tbuckley/cabot-search huggingface dataset:
PD-1 inhibition in cutaneous squamous cell carcinoma (cSCC).
Authors: David Jacob Hermel, Omar Medhat Ragab, Shauna Higgins, Ashley Wysong, Gino Kim In
Journal: Journal of Clinical Oncology (2018)

e15100 Background: There is no established treatment for patients with locally advanced or metastatic cSCC. However, emerging case series and preliminary data from the phase II EMPOWER-CSCC 1 study suggest clinical efficacy of PD-1 inhibitors in this aggressive and frequently hypermutated tumor type. We report our institutional experience treating patients with cSCC using pembrolizumab via the Merck Access Program. Methods: We retrospectively reviewed all patients with advanced cSCC who were treated with a minimum of 1 cycle of pembrolizumab. Tumor responses were evaluated by RECIST 1.1, and adverse events by CTCAE v4.0. Demographic and clinical variables as well as tumor genomic data were obtained from available medical records and investigated in relationship with clinical outcomes and adverse events. Results: A total of 8 patients met inclusion criteria. The median age of patients was 56 (range 22-85). A median of 6.5 cycles of PD-1 blockade were administered. Four of eight patients (ORR 50%) achieved a partial response, and two (25%) had stable disease, for a disease control rate of 75%. The median time to response was 4.3 months. Among the four partial responders, all had ongoing durable responses, and one of the two (50%) patients with stable disease had continued disease control. No grade 3 or 4 toxicity was observed. Correlative PD-L1 status and next generation sequencing was obtained, with three of four (75%) responders (vs 0% of non-responders) having either positive PD-L1 tumor expression, high tumor mutational burden or an MLH1 mutation. Conclusions: In our limited cohort, PD-1 inhibitors appear to produce durable anti-tumor activity with minimal toxicity and an ORR consistent with those reported in trials of PD-1 inhibition for cSCC. Further investigation is needed to identify biomarkers for PD-1 blockade and potential additional targets in advanced cSCC.
Vorolanib (CM082) in Chinese patients with advanced solid tumor: A phase 1, open-label, dose escalation study.
Authors: Yan Song, Jinwan Wang, Ai-Ping Zhou, Wen Zhang, Chris Liang, Lin Yang
Journal: Journal of Clinical Oncology (2018)

2580 Background: Vorolanib (CM082) is a potent and selective inhibitor of VEGFR and PDGFR, which is well tolerated from 20 to 400 mg without G3/4 treatment-related AEs (TRAEs) in patients in US. Here we present a phase I dose escalation study that assessed vorolanib in Chinese patients with advanced solid tumor. Methods: Patients with advanced solid tumors were enrolled to receive escalating dose of vorolanib once daily from 50 mg to 300 mg following the 3+3 design. Primary endpoints included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Results: 19 patients were enrolled and treated, including 12 RCC. Most patients (n = 18) have received at least one prior systemic treatments, in which 10 have been treated with VEGFR TKIs. No DLT was seen, the MTD was not achieved. The most common TRAEs were leukopenia (9/19), fatigue (9/19), diarrhea (8/19), neutropenia (8/19), and hypertension (8/19). G3 or higher events were seen in 7 patients across 100 to 250 mg dose cohort. PK analysis was shown in table 1. Partial response was seen in 1 RCC patients in the 200 mg cohort, and 11 stable disease were seen in all dose cohorts. Conclusions: Vorolanib has an acceptable safety profile and showed preliminary activities in RCC. An expansion of RCC-enriched cohort is ongoing. Clinical trial information: NCT01863485.PK parameters. 50 mg (n = 4) 100 mg (n = 3) 150 mg (n = 3) 200 mg (n = 3) 250 mg (n = 4) Single dose t1/2 hr 3.95 ± 0.56 8.01 ± 1.67 5.78 ± 0.53 5.25 ± 0.40 6.20 ± 1.82 Tmax hr 4.00 2.33 ± 0.58 2.67 ± 0.58 3.67 ± 0.58 2.75 ± 0.96 Cmax ng/mL 239.82 ± 39.24 566.86 ± 253.54 727.75 ± 133.36 857.22 ± 94.49 1003.79 ± 92.73 AUC(0-48 h) hr*ng/mL 1973.24 ± 435.85 5501.26 ± 2972.74 6327.04 ± 654.03 7689.95 ± 1684.58 8435.56 ± 1515.97 AUC (0-inf) hr*ng/mL 1981.85 ± 437.81 5586.84 ± 3011.58 6352.55 ± 669.81 7706.55 ± 1688.32 8481.12 ± 1539.81 Multiple doses t1/2 hr 4.28 ± 0.75 5.03 ± 1.69 6.25 ± 0.81 4.83 ± 0.14 4.46 ± 0.78 Tmax hr 4.00 ± 1.63 2.33 ± 0.58 3.00 ± 1.00 3.00 ± 1.00 2.75 ± 0.05 Cmax ng/mL 254.19 ± 94.23 649.98 ± 147.51 923.83 ± 208.44 811.55 ± 266.45 959.62 ± 431.12 AUC (0-24 h) hr*ng/mL 2168.81 ± 874.37 5910.91 ± 1909.47 9224.53 ± 3153.11 6579.73 ± 2264.7 6968.75 ± 3265.82 AUC (0-inf) hr*ng/mL 2235.38 ± 883.95 6283.97 ± 2337.41 10068.74 ± 3487.21 6823.74 ± 2345.54 7221.1 ± 3439.7
Use of supportive care and risk of febrile neutropenia (FN) among patients receiving myelosuppressive chemotherapy for solid tumors or non-Hodgkin's lymphoma (NHL) at four US health systems.
Authors: Derek Weycker, Amanda Silvia, Erinda Shyta, Kathryn E. Richert-Boe, Mark Bensink, Lois E. Lamerato, Manpreet Kaur, James J. Rooney, David Chandler
Journal: Journal of Clinical Oncology (2018)

e18756 Background: Although clinical practice guidelines recommend use of colony-stimulating factors (CSFs) for prevention of FN among many patients receiving myelosuppressive chemotherapy, detailed real-world evidence on practice patterns and outcomes is limited. Methods: This retrospective study was conducted at four US health systemsGeisinger Health System (PA), Henry Ford Health System (MI), Kaiser Permanente Northwest (OR, WA), and Reliant Medical Group (MA). For patients who received myelosuppressive chemotherapy for selected cancers (breast, colon/rectum, lung, NHL), data on demographics, clinical profile, cancer, treatment, supportive care, and outcomes (2009-2013) were collected via a standardized case report form using electronic data warehouses, medical charts, and cancer registries. Results: Overall, 32% of patients received CSF prophylaxis in cycle 1 (filgrastim, 53%; pegfilgrastim, 47%) and 44% at any time during their course (mean no. cycles, 7.4). Use of AMB prophylaxis was 4% in cycle 1 and 12% during course. FN incidence was 4% in cycle 1, 9% during course, and lower with CSF prophylaxis (e.g., by 40% [p = 0.018] in cycle 1, in adjusted analyses). Most FN episodes (76%) required hospitalization. Conclusions: In this real-world evaluation, 2/3 of patients did not receive CSF prophylaxis beginning in cycle 1 with few additional patients receiving prophylaxis in subsequent cycles. FN was common, typically required inpatient care, and was less frequent with CSF prophylaxis. Careful consideration should be given to identifying patients at elevated FN risk to ensure appropriate use of supportive care. Table. Use of supportive care and risk of FN Breast Cancer Colorectal Cancer Lung Cancer NHL All (N = 1,106) (N = 438) (N = 499) (N = 251) (N = 2,294) Supportive Care, % CSF Prophylaxis Cycle 1 53.3 2.7 11.6 31.9 32.3 Course 65.9 13.0 17.2 50.6 43.5 AMB Prophylaxis Cycle 1 3.9 3.7 3.4 5.2 3.9 Course 14.6 11.4 8.2 12.4 12.3 FN, % Cycle 1 5.3 1.8 3.0 6.4 4.3 Inpatient* 72.9 50.0 100 100 79.6 Mortality* 2.3 -- 6.7 6.3 3.8 Course 10.9 6.4 6.8 13.1 9.4 Inpatient* 68.3 75.0 88.2 93.9 76.3 Mortality* 1.2 4.8 3.3 3.2 2.4 *% of FN episodes
Cost of neutropenia hospitalizations among cancer patients in the United States.
Authors: Eric Tai, Gery P Guy, Lisa Carolyn Richardson
Journal: Journal of Clinical Oncology (2016)

6614 Background: Neutropenia and subsequent infections are life-threatening treatment-related toxicities of chemotherapy. Among cancer patients, hospitalizations related to neutropenic complications result in significant morbidity, mortality, and medical costs. Previous estimates for the cost of cancer-related neutropenia are based on older and limited data. This study aims to provide nationally representative estimates of the cost of cancer-related neutropenia hospitalizations. Methods: We examined data from the Healthcare Cost and Utilization Project National Inpatient Sample on hospital stays in 2012. Hospitalizations for cancer-related neutropenia were defined as those with a principal or secondary diagnosis of cancer (CCS 11-43) and a diagnosis of neutropenia or a fever of unknown origin during the hospital stay. We examined the characteristics of cancer-related neutropenia hospitalizations among both children and adults. Adjusted predicted margins were used to calculate length of stay, and cost per stay adjusting for age, the presence of other chronic conditions, type of cancer, and admission through the emergency department. Results: In 2012, there were 91,565 cancer-related neutropenia hospitalizations among adults and 16,070 cancer-related neutropenia hospitalizations among children. Cancer-related neutropenia hospitalizations accounted for 5% of all cancer-related hospitalizations among adults and 3% among children. The total cost of cancer-related neutropenia hospitalizations was $2.3 billion for adults and $391 million for children. For adults, the mean length of stay for cancer-related neutropenia hospitalizations was 9.6 days with a mean hospital cost of $24,780 per stay. For children, the mean length of stay for cancer-related neutropenia hospitalizations was 8.2 days with a mean hospital cost of $24,363 per stay. Conclusions: We found the costs of cancer-related neutropenia hospitalizations to be significantly high. Expenditures related to cancer-related neutropenia hospitalizations are significant and increasing in the United States. Efforts to prevent and minimize neutropenia-related complications among cancer patients may decrease hospitalizations and associated costs.
TCT-718 A Meta-Analysis of Long-term Clinical Outcomes following Successful Percutaneous Coronary Intervention with Drug-Eluting Stents for Chronic Total Occlusions
Authors: Aravdeep Jhand, Abhishek Thandra, Toufik Mahfood Haddad, Abdul Saadi, Venkata M. Alla, Michael White
Journal: Journal of the American College of Cardiology (2018)
Overall survival (OS) analysis from an expanded access program (EAP) of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (MEL).
Authors: David Hogg, Paul B. Chapman, Mario Sznol, Christopher D. Lao, Rene Gonzalez, Gregory A. Daniels, Michael Smylie, Ragini Reiney Kudchadkar, John A. Thompson, William Howard Sharfman, Michael B. Atkins, Anna C. Pavlick, Joel Jiang, Alexandre Avila, Sheena Demelo, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2017)

9522 Background: NIVO (anti-PD-1) and IPI (anti-CTLA-4), alone and in combination, are approved for the treatment of MEL. Phase II and III trials showed improved efficacy for NIVO+IPI versus IPI alone, but with a higher frequency of adverse events (AEs). In the phase II CheckMate 069 trial, the 2-year OS rate was 63.8% for all patients (pts) in the NIVO+IPI group. We report the first OS analysis, as well as updated safety data, from a North American EAP of NIVO+IPI in pts with MEL (CheckMate 218; NCT02186249). Methods: CheckMate 218 included pts with MEL who could have progressed on other therapies, but were anti-CTLA-4 and anti-PD-1 treatment-naive. Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until disease progression or a maximum of 48 weeks from the first monotherapy dose. We assessed OS in the US cohort (n = 580) and safety in all pts (n = 732). Pts were followed for a minimum of 1 year in the USA and 6 months in Canada. Results: Of 732 pts, 43% had a BRAFmutation, 84% stage IV MEL, 51% M1c disease, 31% LDH &gt; ULN (9% LDH &gt; 2x ULN), and 13% received ≥1 prior systemic therapy in the metastatic setting. All pts received a median of 3 doses each for NIVO (range: 1–4) and IPI (range: 0–4) in the induction phase; 34% of pts received at least 1 dose of NIVO maintenance. The 1- and 2-year OS rates were 78.6% (95% CI: 74.2–82.4) and 65.3% (95% CI: 56.1–73.0), respectively. AEs of any grade occurred in 717 pts (98%), with grade 3/4 AEs in 470 pts (64%). Immune-modulating medications were used to manage any grade AEs, including grade 1/2 skin and gastrointestinal AEs, in 538 of 717 pts (75%), and to manage grade 3/4 AEs in 279 of 470 pts (59%). The most common treatment-related AEs of any grade were diarrhea (39%), pruritus (26%), and an increase in aspartate aminotransferase level (23%). Treatment-related deaths in 2 pts were reported as drug-induced liver injury and myocardial infarction. Conclusions: In this EAP, which included pts who had received prior systemic therapies for MEL and pts with poor prognostic factors generally not included in clinical trials, NIVO+IPI treatment demonstrated survival outcomes and a safety profile consistent with clinical trial data. Clinical trial information: NCT02186249.
Study of toxicity of the conventional treatments in myeloproliferative neoplasms, based on the functional status of the RUNX1/CBF-BETA/P300/HIPK2 complex
Authors: C. Lozano Asencio, R. Cervera Vidal, J. Climent Bataller, J.C. Hernández Boluda
Journal: Annals of Oncology (2018)

Background: Myeloproliferative neoplasms (MPNs) are clonal hematological malignancies with an inherent tendency to progress to acute leukemia, after a variable period of time. Although the mechanisms involved in the disease transformation are still unclear, it´s known that transcription factor RUNX1 (AML1) is frequently deregulated in human leukemia, and recently, it has been described that the activity of RUNX1 together with CBF-β cofactor is regulated by the proteins p300 and HIPK2. In fact, HIPK2 phosphorylates both RUNX1 and p300, activating the whole transcriptional complex. Therefore, the study of the status of this complex seems to be interesting in order to understand the mechanisms involved in the leukemic transformation. Methods: Our aim is to study the effect of different typical drugs in several NMPs cell lines and patient samples with differential expression of these genes and compare it with a context where the complex is downregulated. For this purpose, we knocked down some genes of the studied complex before the treatment and then performed different viability, apoptosis and cell cycle assays, to elucidate if the status of these genes could play an important role in the response to the different biochemical drugs tested, showing a new approach to these diseases and giving us new strategies to study the molecular changes that occur during leukemic transformation. Results: Here we show that the state of the Runx1/CBF-BETA/P300/Hipk2 can play a critical role for the progression of the Chronic Myeloproliferative Neoplasms. Conclusions: The functional status of the components of the complex and its deregulation, could be playing an important role in the progression of leukemogenesis in the Chronic Myeloproliferative Neoplasms. Legal entity responsible for the study: Instituto de Salud Carlos III. Ministery of Sciences. Govern of Spain. Funding: Instituto de Salud Carlos III. Disclosure: All authors have declared no conflicts of interest.
Management of Flat Pigmented Spitz and Reed Nevi in Children
Authors: Aimilios Lallas, Zoe Apalla, Chryssoula Papageorgiou, George Evangelou, Dimitrios Ioannides, Giuseppe Argenziano
Journal: JAMA Dermatology (2018)

Management of Flat Pigmented Spitz and Reed Nevi in ChildrenAccording to recently introduced guidelines, the management of spitzoid-looking lesions should depend on the patient's age. 1 Specifically, any spitzoid-looking lesion after the age of 12 years and any asymmetric and nodular lesion at any age should be excised, whereas lesions with a typical starburst pattern before puberty should be monitored until stabilization. 1,2We aimed to evaluate the efficacy of monitoring flat symmetric pigmented spitzoid-looking lesions in prepubertal children.Methods | We retrospectively screened our databases for eligible cases from January 1, 2015, through December 31, 2017.Inclusion criteria were (1) clinical diagnosis of Spitz or Reed nevus; (2) no older than 12 years at the baseline visit;(3) monitoring as selected management; and (4) availability of follow-up data at least 2 years after baseline.The patients' age and sex and the location of the lesion were recorded.
Dihydropyrimidine dehydrogenase gene (<i>DPYD</i>) polymorphism among pts with 5-FU/capecitabine (CAP)-related adverse events (AEs): Experience of 2 decades.
Authors: Nauman S Siddiqui, Sneha Purvey, Ruchi Hamal, Lulu Zhang, Robert B. Diasio, Wasif M. Saif
Journal: Journal of Clinical Oncology (2018)

2576 Background: DPYD gene encodes DPD, the rate-limiting enzyme responsible for catabolism of 5-FU and is responsible for > 85% of 5-FU elimination. Deficiency of DPD due to DPYD polymorphism gives rise to severe 5-FU AEs from reduced catabolism. This pharmacogenetic ‘DPD syndrome’ manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rare toxicities, such as hepatitis, encephalopathy and acute cardiac ischemia following first or second dose of 5-FU. The most compelling reason to introduce routine DPD testing is to avoid severe AEs in pts who receive 5-FU/CAP. DPYD mutations are found in 50% of severe 5-FU toxicity cases. Methods: We analyzed all pts who were tested for DPD deficiency after excessive toxicities from 5-FU/CAP, treated for GI cancers. DPD activity was evaluated by PBMC radioassay, genotyping of DPYD, or 2-13C uracil breath test after an informed consent. Demographics of pts, grades of toxicity, chemotherapy (dose, route) and outcomes were analyzed. Results: A total of 52 pts with DPD deficiency were identified [age range: 35 - 79 yrs; M:F = 1.3:1; Ethnicities: Caucasian (≥ 60%), African-American, unknown, Asian]. Most commonly used regimens in decreasing order were infusion 5-FU, CAP and bolus. Excessive AEs included mucositis (70%), diarrhea (40%), cytopenias (40%), nausea/vomiting (30%), HFS or skin rashes (20%), neurotoxicity (12%) and cardiotoxicity (5%). 11/12 pts had low DPD activity (range:0.064 – 0.18nmol/min/mg). DPYD genotyping showed: IVS14 + 1 G > A (c.1905+1 G > A, rs3918290) 38%, D949V (c.2846A > T, rs67376798) 21%, C29R (rs1801265) 4%, and Y186C (rs115232898, c.557 A > G) 2%. UraBT confirmed DPD deficiency in 2 pts: DOB50 of 49.4% and 52.5%. Re-challenge with CAP in 5 pts resulted in atypical or similar AE. 6 pts received vistogard; 5 recovered. 3 pts died due to AEs. Conclusions: DPYD genotyping (+ TYMS) may identify ≥ 50% of pts, who are at greatest risk of AEs. At present, no formal recommendations regarding testing for DPYD exist except warning on FDA website and prescription inserts. Our data mandates the need for prospective studies to develop guidelines in pts receiving 5-FU/CAP.
Clinical outcome after multicenter, open-label phase II trial on post-surgery chemoradiation in combination with cetuximab in squamous cell carcinoma of the head and neck with high risk of locoregional recurrence.
Authors: Christiane Matuschek, Edwin Boelke, Claus Belka, Ute Ganswindt, Michael Henke, Petra Stegmaier, Michael Bamberg, Stephan Welz, Juergen Debus, Alexandros Gioules, Thomas G Wendt, Gerd Fabian Volk, Thomas Wiegel, Volker Budach, Martin Stuschke, Thomas Wiegel, Peter Arne Gerber, Joerg Schipper, Juergen Grebe, Wilfried Budach
Journal: Journal of Clinical Oncology (2016)

6028 Background: We performed an open label phase 2 trial and investigated the efficacy and toxicity of additional cetuximab during and after adjuvant radiochemotherapy (RCT) in head and neck cancer. Methods: 83 Patients with SCCHN were eligible for the study. 61.6 Gy (1.8/2.0/2.2Gy, d1-36) were administered using an integrated boost IMRT-technique. Cis-DDP (20 mg/m2, d1-5 and d29-33) and 5-FU (continuous infusion: 600 mg/m2, d1-d5 + d29-33) were given concurrently. Cetuximab started 7 days prior to RCT at 400 mg/m2 followed by weekly doses of 250 mg/m2. Maintenance cetuximab began after RCT at 500 mg/m² every 2 weeks for six months. The study was conducted at 10 investigational sites recruiting in Germany from May 2008- December 2010. Results: The number of patients enrolled was 83. Five patients did not meet inclusion criteria leaving 78 for analysis. Median follow up was 1.5 years. 18 patients had events (death or progression) of which 10 were locoregional relapses. 2 year overall survival, disease free survival, and locoregional tumor control were 86% (95%CL 79-95%), 77% (95% CL 66-86%), and 82% (95%CL 93-78%). A total number of 1542 AEs including 196 SAEs were documented. No formerly unknown toxicities were observed. One patient died during RCT. The death was considered to be treatment related, but not related to cetuximab. Acute grade 3+4 toxicities not taking into account skin toxicity outside the radiation portals were observed in 58% of patients, which was below the predefined rate of 67% that was considered as maximally tolerable in these patients. With the expected exception of skin toxicity outside the radiation portals, most grade 3+4 toxcities regress within 6 weeks after RCT. Grade 3+4 late toxicities ( > day 90) were observed in 34% of patients. 20% of patients refuse further treatment with cetuximab after completion of RCT. Conclusions: Adjuvant RCT with concomitant and maintenance cetuximab is feasible and results in a favorable clinical outcome in high risk SCCHNC. Clinical trial information: EudraCT No. 2007-002659-17.
Efficacy and safety of localized concurrent chemoradiation therapy and sorafenib sequential therapy in advanced hepatocellular carcinoma: A prospective phase II trial.
Authors: Beom Kyung Kim, Do Young Kim, Hye Jin Choi, Seung-Hoon Beom, Hye Won Lee, Seung Up Kim, Jun Yong Park, Sang Hoon Ahn, Jinsil Seong, Kwang-Hyub Han
Journal: Journal of Clinical Oncology (2017)

e15678 Background: Patients with advanced hepatocellular carcinoma (HCC) have a particularly poor prognosis of the median overall survival of less than 12 months. Even though sorafenib has been approved for treating advanced stage HCC, the unsatisfactory objective response rate still remain unresolved. In the current study, we aimed to evaluate the efficacy and safety of localized concurrent chemoradiotherapy (CCRT) followed by sequential sorafenib treatment for advanced hepatocellular carcinoma. Methods: This study is an ongoing, phase II trial. Patients with advanced HCC not amenable for curative treatments were eligible. In the course of radiotherapy for 5 weeks, hepatic arterial infusion of 5-fluorouracil (500mg/day) via implanted port was applied during the first 5 days and the last 5 days of radiotherapy. Four weeks after localized CCRT, sorafenib (400mg bid) was maintained. The primary endpoint was overall survival. Results: A total of 47 patients were enrolled. After the completion of localized CCRT, the objective response rate was 31.9%. During the overall treatment course, the objective response rate was 46.8% respectively. Overall, 7 patients (14.9%) underwent curative resection or transplantation after down-staging. The median overall survival was 18.4 months and the progression-free survival was 6.8 months. Adverse events were predictable and manageable with conservative care. Conclusions: Localized CCRT followed by sequential sorafenib treatment in patients with advanced HCC showed significant activity and good tolerability. Furthermore, such a treatment modality, when compared to the use of sorafenib alone, might provide the additional therapeutic benefit through initial tumor reduction, allowing curative treatment after down-staging in 14.9% of patients, Further randomized trial should be required to make the more robust evidence. Clinical trial information: NCT02425605.