tbuckley/cabot-search huggingface dataset:
Dynamic Bioinks to Advance Bioprinting
Authors: Francis L. C. Morgan, Lorenzo Moroni, Matthew B. Baker
Journal: Advanced Healthcare Materials (2020)

Abstract The development of bioinks for bioprinting of cell‐laden constructs remains a challenge for tissue engineering, despite vigorous investigation. Hydrogels to be used as bioinks must fulfill a demanding list of requirements, mainly focused around printability and cell function. Recent advances in the use of supramolecular and dynamic covalent chemistry (DCvC) provide paths forward to develop bioinks. These dynamic hydrogels enable tailorability, higher printing performance, and the creation of more life‐like environments for ultimate tissue maturation. This review focuses on the exploration and benefits of dynamically cross‐linked bioinks for bioprinting, highlighting recent advances, benefits, and challenges in this emerging area. By incorporating internal dynamics, many benefits can be imparted to the material, providing design elements for next generation bioinks.
Influence of node-positive disease after radical prostatectomy on biochemical recurrence and oncologic outcomes in men with prostate cancer.
Authors: Samuel L. Washington, Janet E. Cowan, Annika Herlemann, Kyle Brian Zuniga, Peter Carroll
Journal: Journal of Clinical Oncology (2020)

306 Background: The diagnostic and therapeutic value of pelvic lymph node dissection (LND) at radical prostatectomy (RP) remains unclear. Thus, we aim to characterize the oncologic value of LND and secondary treatment on oncologic outcomes for a contemporary cohort of men with nodal disease on surgical pathology at RP. Methods: Men who underwent primary RP with LND for PCa were identified and stratified by pN status. Detectable PSA was defined as a PSA&gt;0.05 ng/ml within 2-6 months after RP. Multivariable Cox proportional hazards regression models were fit for biochemical recurrence-free survival (RFS), overall survival (OS), and PCa-specific mortality (PCSM). Results: Of 1,635 identified patients, 167 (10.2%) had nodal disease. Mean age at diagnosis was 62 years (SD 7.1). Median follow-up after RP was 31 months (IQR 13-58). Those with nodal disease had more extensive LND (mean 17.7, SD 8.3 vs mean 13, SD 7.6, p&lt;0.01). The number of positive LNs was associated with worse 7-year outcomes [RFS, HR 1.2, 95% CI 1.1-1.2, p&lt;0.01; OS, HR 1.2, 95% CI 1.1-1.4, p&lt;0.01] but not PCSM (p=0.2) after adjustments. Median number of positive LN was 1 (IQR 1, 3) in pN1 patients. 31 (19%) had an UDT PSA after RP, 25 (15%) had UDT PSA and received adjuvant therapy, and 106 (66%) had a detectable PSA. On multivariable analysis, number of positive LNs (HR 1.1, 95% CI 1.0-12, p=0.02) and detectable PSA (vs UDT, HR 5.1, 95% CI 1.8-14.3, p&lt;0.01) were associated with increased risk of recurrence after RP but not OS (p&gt;0.05 for all). After salvage treatment, 7-year RFS, OS, and PCSM did not differ significantly between the groups (p&gt;0.05 for all). Conclusions: In a contemporary cohort of men with pN1 disease, more extensive LND was not associated with improved outcomes. Amongst those who underwent secondary treatment after RP, UDT PSA after RP conferred greater biochemical recurrence free survival at 7 years. In this subset of men, adjuvant treatment was not associated with improved post-salvage biochemical or treatment-free survival. Further investigation into the potential therapeutic benefit of LND at RP is warranted to better estimate the potential risk overtreatment of men with nodal disease.
Adjuvant Chemotherapy With Etoposide Plus Cisplatin for Patients With Pathologic Stage II Nonseminomatous Germ Cell Tumors
Authors: Deaglan J. McHugh, Samuel A. Funt, Deborah Silber, Andrea Knezevic, Sujata Patil, Devon O’Donnell, Stephanie Tsai, Victor E. Reuter, Joel Sheinfeld, Brett S. Carver, Robert J. Motzer, Dean F. Bajorin, George J. Bosl, Darren R. Feldman
Journal: Journal of Clinical Oncology (2020)

The relapse rate after primary retroperitoneal lymph node dissection (RPLND) for patients with pathologic stage (PS) IIA nonseminomatous germ cell tumors (NSGCTs) is 10%-20% but increases to ≥ 50% for PS IIB disease. We report our experience with 2 cycles of adjuvant etoposide plus cisplatin (EP×2) after therapeutic primary RPLND.
Prevalence, Incidence, and Risk of Cancer in Patients With Psoriasis and Psoriatic Arthritis
Authors: Sofie Vaengebjerg, Lone Skov, Alexander Egeberg, Nikolai Dyrberg Loft
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> The association between psoriasis and risk of cancer remains debatable. <h3>Objective</h3> To evaluate the association and risk of cancer in patients with psoriasis or psoriatic arthritis, including risk of specific cancer subtypes. <h3>Data Sources</h3> Two databases (PubMed and Embase) were screened from inception to January 1, 2019, using the search string<i>psoriasis</i>or<i>psoriatic</i>and<i>neoplasms</i>or<i>malignancy</i>or<i>cancer</i>. The search was filtered to only include human participants and publications in English. <h3>Study Selection</h3> Observational cohort studies with a population of patients with psoriasis or psoriatic arthritis were included. Studies had to be original and report the incidence or prevalence of cancer within this population. Studies evaluating pediatric populations and cancer types not included in the protocol were excluded. <h3>Data Extraction and Synthesis</h3> This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The search string, objectives, and study protocol methods were defined before the study was initiated. A total of 365 studies were included for full-text assessment. Owing to the heterogeneity of the included studies, a random-effects model was used. <h3>Main Outcomes and Measures</h3> Main outcome was cancer (overall and specific subtypes) and measures were prevalence, incidence, and risk estimate for cancer in patients with psoriasis or psoriatic arthritis. <h3>Results</h3> Of the 365 studies assessed, 112 were included in the analysis (N = 2 053 932 patients). The overall prevalence of cancer in patients with psoriasis was 4.78% (95% CI, 4.02%-5.59%), with an incidence rate of 11.75 per 1000 person-years (95% CI, 8.66-15.31) and a risk ratio (RR) of 1.21 (95% CI, 1.11-1.33). There was an increased risk of several cancers, including keratinocyte cancer (RR, 2.28; 95% CI, 1.73-3.01), lymphomas (RR, 1.56; 95% CI, 1.37-1.78), lung cancer (RR, 1.26; 95% CI, 1.13-1.40), and bladder cancer (RR, 1.12; 95% CI, 1.04-1.19). No increased risk of cancer for patients with psoriasis treated with biologic agents was found (RR, 0.97; 95% CI, 0.85-1.10). Psoriatic arthritis was not associated with increased risk of cancer overall (RR, 1.02; 95% CI, 0.97-1.08). <h3>Conclusions and Relevance</h3> Patients with psoriasis appear to have a slightly increased risk of cancer, particularly keratinocyte cancer and lymphomas. Data on treatment with biologic agents did not show an increased risk of cancer. Data on cancer in patients with psoriatic arthritis remain scarce, and further research is warranted in this area.
Preliminary results on mechanisms of resistance to ALK inhibitors: A prospective cohort from the MATCH-R study
Authors: G. Recondo, L. Mezquita, L. Bigot, J. Galissant, R.L. Frias, F. André, C. Massard, J.-C. Soria, B. Besse, L. Friboulet
Journal: Annals of Oncology (2018)

Background: ALK tyrosine kinase inhibitors (TKIs) have shown to be effective in the treatment of patients with ALK rearranged NSCLC. The clinical benefit is eventually limited by the acquisition of resistance to ALK TKIs by tumor cells. The study of the biological mechanisms implied in tumor progression can provide the rational for therapeutic strategies to overcome resistance. Methods: In the MATCH-R prospective study, patients with unresectable or metastatic cancer were included upon acquired resistance to targeted therapies or immunotherapy, defined as progressive disease after partial or complete response or stable disease for 6 months. Upon progression tumor biopsy is performed and serial blood samples are collected. Targeted NGS, CGH, WES and RNAseq were performed on the tissue, and PDX models and patient derived cell lines were established to fully profile the underlying mechanisms of resistance. Results: From June 29th 2015 and as of June 15th 2018, 309 patients were included of which 139 (45%) had advanced lung adenocarcinoma and n = 10 (7.2%) had tumors with ALK rearrangements. In 2 patients, multiple biopsies were taken upon progression to sequential treatments with ALK TKI. Evaluable tumor biopsies were taken upon progression to treatment with crizotinib (n = 3), ceritinib (n = 1), brigatinib (n = 2), lorlatinib (n = 5). PDX models/patient derived cell lines (n = 4) were developed from 2 patients. Mechanisms of resistance: Secondary mutations (n = 5), pathway bypass (n = 3), other non-genetic (n = 3). Novel compound mutations implied in resistance to lorlatinib were characterized by infecting BA/F3 cells with EML4-ALK V3 mutated lentiviral vectors, together with the characterization and reversion of a novel bypass mechanism. We also studied therapeutic strategies aiming at reverting resistance driven by EMT in patient derived cell lines treated with lorlatinib. Conclusions: Mechanisms of resistance were identified in 9 out of 11 tumors from patients with ALK rearranged NSCLC. The development of patient derived cell lines provides further information on how to overcome the resistance to ALK inhibitors. Clinical trial identification: NCT02517892. Legal entity responsible for the study: Gustave Roussy Cancer Campus. Funding: Natixis, European Research Council (ERC), Foundation Nelia et Amadeo Barletta. Disclosure: F. André: Research grants from Novartis. J-C. Soria: Full-time employee of MedImmune. B. Besse: Institutional grants for clinical and translational research from AstraZeneca, BMS, Boehringer-Ingelheim, Inivata, Lilly, Loxo, OncoMed, Onxeo, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, and OSE Pharma. All other authors have declared no conflicts of interest.
A phase II study of M6620 in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.
Authors: Atish Dipankar Choudhury, Wanling Xie, Mamta Parikh, Daniel Lee, Elizabeth R Kessler, David Johnson Einstein, Bose Kochupurakkal, Kent William Mouw, Eliezer Mendel Van Allen, L. Austin Doyle, Alan D. D'Andrea, Mary-Ellen Taplin, Geoffrey Shapiro
Journal: Journal of Clinical Oncology (2020)

TPS5597 Background: Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the DNA damage response, and ATR inhibitors have been demonstrated in preclinical models to have synergistic activity with platinum compounds due to induction of replication stress. Methods: This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC. Patients (pts) previously treated with at least one secondary hormonal therapy and taxane-based chemotherapy undergo mandatory pre-treatment biopsy and are randomized 1:1 to receive Arm A (docetaxel 60 mg/m2 day 1 + carboplatin AUC 4 day 1) or Arm B (M6620 90 mg/m2 days 2,9 + carboplatin AUC 5 day 1) every 21 days. Pts randomized to Arm A who are not candidates for docetaxel receive carboplatin AUC 5 monotherapy. Stratification factors are 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossover to Arm B (M6620+carboplatin) at the earlier of PSA or radiographic progression. For the primary endpoint of overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1), with 65 pts on each arm (total N = 130), there will be 80% power to distinguish ORR of 40% vs. 20% using a chi-square test (one sided α = 0.05). 136 pts will be enrolled to account for 5% dropout. Secondary endpoints include time to PSA progression, radiographic PFS, PFS by PCWG3 criteria, safety and adverse events in each arm. Biomarker studies include whole exome sequencing, RAD51 focus formation, and ATM IHC from tumor specimens. Circulating cell-free DNA from pre-treatment and progression plasma specimens will undergo ultra-low pass whole genome sequencing and deep targeted sequencing. The goal of this study is to expand therapeutic options in mCRPC through a novel approach to targeting the DNA damage response, and to identify biomarkers associating with response and resistance to both standard and trial therapy. Enrollment began June 2019 (NCI/ETCTN #10191, NCT03517969). Clinical trial information: NCT03517969 .
Genetic analysis of the separate morphologic components in combined small cell lung cancer.
Authors: Hongyang Lu, Zhiqiang Ling, Qiao-Yuan Cheng, Bo Chen, Ju-Fen Cai, Wang Xiao Jia, Lei Lei, CaiJin Lou, Jing Qin, Wei-Wu Ye, Weimin Mao
Journal: Journal of Clinical Oncology (2013)

7590 Background: Combined small cell lung cancer (CSCLC) is currently considered a subset of SCLC and have been reported to account for less than 1-3.2% of all SCLCs. Accurate understanding of CSCLCs is of great importance because treatment strategies are significantly different for NSCLC and SCLC. To address molecular features of different components in CSCLC we analyzed mutation status in CSCLC tumor samples in EGFR signal pathway. Methods: Seven CSCLC samples were included in direct sequencing for mutation analysis of EGFR, KRAS, PIK3CA, BRAF, and PTEN. Results: Mutations were detected in 4 of 7 (57.1%) CSCLC patients. EGFR Exon 18 mutations were identified in two patients among whom the mutation was identified in both adenocarcinoma component and SCLC combined adenocarcinoma component of one patient. The similar situation also happened in another one with PTEN C511T mutations both conventional SCLC component and SCLC combined adenocarcinoma component. Both KRAS and PIK3CA were detected in one SCLC combined adenocarcinoma patient and no mutation in BRAF was identified. Conclusions: Our result is consistent with previous work that the individual components of CSCLC are closely related, despite their distinct morphologic appearances.
Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.
Authors: Jonathan E. Rosenberg, Thomas W. Flaig, Terence W. Friedlander, Matthew I. Milowsky, Sandy Srinivas, Daniel Peter Petrylak, Jaime R. Merchan, Mehmet Asim Bilen, Anne-Sophie Carret, Nancy Yuan, Carolyn Sasse, Christopher J. Hoimes
Journal: Journal of Clinical Oncology (2020)

441 Background: Platinum chemotherapy is the standard for patients (pts) with metastatic urothelial carcinoma (mUC) in the first line (1L) setting. In cisplatin-ineligible pts, gem/carbo is a standard therapy, but is poorly tolerated with limited durability and survival. PD-1/PD-L1 inhibitors, such as pembrolizumab (P), have shown promising durability in this setting for PD-L1 high patients. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4, which is highly expressed in UC. EV has shown activity in previously treated mUC. Initial EV + P data were previously presented (Hoimes ESMO 2019); this provides first durability data and an update on safety/ORR. Methods: This multicohort study (NCT03288545) evaluated the safety/activity of EV + P. We report a cohort of 1L cis-ineligible patients treated with EV 1.25 mg/kg + P. In each 3-week cycle, EV was administered on Days 1 and 8 and P on Day 1. The primary endpoint was safety/tolerability; secondary objectives included determination of recommended EV dose, ORR, DCR, DOR/PFS per RECIST v1.1, and OS. Results: As of 8 Oct 2019, 45 mUC pts (median age 69 yr [51–90]) received a median of 9 (range 1-22) cycles of EV + P. The most common treatment-emergent adverse events (AE) were fatigue (58%, 11% ≥G3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% ≥G3). One pt died due to an AE reported as related (multiple organ failure). With a median follow-up of 11.5 mo, confirmed investigator-assessed ORR was 73.3% (95% CI, 58.1, 85.4) including 15.6% CRs; DCR was 93.3%. The ORR in pts with liver metastasis was 53.3% (8/15). The ORR in pts with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). Of the 33 responders, 18 (55%) have ongoing responses including 11 responses beyond 10 months. The median DOR was not reached (range 1.2 to 12.9+ mo). The median PFS was 12.3 mo (95% CI, 7.98, -). Conclusions: In 1L cis-ineligible pts with mUC, EV + P, a potential platinum free option, demonstrates promising activity and durability, with a manageable safety profile. Further evaluation of EV + P in mUC and muscle-invasive UC is ongoing. Clinical trial information: NCT03288545.
Real-world prognostic model for overall survival (OS) in patients (pts) with advanced urothelial cancer (aUC) treated with immune checkpoint inhibitors (ICI).
Authors: Ali Raza Khaki, Leonidas Nikolaos Diamantopoulos, Natalie J. Miller, Mehmet Asim Bilen, Victor Sacristan Santos, Rafael Morales-Barrera, Michael Edward Devitt, Ariel Ann Nelson, Evan Shreck, Hussein Assi, Roubini Zakopoulou, Alejo Rodriguez-Vida, Mark Lythgoe, Alexandra Drakaki, Monika Joshi, Pedro Isaacsson Velho, Lucia Alonso, Matt D. Galsky, Guru Sonpavde, Petros Grivas
Journal: Journal of Clinical Oncology (2020)

447 Background: While ICI prolong OS after platinum chemotherapy in aUC, outcomes vary based on clinical confounders. We aimed to develop a prognostic model in pts receiving ICI in a non-clinical trial setting. Methods: We used a hypothesis driven approach of clinician selected covariates to develop a new prognostic model. Data source was a retrospective cohort of pts treated with ICI at 19 institutions. Demographics, clinicopathologic data, treatment patterns, and OS were collected. Univariate (UVA) Cox regression was done on 24 variables hypothesized to be associated with OS. Variables were retained for multivariate analysis (MVA) if they had statistical relationship with OS (p&lt;0.2) and were included in the final model if p&lt;0.05 on MVA. Each retained covariate was assigned 1 point in the final prognostic model. Stratified median OS and c-statistic were calculated. Results: 415 pts with mean age 69, 26% female, 66% ever smokers, 69% pure UC, 15% upper tract UC, 54% with prior extirpative surgery, Bellmunt risk factors 17%, 51%, 28% and 4% for 0, 1, 2, 3, respectively were included. Non-White race, ECOG PS≥1, albumin&lt;3.5g/dL (lower limit of normal), hemoglobin&lt;10g/dL, absolute neutrophil count (ANC)&gt;8x10 6 /ul (upper limit of normal), and presence of bone or liver metastases (mets) were all associated with worse OS on UVA Cox regression; albumin&lt;3.5 g/dL, ANC&gt;8x10 6 /uL, presence of bone or liver mets remained significant on MVA and were included in the prognostic model. Median (m)OS by new model and Bellmunt are shown in table. C-statistic of the new model was 0.67. Conclusions: Albumin&lt;3.5 g/dL, ANC &gt;8x10 6 /ul, presence of bone or liver mets were negative prognostic factors in pts with aUC treated with ICI. This has comparable features to recently reported 5-factor model using clinical trial data, including LDH (unavailable in our cohort). External validation is being pursued. The proposed model may be used for prognostication, clinical trial design, eligibility and stratification. [Table: see text]
Cost‐effectiveness of grass pollen allergen immunotherapy in adults
Authors: Danilo Di Bona, Massimo Bilancia, Marcello Albanesi, Maria Filomena Caiaffa, Luigi Macchia
Journal: Allergy (2020)

Abstract Background Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value. Objective To assess the cost‐effectiveness of AIT for grass pollen, administered as SCIT or SLIT. Methods We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate‐to‐severe rhino‐conjunctivitis with or without allergic asthma, the cost‐effectiveness of SLIT (tablets, Grazax ® and Oralair ® ) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9‐year horizon to capture AIT long‐term effects. The incremental cost‐effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator. Results In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost‐effective option (ICER for SCIT, €11 418; ICER for SLIT, €15 212). ICERs greater than €120 000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real‐life, lead to absence of long‐term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost‐effective than SCIT (ICER for SCIT, €17 318; ICER for SLIT, €15 212). Conclusion In daily practice, AIT for grass pollens may be a cost‐effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost‐effective AIT form.
A novel sensitization cluster associated with barrier dysfunction and worse clinical outcomes in children with atopic dermatitis: the Mechanisms of Progression from Atopic Dermatitis to Asthma in Children (MPAACH) cohort.
Authors: Michael Sherenian, Arjun Kothari, Jocelyn Biagini Myers, John Kroner, Hanna Johannson, Asel Baatyrbek Kyzy, Gowtham Alturi, Hua He, Lisa Martin, Gurjit Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2020)