tbuckley/cabot-search huggingface dataset:
Diagnosis of Pulmonary Hypertension Using Dynamic Chest Radiography
Authors: Yuzo Yamasaki, Takeshi Kamitani, Kohtaro Abe, Kazuya Hosokawa, Koji Sagiyama, Tomoyuki Hida, Yuko Matsuura, Yoshiyuki Kitamura, Yasuhiro Maruoka, Takuro Isoda, Shingo Baba, Hideki Yoshikawa, Taku Kuramoto, Hidetake Yabuuchi, Kousei Ishigami
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Diagnosis of Pulmonary Hypertension Using Dynamic Chest Radiography." American Journal of Respiratory and Critical Care Medicine, 204(11), pp. 1336–1337
Real-world treatment patterns, adherence, costs, and healthcare resource utilization associated with Waldenström macroglobulinemia in the United States.
Authors: Keri Yang, Jorge J. Castillo, Anna Ratiu, Rachel Delinger, Todd Zimmerman, Boxiong Tang
Journal: Journal of Clinical Oncology (2021)

e18766 Background: Waldenström macroglobulinemia (WM) is a rare, incurable non-Hodgkin lymphoma. Given limited real-world data on WM treatment utilization, this study evaluates real-world treatment patterns and associated outcomes in the US commercially insured population. Methods: A retrospective observational study was conducted using the IBM MarketScan commercial claims and Medicare supplement database. Adults with ≥2 WM diagnoses and ≥1 WM treatment between 2014 and 2019 were identified. Patients included were newly diagnosed, initiating treatment, and enrolled continuously for 6 months before and ≥60 days following the index date, defined as the first date of WM treatment. Treatment regimens were categorized as: rituximab monotherapy, chemotherapy-based (alone or in combination), proteasome inhibitor-based (alone or in combination with rituximab), ibrutinib (alone or in combination with rituximab), and other regimens. Treatment patterns were evaluated by frequency and duration of treatment regimen. Adherence is measured by discontinuation and switching rates. Healthcare resource utilization examined included inpatient, outpatient, and pharmacy visits. Total costs were calculated as sum of inpatient, outpatient and pharmacy costs per-patient-per-month (PPPM). Treatment regimens, costs, and hospitalizations were examined overall, and by line of therapy. Results: A total of 453 patients (mean age: 67 years, 51% male) received 1st-line therapy (mean duration: 246 days); 143 (32%) patients received 2nd-line therapy (mean duration: 231 days), and 24 (5%) received 3rd-line therapy (mean duration: 212 days). The most commonly used treatment regimens by line of therapy are shown in the treatment pattern table. Discontinuation rates were 43.3%, 50.4%, and 45.8%, and the switching rates were 25.4%, 10.5%, 20.8% during 1st, 2nd, and 3rd line of therapy, respectively. The overall hospitalization rate was 20% with an average length of stay (LOS) of 2.3 days. Approximately 17% (LOS: 1.4 days), 20% (LOS: 1.8 days), and 25% (LOS: 7.0 days) of patients had a hospitalization, during 1st, 2nd, and 3rd line of therapy, respectively. Mean total PPPM costs were $26,688 in overall population, and increased by line of therapy (1st: $18,682; 2nd: $19,171; and 3rd: $36,878). Conclusions: There remains a significant clinical and economic burden with suboptimal treatment adherence in US commercially-insured patients with WM. Future studies are needed to further understand factors associated with treatment selection. [Table: see text]
Bench-to-Bedside in Vascular Medicine: Optimizing the Translational Pipeline for Patients With Peripheral Artery Disease
Authors: Tom Alsaigh, Belinda A. Di Bartolo, Jocelyne Mulangala, Gemma A. Figtree, Nicholas J. Leeper
Journal: Circulation Research (2021)

Peripheral arterial disease is a growing worldwide problem with a wide spectrum of clinical severity and is projected to consume >$21 billion per year in the United States alone. While vascular researchers have brought several therapies to the clinic in recent years, few of these approaches have leveraged advances in high-throughput discovery screens, novel translational models, or innovative trial designs. In the following review, we discuss recent advances in unbiased genomics and broader omics technology platforms, along with preclinical vascular models designed to enhance our understanding of disease pathobiology and prioritize targets for additional investigation. Furthermore, we summarize novel approaches to clinical studies in subjects with claudication and ischemic ulceration, with an emphasis on streamlining and accelerating bench-to-bedside translation. By providing a framework designed to enhance each aspect of future clinical development programs, we hope to enrich the pipeline of therapies that may prevent loss of life and limb for those with peripheral arterial disease.
Efficacy and safety of anlotinib combined with liposomal doxorubicin in first-line treatment of advanced soft-tissue sarcoma.
Authors: Xin Sun, Wei Guo, Ranxin Zhang, Lu Xie, Jie Xu
Journal: Journal of Clinical Oncology (2021)

e23530 Background: Anthracycline-based chemotherapy is the main first-line treatment option for advanced soft-tissue sarcoma (STS). Anlotinib has been approved for the treatment of STS by the Chinese agency. This study was performed to evaluate the efficacy and safety of Anlotinib combined with liposomal doxorubicin in first-line treatment of patients with advanced STS. Methods: This is a single-center, retrospective study. Eligible patients were those ≥14 years old, ECOG performance state of 0-1, with histologically confirmed locally advanced, unresectable or metastatic STS, previously untreated, with measurable disease by RECIST v1.1. All patients received Anlotinib (12mg once daily, 2 weeks on and 1 week off) and liposomal doxorubicin (40-50 mg/m 2 , IV, D1, every 3 weeks) until disease progression or unacceptable adverse events. The primary endpoint was progression-free survival (PFS). Disease control rate (DCR), objective response rate (ORR), and side effects were also calculated. Results: Between April 2019 and December 2020, 8 patients were evaluated, including 2 undifferentiated pleomorphic sarcoma, 1 liposarcoma, 4 fibrosarcomas, and 1 synovial sarcoma. The median age was 42 years. 2 patients (25%) achieved a confirmed partial response (PR) and 3(37.5%) had stable disease (SD). The ORR and DCR were 25% and 62.5% respectively. The median PFS was 11.3 months, and the PFS rate at 4 months was 50%. Treatment-related adverse events included hand-foot syndrome (3/8, 37.5%), pneumothorax (1/8, 12.5%), oral mucositis (2/8, 25%), epistaxis (2/8, 25%), hypertension (2/8, 25%), arrhythmias (1/8, 12.5%), and pharyngeal pain (1/8, 12.5%). Three patients experienced grade 3 or 4 adverse events, 2 hand-foot syndrome (2/8, 25%) and 1 pneumothorax (1/8, 12.5%). Conclusions: This study suggested that the combination of Anlotinib and liposomal doxorubicin might have anti-tumor activity and acceptable toxicity in first-line treatment of patients with advanced STS.
Phase II study of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors (GCTs).
Authors: Michal Mego, Daniela Svetlovska, Maria Reckova, Katarina Kalavska, Jana Obertova, Patrik Palacka, Katarina Rejlekova, Valentina De Angelis, Zuzana Sycova-Mila, Michal Chovanec, Jozef Mardiak
Journal: Journal of Clinical Oncology (2021)

e17009 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP is overexpressed in GCTs compared to normal testis and PARP overexpression is early event in GCTs development. Gemcitabine and carboplatin showed activity in refractory GCTs. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and PARP inhibitor, veliparib, in patients with multiple relapsed/refractory GCTs. Methods: Fifteen patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from October 2016 to October 2020. All patients were pretreated with at least 2 cisplatin-based therapies (median 2, range 2 – 4); 3 tumors (20.0%) were absolutely refractory to cisplatin and 5 patients (33.3%) had visceral non-pulmonary metastases. Gemcitabine was administered at a dose 800mg/m2 day 1 and 8 every 3 weeks; carboplatin AUC = 4, day 1, every 3 weeks and veliparib 250mg bid day continuously. The primary end point was 12-months progression-free survival (PFS), if &lt; 8 patients experienced 12-months PFS, the treatment will be considered ineffective. Results: Median age was 31 years (range: 22 – 48 months). Median number of treatment cycles was 4 (range 2 – 8). During a median follow-up period of 9.2 months (range: 1.9 – 23.8), all (100%) patients experienced disease progression and 14 patients (93.3%) died. Twelve-months PFS was achieved in 1 (6.7%) patient. Median PFS was 3.1 months, 95%CI (2.2 – 3.9) and median OS was 10.5 months, 95% CI (8.9 – 11.1). Partial remission was observed in 4 (26.7%) and disease stabilization in 5 (33.3%) of patients. Favorable response (complete or partial remission with negative serum tumor markers) experienced 3 (20%) patients. Treatment was well tolerated, however, 12 (80%) of patients experienced grade 3/4 neutropenia, 9 (60%) anemia, 14 (93.3%) thrombocytopenia and 2 (13.3%) febrile neutropenia. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT02860819.
PTH-109 Inequality of provision of inflammatory bowel disease nurses (ibd-n) across england: correlation with metrics of unplanned hospital care for adult services
Authors: M Shawihdi, A Kneebone, K Bodger
Journal: Gut (2017)

Introduction  Despite better IBD-N provision in the UK, national audit suggests only 48% of patients admitted as an emergency are seen by a specialist nurse.(1) An estimated 1 00 000 people with IBD don’t have access to an IBD-N and 63% of services don’t have enough IBD-N to meet the needs of everyone affected.(2) Duties in elective services may compete with the availability of an IBD-N to support hospitalised patients. Although data is available for basic levels of IBD-N provision, there is no published information relating current levels of staffing to emergency care workload.  Method  Data sources: (a) UK IBD Audit: Hospital data for IBD-N provision, expressed as Full Time Equivalents (FTE) reported in organisation audit for Dec 2013 (3); (b) Hospital Episode Statistics for England (2013/14): relating to all cases coded with an IBD-specific code, including their all-cause hospitalizations. Site mapping: Hospital sites participating in audit were mapped manually to organisational site codes available in HES, matching 140 hospitals. Data Analysis: For HES data, algorithms based on admission method, coded diagnoses and procedures were used to categorise admissions, extracting a series of metrics including annual counts and total emergency bed days (EmBedDays) for IBD-related emergency admissions, aggregated at site level.  Results  Provision tends to increase with higher burden of unplanned care at site level, but only with modest correlation between IBD-N (FTEs) and IBD-specifc EmBedDays, r=0.47 (p  Conclusion  Provision of IBD-N is not matched to unplanned care workloads for English hospitals. The emergency bed days falling within the potential remit of an individual IBD-N may vary as much as nine fold between different hospital sites.  [Funding: Crohn’s and Colitis UK]  References  . Royal College of Physicians. National clinical audit report of inpatient care for people with ulcerative colitis: adult national report. UK IBD audit. London: RCP, 2014.  . https://www.crohnsandcolitis.org.uk/get-involved/campaigning/more-ibd-nurses-better-care-campaign#sthash.79awqrIJ.dpuf  . Royal College of Physicians. National audit report of inflammatory bowel disease service provision: adult national report. UK IBD audit. London: RCP, 2014.  Disclosure of Interest  M. Shawihdi: None Declared, A Kneebone: None Declared, K Bodger Conflict with: AbbVie, Conflict with: Boston Scientific | Takeda
Establishment of EGFR-TKI resistant EGFR mutant NSCLC cell lines in animal model system
Authors: Youngwook Kim, Myung-ju Ahn, Keunchil Park
Journal: Cancer Research (2008)

677  To better understand the mechanism of EGFR-TKI drug action in EGFR dependent lung cancer, EGFR downstream signaling pathways were dissected in EGFR mutant non-small lung cancer cells. EGFR dependent lung cancer cells undergo rapid apoptosis upon treatment with EGFR-TKI. A part of this cell death program is initiated by BH3 only protein, Bim. The induction of Bim and initiation of apoptosis are mediated by several EGFR downstream signaling pathways, including ERK dependent Bim phosphorylation and its inhibition. We note that these results are largely consistent with recently published reports on the role of Bim in mediating the apoptosis of EGFR dependent non-small cell lung cancer (1-3).  Although large clinical trials have shown that EGFR tyrosine kinase inhibitors (TKI) prolong survival of lung cancer patients, those who initially respond to the TKI therapy invariably develop acquired resistance to the drugs. A part of acquired resistance is due to T790M secondary mutation in the kinase domain of EGFR. However, a significant portion of patients develop acquired resistance without alterations in the primary sequence of EGFR kinase domain. A few mechanisms, including transphophorylation by non-ErbB family members, were suggested as possible explanations of acquired EGFR independence, though the physiological relevance of these explanations, mostly based on extreme in vitro studies, still remains unclear. As an alternative pre-clinical model system of the acquired resistance to the current reversible TKI therapy, orthotopic xenografts mice were treated with EGFR-TKI for a prolonged period of time. Refractory clones obtained from the lung of such mice display a series of histological and cellular phenotypes. Possible molecular mechanisms which confer resistance to the reversible EGFR TKI therapy are discussed.
Patient reported outcomes in patients with desmoid type fibromatosis.
Authors: VIKAS GARG, Sameer Rastogi, Adarsh Barwad, Rambha Panday, Sandeep Kumar Bhoriwal, Ekta Dhamija
Journal: Journal of Clinical Oncology (2021)

11574 Background: Desmoid type fibromatosis (DTF) is a rare benign neoplasm with infiltrative growth and high local recurrences. Due to long disease course, unpredictable growth pattern, and low mortality, using only survival outcomes may be inappropriate. In this study we assessed the impact of DTF on health related quality of life (HRQoL). Methods: This was a cross-sectional study done in patients with DTF. The study participants were asked to fill the EORTC QLQ-C30, GAD-7 and PHQ- 9 q uestionnaires to assess HRQoL, anxiety and depression . Outcomes were also compared with healthy controls. Results: 204 subjects (102 DTF patients and 102 healthy controls) were recruited. Study parameters have been summarized in Table. Appendicular skeleton (limbs + girdle) was most commonly involved in 59 % patients and abdominal wall or mesentery was involved in 22.5 %. Patients have received median of 2 lines of therapy. 54 % patients were currently on sorafenib and 41 % were under active surveillance. Mean global health status in DTF patient 65.58 ± 22.64, was significantly lower than healthy controls. Similarly, DTF patients scored low on all functional scales except cognitive functioning. Symptom scale showed significantly higher symptom burden of fatigue, pain, insomnia and financial difficulties. Anxiety &amp; depression was observed in 39.22 % and 50 % of DTF patients respectively. DTF patients had higher rates of mild, moderate and severe anxiety and depression compared to healthy controls. No difference was observed based on site of disease. Conclusions: DTF patients have significant symptom burden, poor functioning, and heightened anxiety and depression. Patient reported outcomes should be routinely used to assess treatment efficacy in DTF patients.[Table: see text]
WX390, a high-potent PI3K-mTOR dual inhibitor, first-in-human (FIH) phase I study in advanced relapsed or refractory solid tumor, and lymphoma.
Authors: Wenbo Tang, Ye Guo, Liqiong Xue, Wei Peng, Xiaoxiao Ge, Junli Xue, Wei Wei, Juncai Xu, Yongguo Li, Jin Li
Journal: Journal of Clinical Oncology (2021)

3106 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. WX390 exhibited anti-tumor activity and high potency in xenograft models with inhibition of AKT phosphorylation. Methods: Patients (pts) with advanced lymphoma and solid tumors who have failed standard therapies were enrolled in dose escalation cohorts and received WX390 administered daily orally in 28-day cycles until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma samples were collected up to 7 days after the first dose and up to 24 hours at C1D28. Results: As of the cut-off date 2021 Feb 10, 25 patients (median age 52 years) were enrolled in 6 dose levels (0.1mg, 0.2mg, 0.4mg, 0.7mg, 1.1mg and 1.4mg) of the dose-escalation cohorts. Cohorts 0.1 mg to 1.1 mg were completed without dose-limiting toxicities (DLT), cohort 1.4 mg was completed with 1 DLT (Diabetic ketoacidosis combined with grade 3 hyperglycemia) out of 4 evaluable patients. Common treatment-related adverse events (TRAEs) (all grades, ≥20%) included hyperglycemia (20 pts, 80%), proteinuria (10 pts, 40%), creatinine increased (11 pts, 44%), hypophosphatemia (10 pts, 25%), anemia (8 pts, 33.3%), thrombocytopenia (7 pts, 29.2%), and aspartate aminotransferase increased (25%). Grade≥3 TRAEs were hyperglycemia (7 pts, 28%, 1 pt combined with diabetic ketoacidosis), hypophosphatemia (2 pts, 8%), neutropenia (2 pts, 8%), dermatitis (1 pt, 4%), and maculopapular rash (1 pt, 4%). PK showed fast absorption (Tmax 0.5-4 h) and dose proportionality for Cmax and AUC 0-∞ . The mean multiple dose T 1/2 was approximately 12.4 hours across all cohorts with minimum accumulation. Among 14 tumor response evaluable patients, there were 3 patients with confirmed PIK3CA mutation. All 3 patients experienced tumor shrinkage and were still on treatment by the cut-off date. 2 (1 pt with head and neck cancer and 1 pt with cervical cancer) of them have achieved partial response (PR). The head and neck cancer patient (PR) was treated with WX390 0.7mg/day without any severe AE and the duration of response was beyond 15 months. Stable disease (SD) was observed in 6 patients (n = 5 with unknown PIK3CA mutation status and n = 1 with confirmed PIK3CA mutation). Of note, 1 patient (follicular lymphoma) treated with 0.1mg experienced SD for 14 months. Another patient (SD, head and neck cancer with PIK3CA mutation) experienced tumor shrinkage for more than 8 months and was still receiving WX390 treatment by the cut-off date. Conclusions: the PI3K-mTOR dual inhibitor WX390 was well tolerated with manageable safety profile, and showed encouraging antitumor activity. A RP2D of 1.1 mg qd is selected to be explored for different indications in solid tumor clinical studies. Clinical trial information: NCT03730142.
Predictors of venous thromboembolism in cancer patients using machine learning.
Authors: Ayse Ece Cali Daylan, Danai Khemasuwan, Hyun S. Kim, Parvathy Geetha, Sylvia Vania Alarcon Velasco, Christopher S. Lathan
Journal: Journal of Clinical Oncology (2021)

e24042 Background: The increased risk of venous thromboembolism (VTE) in cancer patients is clearly documented. However, given the heterogeneity and increased risk of bleeding in cancer population, patient selection for thromboprophylaxis is still challenging. Methods: In order to predict risk factors of VTE in cancer patients, we performed a retrospective study of 706 patients who were diagnosed with either solid or hematological malignancies between 2015 and 2019. Demographics, body mass index, complete blood count with differential, kidney function tests, electrolytes, liver function tests, lipid profile and cancer staging were recorded. Random forest analysis with bagging was used to rank these variables and the Kaplan-Meier survival analysis was implemented to stratify cancer subtypes based on the risk of VTE occurrence. Results: The mean follow-up time was 19 months. 8.2% of the patients developed VTE. Based on the random forest analysis, the most important five factors in prediction of VTE in cancer patients were determined as cancer subtype, white blood cell count, platelets, neutrophil and hemoglobin. At one-year mark, the risk of VTE in lung cancer and hematological malignancies was found to be significantly higher than breast, colorectal and endometrial cancer (p&lt;0.05). Conclusions: Machine learning approach is infrequently used in risk factor prediction of VTE in cancer patients. The risk factors identified by the machine learning algorithm in our study are consistent with prior studies and show a clear difference in risk of VTE in various cancer subtypes. Moreover, hematological malignancies and lung cancer patients may develop VTE earlier than other cancer subtypes based on the Kaplan-Meier analysis. Further prospective studies with longer follow up are needed to better risk-stratify cancer patients and explore the temporal associations of VTE risk factors. [Table: see text]
Induced Pluripotent Stem Cells Enable Disease Modeling and Drug Screening in Calreticulin del52 and ins5 Myeloproliferative Neoplasms
Authors: Lise Secardin, Cintia Gomez Limia, Suzana da Silva-Benedito, Larissa Lordier, Mira El-Khoury, Caroline Marty, Jean-Christophe Ianotto, Hana Raslova, Stefan N. Constantinescu, Martín Hernán Bonamino, William Vainchenker, Barbara Monte-Mor, Antonio Di Stefano, Isabelle Plo
Journal: HemaSphere (2021)

Mutations in the calreticulin ( CALR ) gene are seen in about 30% of essential thrombocythemia and primary myelofibrosis patients. To address the contribution of the human CALR mutants to the pathogenesis of myeloproliferative neoplasms (MPNs) in an endogenous context, we modeled the CALRdel52 and CALRins5 mutants by induced pluripotent stem cell (iPSC) technology using CD34 + progenitors from 4 patients. We describe here the generation of several clones of iPSC carrying heterozygous CALRdel52 or CALRins5 mutations. We showed that CALRdel52 induces a stronger increase in progenitors than CALRins5 and that both CALRdel52 and CALRins5 mutants favor an expansion of the megakaryocytic lineage. Moreover, we found that both CALRdel52 and CALRins5 mutants rendered colony forming unit–megakaryocyte (CFU-MK) independent from thrombopoietin (TPO), and promoted a mild constitutive activation level of signal transducer and activator of transcription 3 in megakaryocytes. Unexpectedly, a mild increase in the sensitivity of colony forming unit-granulocyte (CFU-G) to granulocyte-colony stimulating factor was also observed in iPSC CALRdel52 and CALRins5 compared with control iPSC. Moreover, CALRdel52-induced megakaryocytic spontaneous growth is more dependent on Janus kinase 2/phosphoinositide 3-kinase/extracellular signal-regulated kinase than TPO-mediated growth and opens a therapeutic window for treatments in CALR -mutated MPN. The iPSC models described here represent an interesting platform for testing newly developed inhibitors. Altogether, this study shows that CALR-mutated iPSC recapitulate MPN phenotypes in vitro and may be used for drug screening.