of Clinical Oncology (2016)

e20111 Background: Thymic carcinoma (TC), as largely known, has more aggressive behaviour than thymoma. Usually, patients affected by TC received at the beginning, a diagnosis of advanced disease, which is inoperable in around half of the cases. Among those who underwent a total resection, more than half presented a recurrence. Furthermore, the 5-year survival rate is significantly different between TC (50.5%) and thymoma patients (94.4%). Methods: In this retrospective monocentric study, we presented the clinical-pathological features of 20 consecutive patients referred to our centre of Rare tumors from January 2008 to December 2014. All of them, with a median age of 55 years (33-78) and a female/male ratio of 0.53 (7 F and 13 M), received an histological diagnosis of TC revised by central review. A radical surgery was performed only in 5 cases, all the pts had an advanced disease at diagnosis, IVB stage disease according to Masaoka-Koga stage system was detected in 14 pts, IVA and III in 4 and 2 pts, respectively. They all underwent first line platinum based chemotherapy, most of them progressed very soon and several biological agents were administrated for control disease. We evaluated time to progression (TTP) of six pts who subsequently were treated with platinum chemotherapy; long acting somatostatin analogues (LAR octreotide 30 mg/4 weeks) plus prednisone (0.2mg/Kg); everolimus (10 mg/daily). Also Median overall survival of this series was calculated. Results: Six patients treated in a multimodality way, had a IVB stage disease. Considering the sequence of chemotherapy, somatostatin analogues plus prednisone and everolimus, they reached a TTP of 4, 13 and 5.5 months, respectively. Median Overall survival of all 20 pts was 28 months (5-180). Conclusions: Advanced Thymic carcinoma should be managed in a multimodality setting with individualized treatment, according to improved biological and histological informations/new biomarkers that are still missing. Functional imaging like OctreoScan and 18FDG/PET should help clinicians for the best choice also in thymic carcinoma treatment.
FDA acceptance of surrogate endpoints in later lines of therapy.
Authors: Emerson Yu-sheng Chen, Sunil K. Joshi, Vinay Prasad
Journal: Journal of Clinical Oncology (2018)

6517 Background: U.S. Food and Drug Administration (FDA) utilizes surrogate endpoints in order to speed drugs to market. Surrogates reduce development time, though they do so to a larger extent in the front line rather than in later line settings. Methods: We examined all adult cancer drugs approved by the FDA from 01/2006 to 12/2017. Data regarding the approval type (regular or accelerated), cancer type, treatment indication, and basis for approval were extracted from the FDA website and any relevant publications. Basis for approval was categorized into response rate (RR), progression-free or relapse-free survival (PFS/RFS), and overall survival or quality-of-life (OS/QoF) endpoints. Drugs for mainly pediatric cancers and cancers limited to genetic syndromes were not included in this study. Statistical analysis was performed using SAS 9.4 version. Results: 182 drug indications among 108 cancer drugs were identified. 67 (36.8%) drug indications were approved for first-line setting, 75 (41.2%) for second-line setting, 24 (13.2%) for third-or-later-line setting, and 16 (8.8%) for adjuvant or maintenance settings. 49 (26.9%) were approved based on OS/QoF endpoints. 133 (73.1%) were approved based on surrogate endpoints: 69 (37.9%) being RR and 64 (35.2%) being PFS/RFS. Accelerated instead of regular approval was more likely to be sought in subsequent lines of therapy (19.4% in first-line, 30.7% in second-line, 62.5% in third line, p < 0.01). Surrogate endpoints had a trend toward being used in subsequent lines of therapy (68.7% in first-line, 70.7% in second-line, and 87.5% in third-line approvals, p = 0.18). However, RR specifically was used more frequently in subsequent lines of therapy compared to PFS/RFS or OS/QoF (22.4% in first-line, 45.3% in second-line, and 79.2% in third-line approvals, p < 0.01). Conclusions: Surrogate endpoints are increasingly used in oncology trials with the intention of speeding drugs to market. They are used most often in later lines of therapy, when definite endpoints like OS or QoF can be expeditiously evaluated, and the ‘acceleration’ of approval is actually limited. Accelerated approval based on surrogate endpoints is thus granted preferentially in later lines of therapy, when the impact is likely modest.
International retrospective cohort study of conversion therapy for stage IV gastric cancer 1 (CONVO-GC-1).
Authors: Masanori Terashima, Kazuhiro Yoshida, Sun Young Rha, Jae Moon Bae, Guoxin Li, Hitoshi Katai, Masahiko Watanabe, Yasuyuki Seto, Han-Kwang Yang, Jiafu Ji, Hideo Baba, Yuko Kitagawa, Satoshi Morita, Masahiko Nishiyama
Journal: Journal of Clinical Oncology (2018)

4042 Background: In spite of the recent advancement of palliative chemotherapy for stage IV gastric cancer (GC), its median survival time (MST) still remains around 13 to 16 months. Much attention has been paid to conversion therapy, however, its definition, operative indication nor survival benefit has not been demonstrated so far. CONVO-GC-1, a retrospective international cohort study, was designed to investigate the role of conversion surgery in Japan, Korea and China. Methods: Conversion therapy of GC was defined as a surgical treatment aiming at an R0 resection after chemotherapy, for tumors that were originally technically and/or oncologically unresectable or marginally resectable. Primary endpoint was the rate of operative complications (Clavien Dindo Grading) and the secondary endpoint was overall survival (OS) according to the 4 category criteria which we have previously published (Gastric Cancer:19; 2016.) (Category 1: resectable metastasis. Category 2: marginally resectable metastasis. Category 3: Macroscopically peritoneal dissemination. Category 4: non-curable metastasis with peritoneal and other organ metastasis.) Results: 1902 patients from 55 institutions were enrolled and 1206 patients (category 1: 206, category 2:583, category 3:300, category 4: 117) were performed surgery after chemotherapy with curative intent. Operative complications were observed in 290 (24.0%) in all grade including pancreatic fistula and SSI etc, which were consistent with other studies (category 1: 19.9%, category 2:29.0%, category 3:18.3%, category 4: 21.4%). The MST of all resected patients were 36.7M (category 1: 42.4 M, category 2: 38.7 M, category 3: 33.4 M, category 4: 34.1 M). The MST of R0 resected patients was 56.6 M (category 1: 49.1 M, category 2: 82.2 M, category 3: 44.9 M, category 4: not reached) and R1 was 25.8 M (category 1: 26.8 M, category 2: 20.3 M, category 3: 30.4 M, category 4: 23.4 M) and R2 was 21.7 M (category 1: 25.0 M, category 2: 22.1 M, category 3: 18.5 M, category 4: 23.5 M), respectively. Conclusions: Conversion therapy for stage IV GC is a safe and might be a new therapeutic strategy to improve the survival of the patients, especially with R0 resection. Clinical trial information: UMIN000022321.
Oncological outcomes of intravesical gemcitabine and docetaxel for select patients with high grade recurrent NMIBC.
Authors: Niv Milbar, Max Kates, Meera R. Chappidi, Mark P. Schoenberg, Trinity Bivalacqua
Journal: Journal of Clinical Oncology (2017)

4546 Background: Bacillus Calmette-Guerin (BCG) unresponsive patients with Non-Muscle Invasive Bladder Cancer (NMIBC) who prefer bladder preservation over Radical Cystectomy (RC) or are poor surgical candidates may be offered intravesical therapies. 2nd line intravesical Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). Our objective was to evaluate JHH experience with GEM/DOCE, and specifically to address appropriate endpoints for 2 nd -line therapies in NMIBC. Methods: 33 patients who received full induction courses of GEM/DOCE since 2011, per the protocol adapted from Michael O’Donnell at U. Iowa, were identified in the IRB-approved JHH NMIBC database. Multivariable logistic regression determined factors associated with LG and HG recurrence. Cox proportional hazard models evaluated risk factors for disease free survival (DFS) and HG recurrence-free survival (HG-RFS). Results: Median DFS was 6.5 months with 42% 1-year and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2- year HG-RFS. Median HG-RFS among patients who initiated GEM/DOCE with HG pathology was 15.7 months, with 51% 1-year HG-RFS and 34% 2-year HG-RFS. Within initial HG-NMIBC presentation, 46% (13/28) had HG recurrence. 80% (4/5) of patients with initial LgTa had LG recurrence and 20% (1/5) had HG recurrence. There were no significant predictors for HG-RFS or DFS. There were 5 LG recurrences, and 16 HG recurrences, with 6 progressions among these. 7 patients underwent RC at a median of 14.9 months. Conclusions: GEM/DOCE is a well-tolerated alternative to immediate RC for highly selected patients with HG-NMIBC. As anticipated, including LG recurrence as an endpoint made GEM/DOCE appear less efficacious. However, since standard of care for LG recurrence is further intravesical therapy and recurrence does not result in worse cancer outcomes, it may not be an appropriate endpoint. Future studies of 2nd line therapies for NMIBC should identify endpoints based on clinically meaningful outcomes of interest.