tbuckley/cabot-search huggingface dataset:
Novel systemic therapies in the treatment of fibrolamellar carcinoma.
Authors: Sara Gottlieb, Ariel Gliksberg, Erik Schadde, Paul Kent
Journal: Journal of Clinical Oncology (2021)

e16161 Background: Fibrolamellar carcinoma (FLC) is an exceedingly rare liver cancer affecting children and young adults without underlying liver disease. Complete surgical resection is the primary treatment option, but recurrence is common. There are currently no established systemic therapies. We have treated patients in both the neoadjuvant and adjuvant setting with three novel combination therapies: 5-fluorouracil/interferon/nivolumab (“Triple Therapy” or TT), gemcitabine/oxaliplatin/lenvatinib (GOL), and nivolumab/lenvatinib/quercetin (NLQ). The purpose of this study was to evaluate objective responses and tolerability of three multi-agent systemic therapies in the treatment of FLC. Methods: Data from all patients with FLC who received TT, GOL, or NLQ between May 2018 and February 2021 were reviewed. Patients who received a minimum of six cycles of systemic therapy with follow up scans at least two months after initiation were assessed based on objective response, survival, and toxicity. Results: Twenty-nine patients with FLC who were treated with novel multi-agent systemic therapy were evaluable based on the above criteria. Median age at start of treatment was 20 (7-52; 16F, 12M, 1 non-disclosed). Twenty-three patients received one combination therapy (13 TT, 8 GOL, 2 NLQ), five received two different lines (3 TT/NLQ, 2 TT/GOL), and one patient received all three novel combinations. Between our 29 patients, they had relapsed 36 total times, and 11 had already tried 2+ systemic therapies. Best RECIST 1.1 objective response (clinical remission + partial response) and tumor control rate (clinical remission + partial response + stable disease) were 58%/95%, 55%/100%, and 33%/83% for TT, GOL, and NLQ respectively. The median longest Progression Free Survival (PFS) on any novel multi-agent regimen was 9 months (2-29; 9.5 for TT, 7 for GOL, 6.5 for NLQ), with 18 patients still receiving the therapy extending their PFS. Of those with previous relapses, 56% have a PFS longer than their previous longest remission and 69% have a PFS longer than their previous shortest time to relapse. Half of patients with previous relapses are still receiving the treatment responsible for their longest PFS. Fever, chills, and nausea were the most common adverse effects experienced throughout all three regimens. Seven patients experienced 1+ grade 3 adverse event. There were no toxic deaths or organ failure. Two patients died as a result of disease; their longest PFS (1 on GOL, 1 on TT) were nine and 10 months. Conclusions: FLC is a devastating cancer with patients often relapsing even after successful surgical remission. There is a strong need for effective and tolerable systemic therapies for those with unresectable, relapsed, progressive, or metastatic disease. We have had promising results in treating FLC and prolonging survival with minimal toxicities using novel multi-agent regimens.
Five-day accelerated partial breast irradiation (APBI) using intensity modulated radiation therapy (IMRT) in stage 0-II breast cancer: A report of 214 cases with up to 39 month follow-up.
Authors: Rufus J. Mark, Valerie Gorman, Michal Wolski, Steven McCullough
Journal: Journal of Clinical Oncology (2021)

e12508 Background: Randomized trials in stage 0-II breast cancer have proven that APBI given via HDR implant in 5 days is equivalent to whole breast irradiation (WBI) given in 5-6 weeks in regard to breast tumor local recurrence (LR). However, complications have been significant. Recently APBI using non-invasive IMRT given in 5 fractions has been shown in another randomized trial with 10 year follow-up to be equivalent to WBI in 6 weeks, with respect to LR. IMRT was superior in regard to acute effects, late effects, and cosmesis. In the randomized clinical trial of APBI IMRT, the Clinical Target Volume (CTV) was defined by the injection of individual fiducial markers bordering the surgical cavity. We have used the Biozorb fiducial system to localize the CTV for IMRT. We sought to confirm the APBI IMRT results with this simpler less labor intensive fiducial placement system. Methods: Between 2017 and 2021, 214 patients have undergone IMRT targeted to a Biozorb defined CTV with the walls of the surgical cavity sewn to the Biozorb device. Eligible patients were older than age 40, had tumor sizes &lt; 3 cm, negative surgical margins, and negative sentinel node dissections. IMRT dose was 30 Gy given in 5 fractions. Dose Constraints were as follows : V-30 Gy &lt; 105%, Ipsilateral Breast V-15 Gy &lt; 50%, Ipsilateral Lung V-10 Gy &lt; 20%, Contralateral Lung V-5 Gy &lt; 10%, Heart V-3 Gy &lt; 20%, Contralateral Breast Dmax &lt; 2 Gy and Skin Dmax &lt; 27 Gy. The Planning Target Volume (PTV) ranged from 27 to 355 cc with a median of 80 cc. PTV = CTV + 1-2 cm. Results: Follow-up ranged from 1-39 months with a median of 20 months. LR has been 0% (0/214). There have been no skin reactions or seromas. Infection has occurred in one patient (0.5%). Four (1.9%) patients developed pain around the Biozorb site. This resolved on a short courses of steroids in all cases. Cosmetic results as rated by the Surgeon, Radiation Oncologist, and Nurse, were rated excellent in 99.0% (212/214) of cases. Conclusions: Non-invasive APBI with IMRT given qd over 5 days targeted to Biozorb has resulted in LR, complications, and cosmetic results which compare favorably to invasive APBI given bid with HDR implant. At last follow-up, there have been no LR, skin reactions, or significant complications. Cosmesis has been excellent in 99.0% of patients.
Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia
Authors: Fei Sun, Guolun Wang, Arun Pradhan, Kui Xu, Jose Gomez-Arroyo, Yufang Zhang, Gregory T. Kalin, Zicheng Deng, Ronald J. Vagnozzi, Hua He, Andrew W. Dunn, Yuhua Wang, Allen J. York, Rashmi S. Hegde, Jason C. Woods, Tanya V. Kalin, Jeffery D. Molkentin, Vladimir V. Kalinichenko
Journal: Circulation (2021)

Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy.We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy.Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling.Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.
Circulating tumor DNA as a noninvasive marker of resectability in ovarian carcinomas.
Authors: Roxane Mari, Christophe Pomel, Pierre-Emmanuel Colombo, Fabrice Narducci, Séverine Garnier, Nadine Carbuccia, Arnaud Guille, Magali Provansal, Maria-Antonietta Cappiello, Fréderique Rousseau, Guillaume Blache, Eric Lambaudie, Daniel Birnbaum, Francois Bertucci, Renaud Sabatier
Journal: Journal of Clinical Oncology (2021)

5548 Background: Ovarian cancer is the leading cause of death by gynecological cancer. Complete surgery remains one of the main prognostic factors. Laparoscopic exploration is mandatory to assess surgical resectability at diagnosis or after neoadjuvant chemotherapy. However, there is no clinical or biological marker that can correctly predict resectability and may be able to avoid a second laparoscopic exploration for initially unresectable diseases. Our aim was to assess circulating tumor DNA (ctDNA) value as a predictive non-invasive marker of evolution towards resectability for patients with epithelial ovarian cancer receiving first-line chemotherapy. Methods: We explored in this work one of the secondary objectives of the CIDOC study (NCT03302884). CIDOC is a multicenter prospective study aiming to explore ctDNA value as early marker of disease relapse after first-line treatment for epithelial ovarian cancer. Patients with mucinous histology or early stages not requiring chemotherapy are excluded. Plasma samples are collected at diagnosis, during neoadjuvant chemotherapy, and during follow-up. After DNA extraction, panel-based next generation sequencing is performed on both tumor samples and germline DNA, and somatic mutations of interest are selected for ctDNA monitoring. ctDNA analyses are conducted using droplet digital PCR (BioRad QX200) by measuring the variant allele fraction (VAF) of previously identified mutations. Results: This intermediary analysis has included 47 patients diagnosed between March 2017 and December 2019. Median age was 69 years old (48 – 84). Most of the patients had advanced disease (89.4% stage FIGO III or IV), serous histology (94.8%), and high grade tumor (92.3%). Most of the patients underwent complete interval cytoreductive surgery (76.3% vs 17.4% complete upfront surgery). Most of the tumors had TP53 mutations (85.1%), following by alterations involving DNA repair genes (38.3%). Median cell-free DNA concentration at baseline was 0.38 ng/µL (0 – 12.8). ctDNA was identified in 92.1% of patients at baseline with a median VAF of 1.84% (0 – 42.52%). ctDNA VAF was correlated to the peritoneal dissemination ( p= 0.039) assessed with the peritoneal cancer index. ctDNA clearance after preoperative chemotherapy tended to be correlated to achievement of complete interval surgery for patients receiving neoadjuvant chemotherapy ( p= 0.108). Conclusions: ctDNA may be a promising non-invasive marker to assess peritoneal cancer spreading and to predict surgical resectability after neoadjuvant chemotherapy. If confirmed in larger populations, this may enable to avoid additional surgical explorations for patients who remain ctDNA positive after chemotherapy. Clinical trial information: NCT03302884.
Hospital admissions and subsequent outcomes from immune-related adverse events.
Authors: Hui Jan Ho, Melissa Arneil, Wen Xu, Victoria Atkinson
Journal: Journal of Clinical Oncology (2021)

e21590 Background: Checkpoint inhibitor (CPI) use has been increasing in recent years. Immune related adverse events (irAEs) are a known complication of CPIs, particularly with the concurrent use of PD-1 and CTLA-4 inhibitors (combination therapy). IrAEs are associated with increased hospital resource utilisation including admissions and immunomodulator therapy. This is a retrospective analysis of patients receiving CPI therapy for metastatic melanoma. Methods: Data was collected from a Queensland Health centre using electronic medical records and immunotherapy prescribing software. Patient demographics, CPIs, irAEs, admissions, and outcomes were recorded from 2015-2019. All patients had metastatic disease; they either received single agent or combination CPI as first line metastatic treatment or received single agent CPI as adjuvant therapy. Patients admitted to hospitals without electronic medical records were not included. Results: 51 out of 343 patients were eligible for analysis, indicating 15% of patients receiving CPI required hospital admissions due to irAEs. The mean age was 64.7 years, with 64.7% male patients. The commonest BRAF status was wild type (60.8%, n = 31). 54.9% (n = 28) of patients received combination therapy, 39.2% (n = 20) received PD-1 inhibitors, and 5.9% (n = 3) received CTLA-4 inhibitors. 24% (n = 12) of patients experienced early toxicity, defined as hospital admission after one dose. The commonest early toxicity was pneumonitis; all had received PD-1 inhibitors. In the rest of the cohort, the most frequent irAE was colitis (35.3%, n = 18). Regardless of CPI, average length of admission was 6-7 days. 17.6% (n = 9) patients had greater than one admission. Rescue immunomodulators were required in eight patients (15.7%), seven of whom had received combination therapy. Of patients with irAE from combination therapy, 28.7% (n = 8) were palliated due to progressive disease (PD), and 25% (n = 7) continued on single agent PD-1 inhibitor. In patients with irAE from PD-1 inhibitors, the majority (70%, n = 14) ceased treatment; of these, 8 had stable disease and 6 developed PD and were subsequently palliated. Conclusions: IrAEs are a well-documented complication of CPIs. Important considerations for CPI use include severe irAEs requiring admission and subsequent hospital resource utilisation. This occurs not infrequently, as demonstrated in this analysis. It is important to consider individual patient risks and benefits prior to commencement of treatment.
Impact of disruptions in breast cancer control due to the COVID-19 pandemic on breast cancer mortality in the United States: Estimates from collaborative simulation modeling.
Authors: Oguzhan Alagoz, Kathryn P. Lowry, Allison W. Kurian, Jeanne S. Mandelblatt, Mehmet Ali Ergun, Hui Huang, Sandra J. Lee, Clyde Schecter, Anna N.A. Tosteson, Diana L. Miglioretti, Amy Trentham-Dietz, Sarah Nyante, Karla Kerlikowske, Brian L. Sprague, Natasha K. Stout
Journal: Journal of Clinical Oncology (2021)

6562 Background: The COVID-19 pandemic has disrupted breast cancer control through short-term declines in screening, delays in diagnosis and reduced/delayed treatments. We projected the impact of COVID-19 on future breast cancer mortality.Methods: Three established Cancer Intervention and Surveillance Modeling Network (CISNET) models projected the impact of pandemic-related care disruptions on breast cancer mortality between 2020 and 2030 vs. pre-pandemic care patterns. Based on Breast Cancer Surveillance Consortium data, we modeled reductions in mammography screening utilization, delays in symptomatic cancer diagnosis, and reduced use of chemotherapy for women with early-stage disease for the first six months of the pandemic with return to pre-pandemic patterns after that time. Sensitivity analyses were performed to determine the effect of key model parameters, including the duration of the pandemic impact. Results: By 2030, the models project 1,297 (model range: 1,054-1,900) cumulative excess deaths related to reduced screening; 1,325 (range: 266-2,628) deaths from delayed diagnosis of symptomatic women, and 207 (range: 146-301) deaths from reduced chemotherapy use for early-stage cancer. Overall, the models predict 2,487 (range 1,713-4,875) excess deaths, representing a 0.56% (range: 0.36%-0.99%) cumulative increase over deaths that would be expected by 2030 in the absence of the pandemic’s disruptions. Sensitivity analyses indicated that the impact on mortality would approximately double if the disruptions lasted for a 12-month period. Conclusions: The impact of the initial pandemic-related disruptions in breast cancer care will have a small long-term cumulative impact on breast cancer mortality. The impact of the initial pandemic-related disruptions on breast cancer mortality will largely be mitigated by the rapid return to usual care. As the pandemic continues it will be important to monitor trends in care and reassess the mortality impact.[Table: see text]
To Solve Racial and Ethnic Disparities in COVID-19 Outcomes, Look Upstream for Solutions
Authors: Yvonne Commodore-Mensah, Deidra C. Crews
Journal: Circulation (2021)

s of April 30, 2021, almost 33 million people in the United States had been diagnosed with coronavirus disease 2019 (COVID-19), and almost 580 000 had lost their lives. 1The actual human, economic, and social toll of the COVID-19 pandemic on families, communities, and the nation is incalculable.Although there were initial reports of disparities in transmission rates along race and class, the data are too incomplete to thoroughly understand the burden of the pandemic on specific racial and ethnic groups.Of note, the federal government did not require laboratories to report the race and ethnicity of people tested for COVID-19 until August 1, 2020.
Impact of anticoagulation on recurrent thrombosis and bleeding after hematopoietic cell transplantation
Authors: Kylee L. Martens, Christopher I. Amos, Cristhiam Rojas Hernandez, Partow Kebriaei, Wilson L. da Costa, Ryan Basom, Chris Davis, Madeline Kesten, Marc Carrier, David A. Garcia, Stephanie J. Lee, Ang Li
Journal: American Journal of Hematology (2021)

History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p = 0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p = 0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery.
Camrelizumab combined with FLOFOX as neoadjuvant therapy for resectable locally advanced gastric and gastroesophageal junction adenocarcinoma: Updated results of efficacy and safety.
Authors: Ying Liu, Guangsen Han, Hongle Li, Yuzhou Zhao, Zhi Li, Jing Zhuang, Gangcheng Wang, Baodong Li, Jinbang Wang, Zhimeng Li, Qingxin Xia, Chengjuan Zhang, Juan Yu, Ke Li, Shuning Xu, Lei Qiao, Gaizhen Kuang, Danyang Li
Journal: Journal of Clinical Oncology (2021)

4036 Background: Although anti-PD-1 antibody in combination with chemotherapy has shown promising antitumor activity in advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), the evidence of neoadjuvant therapy for locally advanced GC/GEJC is limited. Camrelizumab combined FOLFOX as neoadjuvant therapy for resectable locally advanced GC/GEJC was a prospective, single-arm, phase 2 study we conducted. Here, we updated the results of efficacy and safety of this study. Methods: Patients confirmed by endoscopic ultrasonography (EUS) and imaging with clinical stage≥T2 and/or positive lymph nodes were enrolled. They received 4 cycles of camrelizumab (200mg ivgtt on day1, q2w) plus FOLFOX (oxaliplatin 85mg/m 2 ivgtt, LV 200mg/m 2 ivgtt, 5-Fu 400mg/m 2 iv followed by 2.4mg/m 2 CIV 46 hours on day 1, q2w) as neoadjuvant therapy. Then patients without disease progression evaluated by imaging underwent gastrectomy of D2 lymph node dissection. The primary endpoint was pCR, the secondary endpoints were R0 resection rate and safety. Results: Between Jul 24 2019 and Nov 30 2020, 49 patients were enrolled. The median age was 57 years (29-72 years). All patients completed 4 cycles treatment. Unfortunately, 2 of them were confirmed PD by imaging. In addition, two patients refused gastrectomy and withdrew from the study. Eventually, 45 patients underwent gastrectomy, of which 3 patients had intraperitoneal metastases during the operation. A total of 42 patients were evaluable, all of them gained R0 resection (100%), 4 patients (10%) achieved pCR and 10 patients (24%) reached TRG1. Among the patients experienced pCR, one of them was Her-2 positive, one was MSI-H, the rest two of them were PD-L1-positive (CPS≥10). The most common ≥grade 3 adverse events (AEs) were neutropenia (35%) and leukopenia (16%). Only 1 patient (2%) experienced grade 3 immune-related AEs of alanine aminotransferase and aspartate aminotransferase increase. No serious AEs resulted in termination of treatment or death. Conclusions: Camrelizumab combined with FOLFOX was an effective and safe neoadjuvant therapy strategy for patients with resectable locally advanced GC/GEJC. Furthermore, the analysis of biomarkers with clinical benefits is undergoing. Clinical trial information: NCT03939962. [Table: see text]