tbuckley/cabot-search huggingface dataset:
Final results of a phase II trial of first-line FOLFIRINOX for advanced gastroesophageal cancers.
Authors: Ramon Jin, Haeseong Park, Andrea Wang-Gillam, Rama Suresh, Caron E. Rigden, Manik A. Amin, Benjamin R. Tan, Katrina Pedersen, Kian-Huat Lim, Nikolaos Trikalinos, Abhi Acharya, Megan Copsey, Katie Navo, Ashley Morton, Feng Gao, A. Craig Lockhart
Journal: Journal of Clinical Oncology (2020)

4532 Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have moderate clinical benefit with objective response rates (ORR) of approximately 40-50%. FOLFIRINOX has been shown to be an effective and well-tolerated first line therapy in other GI cancers. In this open-label, single-arm phase II study of patients with advanced gastroesophageal adenocarcinomas, we sought to evaluate the safety and clinical activity of FOLFIRINOX. Methods: The primary endpoint was ORR, and secondary endpoints included safety profile, progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Estimated sample size included 41 patients with HER2 negative disease with 90% power to detect an ORR≥60% with alpha of 0.10. No enrollment goal was planned for HER2 positive patients, but they were allowed participation to receive study treatment in combination with trastuzumab. Treatment consisted of 400mg/m2 5-FU bolus, 400 mg/m2 leucovorin, 2400 mg/m2 5-FU infusion over 46 hours, 180 mg/m2 irinotecan, and 85 mg/m2 oxaliplatin. Trastuzumab was administered intravenously as a 6 mg/kg loading dose then given 4 mg/kg every 14 days for HER2 positive patients. This trial is registered with ClinicalTrials.gov, NCT01928290. Results: From November 2013 to May 2019, 67 patients were enrolled, of which 26 (39%) had HER2 positive disease. Median follow-up was 16.1 months. ORR was 61% (25/41) for HER2 negative and 85% (22/26) for HER2 positive groups. Overall, one patient (2%) had a complete response, 36 patients (69%) had partial responses, and 13 patients (19%) had stable disease for &gt;6 months; therefore, CBR was 96%. Median PFS was 11.9 months, median OS was 17.4 months. 41 patients (83.7%) had dose modification or treatment delay with the most common toxicities being neutropenia, diarrhea, peripheral sensory neuropathy, and nausea with no unexpected toxicities. Conclusions: FOLFIRINOX is a highly effective three-drug regimen for first-line treatment of advanced gastroesophageal cancer with expected, tolerable toxicities. Clinical trial information: NCT01928290 .
深静脉血栓的康复预防与康复治疗
Authors: 励建安
Journal: BMJ (2008)

深静脉血栓形成(DVT)是临床常见问题,尤其是长期制动的患者.DVT不仅给患者带来痛苦,而且也严重影响患者的功能恢复和康复治疗,甚至危及生命.本文简要介绍制动对DVT的影响,DWT的康复预防和康复治疗。
Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).
Authors: Manuel Ricardo Espinoza Gutarra, Nasser H. Hanna, Lawrence H. Einhorn, Nabil Adra
Journal: Journal of Clinical Oncology (2020)

e19053 Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p &lt; 0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P &lt; 0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]
Modulation of inhibitory signals in CAR T cells leads to improved activity against glioblastoma.
Authors: Khaled Sanber, Zeid Nawas, Vita Salsman, Ahmed Gad, Pretty Matthew, Ciaran Lee, Sujith Joseph, Nabil Ahmed, Meenakshi Hegde
Journal: Journal of Clinical Oncology (2020)

3031 Background: Early clinical trials have demonstrated the safety of chimeric antigen receptor (CAR) T cells targeting glioblastoma (GBM), however, their efficacy remains limited by multiple obstacles including the immunosuppressive tumor microenvironment. Adoptively transferred CAR T cells remain susceptible to inhibition via the engagement of co-inhibitory receptors on their surface such as PD1, BTLA, CTLA4 and LAG3. The subsequent recruitment of Src homology region 2 containing protein tyrosine phosphatase 2 (SHP2) by these receptors to the immune synapse may represent a common mechanism of T cell inhibition, as SHP2 can de-phosphorylate key signaling molecules that mediate T cell activation (including CD28 and CD3ζ). We hypothesized that SHP2 deletion will simultaneously offset the effects of multiple co-inhibitory receptors, thereby improving the anti-tumor activity of CAR T cells. Methods: Electroporation of sgRNA/Cas9 ribonucleoprotein complexes into human T cells was used to knockout (KO) SHP2. Retroviral vector transduction was used to express a clinically-utilized second generation CAR (with a CD28 endodomain) targeting HER2. The phenotype of wild-type (WT) and SHP2 KO CAR T cells was evaluated with mass cytometry and flow cytometry. Their anti-tumor function was tested in vitro using the xCELLigence assay (an impedance-based cytotoxicity assay), and in vivo, in an orthotopic xenograft mouse model of GBM. Results: Efficient and reproducible depletion of the SHP2 protein in human T cells was verified using western blotting. The Inference of CRISPR Efficiency (ICE) Assay confirmed efficient editing of the PTPN11 gene encoding SHP2. An anti-HER2 CAR was efficiently expressed in the SHP2 KO T cells. SHP2 deletion did not significantly affect CAR T cell expansion, proliferation or baseline phenotype. However, following co-culture with HER2+ LN229-GBM cells, the CD8+ central memory (CCR7+ CD45RA-) and effector memory (CCR7- CD45RA-) subsets were enriched to a greater extent in the SHP2 KO CAR T cells. The pattern of cytokine co-expression varied between donors in a single-cell analysis comparing SHP2 KO to WT CAR T cells after encountering LN229 cells. Functionally, SHP2 KO CAR T cells derived from the majority of healthy donor and patient peripheral blood eliminated LN229 cells more rapidly in vitro. In an orthotopic mouse model of GBM, SHP2 KO CAR T cells showed better early control of established LN229 xenografts and improved survival in comparison to WT CAR T cells. Conclusions: SHP2 deletion in CD28ζ.CAR T cells improves their anti-tumor activity.
Phase Ib study of olinvacimab (O) with pembrolizumab (P) in patients with recurrent glioblastoma (rGBM).
Authors: Anna K. Nowak, Lawrence Cher, Samantha Bowyer, Hui Kong Gan, Anne Poh Long, Adithya Balasubramanian, Seon Young Lee, Weon Sup Lee, Jin-San Yoo
Journal: Journal of Clinical Oncology (2020)

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose level 1) or O 16mg/kg day 1/8/15 q21d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Pts were reviewed weekly and underwent DCE-MRI at baseline and 6-weekly. Treatment continued to progression, toxicity or withdrawal. Results: 9 pts, median age 53 (range 34-67) were recruited and received at least one study treatment. Median time since diagnosis was 15.6 months. 7 (78%) had KPS 90 and 2 (22%) KPS 80. 3 pts received O 12mg/kg with P, completing a median 3 cycles (range 2-6). As no Dose Limiting Toxicities (DLTs) were seen, 3 pts were treated with O 16mg/kg with expansion total 6 when no DLTs were observed. At 16mg/kg, a median of 2 treatment cycles was received (range 2-6). Treatment was ceased due to progressive disease (PD) in 8 pts with one ongoing at data cutoff. No DLTs were observed in any pts. Three grade 3 treatment emergent adverse events (TEAEs) were noted (blurred vision, fatigue, and seizure). Hemangioma is a known toxicity of O and was seen in 6 pts, with 11 grade 1 and 1 grade 2 event. 4 pts (44%) had stable disease (SD) and 5 pts (56%) had PD as best response. Conclusions: The combination of O with P was safe and tolerable at the full single agent dose of each drug. No DLTs were observed. The combination did not show efficacy in this setting. Clinical trial information: NCT03722342.
Observational cross-sectional study evaluating the sociodemographic and clinical characteristics of patients with metastatic melanoma harboring a BRAF V600 mutation, treated with cobimetinib and vemurafenib based on routine clinical practice.
Authors: Maria Carmen Álamo de la Gala, Sebastian Ochenduszko, Guillermo Crespo, Monica Corral, Juana Maria Oramas Rodriguez, Maria Pilar Sancho, Javier Medina, Fernando Garicano Goldaraz, Pedro López Leiva, Begona Campos Balea, Analia Adela Rodriguez, Eva Muñoz-Couselo
Journal: Journal of Clinical Oncology (2020)

e22028 Background: The drug combination of BRAF inhibitors with MEK inhibitors delays the onset of resistance and enhances apoptosis. Objectives: The main objective was to evaluate the percentage of long responders to the combination therapy. Methods: Participants were patients with advanced melanoma harboring a BRAF V600 mutation, who received Cobimetinib + Vemurafenib as first line, and who started treatment at least 12 months before inclusion. Patients were classified as long responders (patients who have reached at least 12 months of objective response -complete response CR/ partial response PR- to the treatment) or non-responders. Sociodemographic, anthropometric, clinical characteristics, baseline tumor characteristics and treatment dose modification were compared between long responders and non-responders. HADS scale, WPAI-GH and SMAQ questionnaires were used to evaluate the anxiety and depression, productivity and treatment compliance respectively, in patients under active treatment at the moment of the study visit. Results: 41 patients were evaluated. Mean (±SD) age was 57.8 (14.0) years. 56.1% were male. Almost one third of the population (29,3%) was classified as long responder. There were no statistically significant differences in the baseline tumor characteristics, demographic data nor in the clinical characteristics neither in treatment dose modification. CR was the best response achieved by 29.3% of patients, 46.3% achieved PR and 12.2% SD (stable disease). Mean of time to response was 6.9 months for CR patient, and 3.3 and 2.2 months for PR and SD patients respectively. Mean of duration of response was 9.4 months for CR patients, and 10.1 and 9.5 months for PR and SD patients respectively. 42.5% of Adverse Events (AEs) were related with the combination treatment. In the 68.5% of AEs the severity was mild, and in 19.4% moderate. In most cases no action was taken (74.9%) and the outcome was recovered (83.4%). Conclusions: Vemurafenib and Cobimetinib have an important impact in long term survival, leading to a steady complete response in one third of the patients.
Dynamic changes of lymphocyte subsets during multimodal treatment of patients with inoperable stage III NSCLC.
Authors: Thomas Philipp Hofer, Lukas Käsmann, Carolyn Pelikan, Saloni Mathur, Chukwuka Eze, Monika Karin, Julian Taugner, Olarn Roengvoraphoj, Claus Belka, Elfriede Noessner, Farkhad Manapov
Journal: Journal of Clinical Oncology (2020)

e21011 Background: Lymphocytopenia is associated with deterioration of patient survival in solid cancers treated with concurrent chemo/radiotherapy (cCRT). A prospective analysis of peripheral blood mononuclear cells during cCRT in inoperable stage III NSCLC patients was performed to determine dynamic changes of individual lymphocyte subsets. Methods: Twenty-one patients were prospectively enrolled in this study. Eighteen patients received platinum-based cCRT, seven of them received, additionally, concurrent and/or sequential immune checkpoint-inhibition (ICI). Thoracic irradiation (TRT) was delivered with median total dose of 62Gy (31 daily fractions of 2Gy) in all patients. Peripheral blood was collected 5-10 days before treatment (A1), three weeks after start of cCRT (A3), on the last day of TRT (RTend) and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for time-points A1, A3 and RTend. Results: Sixteen patients met final analysis criteria, 50% of them received concurrent and/or sequential ICI. All patients developed severe lymphocytopenia; in 81% of them lymphocyte nadir was documented at A3. Lymphocyte subsets, B cells, T cells (CD4, CD8), regulatory T cells, and NK cells, decreased with medians between 99.9% and 59%. Lymphocyte nadir was independent of the absolute numbers of immune cells that a patient had before start of cCRT or whether additional ICI was applied. From A3 to RTend, all lymphocyte subsets started to recover in patients treated with cCRT alone, while they remained low in patients who received additional ICI. The ratios of CD4/CD8 and CD8/Treg cells did not change during treatment (A1 to RTend) and was not different between the patients treated with or without ICI. However, the fraction of PD-1 cells among CD8 T-cells decreased in patients treated with ICI and remained low until RTend (range 0.55%-13.8%). In contrast, in 50% of patients treated with cCRT alone, PD-1 T-cell among CD8 T-cells increased and remained high (range 6.8%-46.3%) until RTend. Conclusions: Delayed recovery of lymphocyte subsets in peripheral blood was observed in patients treated with cCRT combined with concurrent or sequential ICI. A decrease of PD-1 T-cells among CD8 T-cells was described exclusively in patients treated with additional ICI.
Effect of access to care on outcomes of rural and elderly patients with primary central nervous system lymphoma.
Authors: Scott C. Howard, Nicholas Napier, Xueyuan Cao, Ryan Combs, Mark Layton Watson, Catherine Lam
Journal: Journal of Clinical Oncology (2020)

e14008 Background: Primary central nervous system lymphoma (PCNSL) can often be cured, especially in younger patients, but requires intense chemotherapy with high-dose methotrexate (HDMTX) and rituximab to optimize outcomes. Toxicities can lead to dose reduction or omission that may increase relapse risk, or lead clinicians to select less effective regimens that do not contain HDMTX. Methods: Anonymized, de-identified data of patients from 110 community oncology practices of the Guardian Research Network (GRN, www.GuardianResearch.org ) was analyzed to determine treatments, toxicities, and outcomes of adults with PCNSL. All data from the medical record is available from GRN (diagnoses, demographics, labs, medicines, toxicities, radiology, pathology, procedures, and encounters), so each patient’s journey can be fully characterized. Results: Of 533805 adults with cancer, 49 were treated for PCNSL with HDMTX-containing regimens (n = 35), other chemotherapy regimens (n = 3), or radiation therapy (RT) alone (n = 11). HDMTX patients received HDMTX only in 8 cases, HDMTX plus rituximab in 23 cases, addition of RT in 11 cases, and HDMTX with other chemotherapy but no rituximab in 3 cases. Survival at 5 years was 53% (standard error [SE] 8.6%) for patients treated with HDMTX versus 33% (SE 13%) for those treated with other therapies. Of those treated with HDMTX, survival was 0% for patients who experienced early toxicity that required cessation of HDMTX prior to receiving 3 doses and having response evaluated versus 62% (SE 9.1%) for patients who received 3 or more courses of HDMTX (p &lt; 0.001). In a multivariable Cox proportional hazards model including completion of at least 3 doses of HDMTX, age, race, and sex, only lack of HDMTX toxicity was associated with survival (hazard ratio 0.22, 95% confidence interval 0.07 to 0.70, p = 0.01). Conclusions: Use of HDMTX and prevention of toxicity improves outcomes for PCNSL patients treated in the community.
Efficacy and safety of CT-guided percutaneous catheter drainage in treatment of uniloculated deep neck abscesses
Authors: Juebo Yu, Zexing Cheng, Zhuang Lian, Yiling Wei, Mingjun Zhao
Journal: BMJ (2017)

Twenty-three patients with uniloculated deep neck abscesses(UDNA), in whom the antibiotic therapy failed and CT-guided percutaneous catheter drainage (PCD) was performed from January 2005 to June 2015, were included in the study.Catheter placement was carried out using Trocar technique in all cases.Open surgical drainage was performed when PCD procedures failed.The abscess was completely drained and open surgical drainage was avoided in 19 cases (83%); the surgical drainage was performed because of multiple internal septation in 3 (13%) case, and 1 (4%) case died from uremia.In this series the technical success rate and clinical success rate of PCD were 96% (22/23) and 83%(19/23), respectively.All patients were followed-up by CT scan.No other complications and no mortality occurred during the procedure, while postoperative pneumatosis developed in 1 case.CT-guided PDC is a safe and highly effective low-cost procedure for the treatment of patients with UDNA who failed medical therapy, it may be considered as an alternative to open surgery.


Key words: 
Abscess, deep neck; Diabetes mellitus; Drainage, CT-guided
Combinatorial expression of androgen receptor splice variants: No predictive value in castration-resistant prostate cancer patients treated with enzalutamide (enza) or abiraterone (abi).
Authors: Katrin Schlack, Konstantin Seitzer, Martin Boegemann, Laura-Maria Krabbe, Andres Jan Schrader, Norbert Grundmann, Dorothee Tiedje, Julie Steinestel, Christof Bernemann
Journal: Journal of Clinical Oncology (2020)

e17547 Background: Playing an important role in prostate cancer, androgen receptor (AR) signaling is a common therapeutic target. Novel hormonal treatment (NHT) using enza or abi prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, biomarkers predicting therapy response are limited. AR-V7, as the most abundant AR splice variant, has gained clinical interest. Nonetheless, current discussions on its predictive power are diverse. Given that AR-V7 as a sole biomarker is not efficient in predicting response to NHT, we aimed to increase the predictive potential by analysis of combinatorial AR splice variant (AR-V) expression in mCRPC patients undergoing NHT. Methods: We prospectively enrolled 60 patients who started on either abi or enza. Presence of circulating tumor cells (CTC) as well as expression of AR-V3, -7 and -9 were assessed. Outcomes in CTC-, CTC+/AR-V- and CTC+/AR-V+ patients were analyzed considering PSA reduction, PSA-PFS, PFS and OS. Results: PSA reduction of 50% was predominantly found in CTC- patients (78.5%) compared to CTC+/AR-V- (55.5%) and CTC+/AR-V+ (39.3%) without statistical significance (P = 0.059). When taking co-expression of two or more AR-V into account there was no difference in PSA response either (one AR-V 42.9%, two AR-V 33.3%, three AR-V 41.6%, P = 0.154). Median PSA-PFS was 17 months (95%CI 15.7 – 18.3), 13 months (95%CI 6.8 – 19.2) and 5 months (95%CI 3.6 – 6.4) for CTC- pts, CTC+/AR-V- pts and CTC+/AR-V+ pts, respectively (P = 0.005). However, comparing CTC- and CTC+ pts, differences become even more apparent (P = 0.004), CTC+/AR-V- and AR-V+ pts showed less statistically significant differences (P = 0.029). Median PFS and OS were not reached for CTC- pts. PFS was 10 months (95%CI 6.2 – 13.8) for CTC+/AR-V- pts and 9 months (95%CI 1.1 – 16.9) for CTC+/AR-V+ pts (P = 0.004, only CTC- vs. CTC+ P = 0.002). OS was 28 months (95%CI 16.8 – 39.2) for CTC+/AR-V- pts and 15 months (95%CI 7.9 – 22.1) for CTC+/AR-V+ pts (P = 0.014, only CTC- vs. CTC+ P = 0.006). Regarding PFS and OS, there was no difference comparing only CTC+/AR-V- and AR-V+ pts (P = 0.356 and P = 0.244). Conclusions: AR splice variants have prognostic power in stratifying mCRPC patients suffering from a more advanced stage of disease. Nonetheless, our study clearly demonstrates the lack of predictive power of AR splice variants for response to NHT. Additionally, we prove the importance of CTC analysis rather than AR-V expression being more valuable in mCRPC.