tbuckley/cabot-search huggingface dataset:
A comparison of the burden of thyroid cancer amongst European Union 15+ countries, 1990-2017: Estimates from the Global Burden of Disease Study.
Authors: James Schuster-Bruce, Chinmay Jani, Richard Goodall, Dae Kim, William Hughes, Justin D Salciccioli, Dominic C Marshall, Joseph Shalhoub
Journal: Journal of Clinical Oncology (2021)

e18048 Background: The global incidence of thyroid cancer has been increasing rapidly and this has an attendant burden on health-systems. The Global Cancer Observatory reported an estimate of 567,233 new cases of thyroid cancer and 41,071 deaths in 2018. The objective of this study is to observe the trends in mortality, incidence and disability-adjusted life years (DALYs) from thyroid cancer between 1990-2017 in European Union (EU) 15+ nations. Methods: We extracted thyroid cancer mortality data from the Global Burden of Disease Study database based on the International Classification of Diseases versions 10 and 9. Age-standardised incidence rates (ASIR), age-standardised mortality rates (ASMR) and disability-adjusted life years (DALYs) were extracted for individual EU15+ countries per sex for each of the years 1990-2017, inclusive, and mortality-to-incidence indices (MII) were computed. Joinpoint regression analysis was used to describe trends. Results: Between 1990 and 2017, thyroid cancer ASIRs increased in all EU15+ countries for males, and in 15/19 countries for females. We identify ASIR to have plateaued in the majority of nations in the time period covered by the most recent trends. 16/19 countries observed decreasing ASMRs. Australia showed the highest increasing trends in both males (+19.2%) and females (+7.5%). The greatest decreases were seen in Belgium (-63.3%) for females and Austria for males (-34.9%). For both sexes, the MIIs decreased in all EU15+ countries. The smallest reductions were observed in the US (-22.4%) and Denmark (-22.4%) for males, and the US (-30.6%) for females. Variable directions of trends in DALYs were observed. Increasing DALYs for both genders were observed in the US and Australia. In 2017, highest ASIR was seen in Luxembourg for males (5.89/100,000) and Italy for females (8.81/100,000), highest ASMR was seen in Luxembourg for males (0.69/100,000) and females (0.53/100,000), highest MII was observed in Portugal for males (2.60/100,000) and in Finland for females (0.10/100,000) and, highest DALY was observed in Luxembourg for males (17.77/100,000) and Greece for females (16.69/100,000). Conclusions: Overall, we report EU15+ countries to be managing the burden of thyroid cancer, as evidenced by plateauing incidence rates and reductions in mortality and DALYs over the 28-year study period. However, some EU15+ countries, including the United States, demonstrate unfavorable ASMR and DALY trends. Ongoing vigilance is required to ensure changes in clinical practice and risk factor prevalence do not negatively impact on DALYs and mortality.
Patient-reported outcomes in clinical trials for multiple myeloma: Where we are.
Authors: Marike Andreas, Sam Salek, Nina Kreuzberger, Vanessa Piechotta, Esther Natalie Oliva, Tatyana Ionova, Ina Monsef, Nicole Skoetz, Edward Laane
Journal: Journal of Clinical Oncology (2021)

e18615 Background: It is recommended to include patient-reported outcomes (PROs) in cancer trials to ensure clinical benefit based on patients’ perceptions. For multiple myeloma patients, PRO measurement is essential to understand the impact of treatment on their physical and psychosocial functional behaviour. However, it is unclear which PRO instruments are utilized in multiple myeloma trials, how often they are used and whether results are consistently reported. The aim of this project was to explore the use and frequency of PRO instruments in randomized controlled trials for multiple myeloma and to assess the consistency of their reporting. Methods: Within the European Hematology Association (EHA) project to develop guidelines for the use of PROs in adult patients with hematological malignancies, MEDLINE and CENTRAL were systematically searched for randomized controlled trials investigating multiple myeloma between 2015 and 2020. Study design, disease and treatment characteristics, the primary outcome and used PRO instrument(s) were extracted using a pre-defined template. To assess the consistency of PRO reporting, study registries were compared with publications, study protocol and Health Technology Assessment (HTA) reports where available. Results: Overall, 10,707 records were found. Following screening for randomized-controlled trials, 283 ongoing, completed or published studies were included for review. 118 studies planned the use of PROs. The most frequently used PRO instrument (92 studies) was the EORTC QLQ-30, an instrument that measures health-related quality-of-life (HRQoL) in cancer patients. The disease-specific questionnaire EORTC-MY20 was also frequently used (50 studies). Likewise, the HRQoL instrument EQ-5D was used in 50 studies. Overall, 38 different PRO instruments were reported. In 39 studies for which a study protocol was found, only 19 reported PRO instruments consistently with the trial registry for the study. In addition, in 30 studies, for which a publication reported PRO results (58 overall), the information on PRO instruments differed between publication and the trial registry. For example, PRO instruments mentioned in the registry were omitted in the respective publications. Additionally, information on PRO in HTA reports was available for 26 studies, of which 18 reports were consistent with the trial registries. Conclusions: The results show that measurement of PROs still remain under-utilized in multiple myeloma research. While most PRO instruments identified in this review comply with the recommendations for incorporating PROs into clinical research in adult oncology, they are often inconsistently reported. Thus, reporting standards for the use of PROs are needed to ensure consistency in the use and reporting of PROs.
A multicenter phase II study of S-1 plus ramucirumab as first-line treatment in elderly patients with advanced/recurrent gastric cancer (KSCC1701).
Authors: Hiroo Katsuya, Koichi Suyama, Kazuma Kobayashi, Naoki Izawa, Yoshikazu Uenosono, Qingjiang Hu, Tetsuya Kusumoto, Hajime Otsu, Hiroyuki Orita, Hirofumi Kawanaka, Kazunori Shibao, Satoshi Koga, Mototsugu Shimokawa, Akitaka Makiyama, Hiroshi Saeki, Eiji Oki, Hideo Baba, Masaki Mori
Journal: Journal of Clinical Oncology (2021)

4043 Background: Elderly patients are often intolerable in the combination with cytotoxic agents. Therapy with S-1 alone is a key option for initial chemotherapy for Japanese elderly patients with unresectable gastric cancer in clinical practice. However, there are some cases in which the antitumor effects with S-1 alone are insufficient. We aimed to investigate the efficacy and safety of S-1 plus ramucirumab therapy to elderly patients with advanced/recurrent gastric cancer. Methods: Patients aged 70 years and older with previously untreated unresectable or recurrent gastric cancer patients were included in Japan. They received S-1 therapy (40-60 mg twice daily for 28 days, every 6 weeks) plus ramucirumab therapy (8 mg/kg, every 2 weeks) until disease progression. The primary endpoint was the one-year survival rate and null hypothesis of one-year survival was set as 40%, which is the lower bound of the 95% confidence interval in previously reported studies on S-1 therapy. The secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. Results: Between September 2017 and November 2019, 48 patients were enrolled in this study. The characteristics of patients were male/female: 34/14, median age: 77.5 years (range: 71-87), and PS (0/1): 20/28. The one-year survival rate was 65.2% (95% confidence interval 49.8-78.6%), which means this trial met the primary endpoint. The median OS and PFS were 16.4 months (95%CI:12.0–20.7) and 5.8 months (95%CI:4.0–7.2), respectively. The best RR (CR+PR) was 60.9%. The frequent grade 3 or grade 4 adverse events were neutropenia (27.7%), anorexia (23.4%), anemia (19.1%), hypertension (14.9%), leucopenia (12.8%) and hypoalbuminemia (12.8%). Conclusions: Based on the observed efficacy and safety, S-1 plus ramucirumab is an appropriate first-line treatment for elderly patients with advanced/recurrent gastric cancer. Clinical trial information: UMIN000028309.
A phase 1 dose-escalation study of intravenously (IV) administered TAK-676, a novel STING agonist, alone and in combination with pembrolizumab in patients (pts) with advanced or metastatic solid tumors.
Authors: Gerald Steven Falchook, Jason J. Luke, James F. Strauss, Xin Gao, Patricia LoRusso, PEI JYE VOON, Cong Li, Michael Shaw, Richard C. Gregory, Kristin Horn, John Gibbs, Neil Lineberry, Kate Stumpo, Karim Malek, Anthony J. Olszanski
Journal: Journal of Clinical Oncology (2021)

TPS2670 Background: Immuno-oncology therapies, including immune checkpoint inhibitors (CPIs), are revolutionizing cancer treatment. However, primary and secondary resistance to CPIs remains a significant challenge. CPI resistance has been associated with reduced interferon (IFN) signaling, altered antigen presentation, and an immunosuppressive tumor phenotype. Stimulating innate immune cells to develop a proinflammatory tumor environment that activates IFN signaling and downstream adaptive antitumor immune mechanisms is predicted to overcome such resistance. Stimulator of Interferon Genes (STING) is a key mediator of type 1 IFN-dependent innate immune modulation. Most STING agonists evaluated clinically have required intratumoral administration, which has significant logistical challenges and excludes many pts whose tumors are not accessible for injection. TAK-676 is a novel STING agonist under clinical investigation as an IV administered systemic therapy in pts with solid tumors. Methods: The primary objective of this study is to determine the safety and tolerability of TAK-676 alone and in combination with pembrolizumab. Secondary objectives are to: determine the pharmacologically active dose and recommended phase 2 dose; characterize TAK-676 pharmacokinetics; assess preliminary antitumor activity; and assess STING agonism gene signature induction. An exploratory objective is to assess immune cell activation and clinical response. The study comprises a single-pt safety lead-in with single-agent (SA) TAK-676 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation will start in the combination arm when ≥2 dose levels in the SA arm have been evaluated and considered safe. In both arms, pts will receive TAK-676 on days 1, 8, and 15 in 21-day cycles for up to 1 year. In the combination arm, pts will also receive pembrolizumab 200 mg IV on day 1 of each cycle. Adult pts with histologically confirmed advanced or metastatic solid tumors who have no standard therapeutic options or are intolerant to them, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and ≥1 Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1- evaluable lesion are eligible; pts with tumors that have relapsed, are refractory or naïve to anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy are eligible for the combination arm. Planned enrollment is ̃76 pts; recruitment is ongoing. Clinical trial information: NCT04420884.
Phase 1b/2 SEASTAR trial: Safety, pharmacokinetics, and preliminary efficacy of the poly(ADP)-ribose polymerase (PARP) inhibitor rucaparib and angiogenesis inhibitor lucitanib in patients with advanced solid tumors.
Authors: Ecaterina Elena Dumbrava, Geoffrey Shapiro, Johanna C. Bendell, Timothy A. Yap, Rinath Jeselsohn, Denise M. Lepley, Sabrina Hurley, Kevin K. Lin, Michelle Liao, Jenn Habeck, Aaron Enke, Erika P. Hamilton
Journal: Journal of Clinical Oncology (2021)

3102 Background: Lucitanib is an oral, potent tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, PDGFRα/β, and FGFR1–3. In preclinical studies, antitumor activity of rucaparib is enhanced by lucitanib through antiproliferative, antiangiogenic, and immunological mechanisms. We hypothesize that combining lucitanib and rucaparib is tolerable and can induce a higher hypoxic state and homologous recombination repair deficiency that may lead to greater sensitivity to PARP inhibition. Methods: Patients with advanced solid tumors who had ≥1 prior line of therapy were eligible. Patients with BRCA1/2-mutated ovarian cancer must have received prior PARP inhibitor. Rucaparib and lucitanib were escalated using a 3+3 phase 1b dose-escalation design from starting doses of 300 mg BID and 4 mg QD, respectively. Dose-limiting toxicities (DLTs) were assessed during the first 28 days of treatment. Plasma samples were collected for pharmacokinetic analyses. Genomic alterations were identified by local testing, or through central testing of plasma or tumor tissue. Results: As of February 1, 2021, 16 patients were treated with rucaparib + lucitanib and included in the analyses (Table). Patients had a median of 4 prior therapies; 1 patient had prior PARP inhibitor (olaparib) treatment. Median time on treatment was 58.5 days, with 2 patients ongoing as of the data cutoff date. A DLT of grade 3 proteinuria was seen in Cohort 1; no other DLTs have been reported. Across all cohorts, the most common any-grade treatment-emergent adverse events were nausea (n=9; grade ≥3, n=1), hypertension (n=8; grade ≥3, n=2) and ALT/AST increased (n=7; grade ≥3, n=3). Initial pharmacokinetic data indicated no drug interactions between the 2 agents. To date, 1 patient in Cohort 1 with PALB2-mutated advanced endometrial cancer had a confirmed partial response per RECIST v1.1, lasting 30 weeks; 6 patients had RECIST v1.1 stable disease (SD), including 1 patient each in Cohorts 1 and 3 with SD for ≥16 weeks. In addition, 1 patient in Cohort 2 with BRCA2-mutated castration-resistant prostate cancer continued to receive treatment despite initial progressing bone metastases, resulting in a prostate-specific antigen response (≥50% change) lasting 16 weeks and a best change in sum of target lesions of −46.3%. Conclusions: Initial findings suggest that rucaparib + lucitanib has an acceptable safety profile. The safety and efficacy of the combination are being further evaluated. Clinical trial information: NCT03992131. [Table: see text]
Transcriptome (RNA next generation sequencing) for personalizing of cancer treatment: A correlation with previous clinical resistance.
Authors: Manuel Sureda, Joseba Rebollo, Ramón González-Manzano, Elena Ma Martínez, Roman Rostagno, Juan José Mata, Elena Monedero, Jose Ortega, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2021)

e15046 Background: RNA Next Generation Sequencing (transcriptome) is a potential useful tool to predict chemoresistance to available anticancer drug therapy. A correlation between previous clinical resistance and drug resistance profiling according to RNA NGS results has been studied. Methods: Since March 2018, whole transcriptome RNA NGS has been performed using Ion-Torrent GeneStudio S5 System in fresh-frozen biopsies obtained from tru-cut or surgical excision procedures from patients with resistant metastatic cancer. We have selected patients with clinically unequivocal drug resistance to previous therapies (tumor progressing to ongoing therapies or less than six months of stopped therapy). Drugs evaluated includes anthracyclines, alkylating agents (temozolomide), platinum derivatives, taxanes, TOPO 1 inhibitors (irinotecan and topotecan), antimetabolites (fluoropyrimidines, gemcitabine, methotrexate and pemetrexed), and more recently, immune checkpoint inhibitors. Results: A total of 111 procedures have been performed. In 64 patients an unequivocal clinical resistance to previous therapies could not be demonstrated, so the analyses has been performed in 47 patients with a number of different tumor histologies: colorectal cancer (13 patients), ovary/peritoneum (8), pancreas (4), NSCLC (4), breast (3), prostate (3), sarcoma (3), head and neck (2), uterus (2), kidney, bladder, cholangiocarcinoma, stomach and cervix (1 patient each). One hundred and fifty two drugs have been used in these patients (Median 3, Range 1 to 8) previous to the RNA NGS procedure. Resistance profile has been found in 120 out of 152 (78.9% of coincidence), and a favourable profile has been found in 32 (21%) previously used drugs, that could be re-used again in these patients. RNA NGS procedure gives additional information about drugs not previously used that helps in the treatment selection for the patients. Conclusions: Transcriptome provide drug resistance information that correlates in 78.9% of drugs with the previous clinical information. However, in 21% of the previously used drugs transcriptome informs as potentially active and could be tried again in subsequent therapies. Transcriptome (RNA sequencing) provides useful clinical information for treatment decision in the vast majority of pretreated cancer patients.
Evolutionary and Ecological Drivers Shape the Emergence and Extinction of Foot-and-Mouth Disease Virus Lineages
Authors: Antonello Di Nardo, Luca Ferretti, Jemma Wadsworth, Valerie Mioulet, Boris Gelman, Sharon Karniely, Alexey Scherbakov, Ghulam Ziay, Fuat Özyörük, Ünal Parlak, Pelin Tuncer-Göktuna, Reza Hassanzadeh, Mehdi Khalaj, Seyed Mohsen Dastoor, Darab Abdollahi, Ehtisham-ul-Haq Khan, Muhammad Afzal, Manzoor Hussain, Nick J Knowles, Donald P King
Journal: Molecular Biology and Evolution (2021)

Abstract Livestock farming across the world is constantly threatened by the evolutionary turnover of foot-and-mouth disease virus (FMDV) strains in endemic systems, the underlying dynamics of which remain to be elucidated. Here, we map the eco-evolutionary landscape of cocirculating FMDV lineages within an important endemic virus pool encompassing Western, Central, and parts of Southern Asia, reconstructing the evolutionary history and spatial dynamics over the last 20 years that shape the current epidemiological situation. We demonstrate that new FMDV variants periodically emerge from Southern Asia, precipitating waves of virus incursions that systematically travel in a westerly direction. We evidence how metapopulation dynamics drive the emergence and extinction of spatially structured virus populations, and how transmission in different host species regulates the evolutionary space of virus serotypes. Our work provides the first integrative framework that defines coevolutionary signatures of FMDV in regional contexts to help understand the complex interplay between virus phenotypes, host characteristics, and key epidemiological determinants of transmission that drive FMDV evolution in endemic settings.
A review of evidence supporting NCCN category 2B off-label recommendations for determination of Medicare reimbursement eligibility.
Authors: Molly Erin DiScala, Kenneth Robert Carson, Gary Irving Grad, Brett Mahon
Journal: Journal of Clinical Oncology (2021)

6576 Background: Antineoplastic indications supported by a category 1 or 2A NCCN recommendation are reimbursed by insurance and Medicare, as are FDA-approved indications. While initial reimbursement requests for “off-label” NCCN category 2B indications may be denied, Medicare will reimburse off-label antineoplastic use supported by evidence from a peer-reviewed publication from one of 26 designated journals. Here, we evaluated the published clinical evidence supporting NCCN category 2B indications. Methods: Category 2B drug indications for the 10 most common solid tumor types were identified in the NCCN compendium (n=104). The results were then filtered to include drugs with only category 2B indications in a particular tumor type (n=14). Similarly, FDA-approved indications were excluded, resulting in a list of drugs with only a 2B indication that are not FDA approved in the specified cancer type (n=8). Published clinical studies supporting these category 2B indications were assessed for study type and journal name in PubMed, and journal names were cross-referenced with the CMS-supported list. Results: Among the 8 non-FDA-approved drug indications with only category 2B recommendations, 7 (87%) had at least one publication of a clinical trial in one of the 26 designated journals. The only 2B indication without supporting literature was single-agent gemcitabine hydrochloride in bladder cancer. For further details, see Table. Conclusions: These results suggest that clinicians should consider pursuing the appeals process and provide supporting evidence in cases of claim denial. While coverage is not guaranteed, the evidence supporting 2B indications frequently meets the criteria identified in the Medicare statute. Further studies will evaluate if these findings extrapolate to less common tumor types.[Table: see text]
Acute Treatment for Migraine
Authors: Rebecca Burch, Melissa Rayhill
Journal: JAMA (2021)

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