tbuckley/cabot-search huggingface dataset:
Detection of FGFR3 alt in plasma cfDNA in metastatic UC patients receiving Erda therapy.
Authors: Michal Sarfaty, Min Yuen Teo, Samuel Aaron Funt, Chung-Han Lee, David Henry Aggen, Neha Ratna, Ashley Marie Regazzi, Andrew Thomas Lenis, Ziyu Chen, Hikmat A. Al-Ahmadie, Angela Rose Brannon, Michael F. Berger, David B. Solit, Jonathan E. Rosenberg, Dean F. Bajorin, Gopa Iyer
Journal: Journal of Clinical Oncology (2021)

e16519 Background: The pan-FGFR inhibitor erdafitinib (erda) is FDA-approved for pretreated mUC pts harboring FGFR2/3 alterations. We explored concordance of FGFR3 alt profiles between primary tumor and cfDNA using the next generation sequencing assay MSK-ACCESS. We also correlated changes in FGFR3 cfDNA mutant allele fraction (MAF) with response to erda. Methods: After consent on an approved biomarker protocol, plasma samples were collected from mUC pts on erda at baseline, on treatment (tx), and at progression along with patient clinical characteristics. Baseline tumors were sequenced with MSK-IMPACT and plasma samples sequenced with MSK-ACCESS, a cfDNA platform that sequences select exons and introns of 129 genes and uses unique molecular indexes to detect somatic mutations down to 0.1% MAF. Results: Between 8/2019-12/2020, 18 pts started erda 8mg daily and had plasma drawn for MSK-ACCESS. Three pts increased to 9mg daily, 7 required dose reductions and 10 had dose interruptions. Treatment was discontinued in 13 pts for disease progression and 3 for toxicity. Median PFS was 3.7 months. FGFR3 S249C was the most frequent alt detected (11/18, 61%), then Y373C (3/18, 16%), and R248C (2/18, 11%) (Table). FGFR3 alt were detected in 15/18 (83%) baseline plasma samples, all of which were of the same alt as tumor tissues. In 3 samples, additional FGFR3 alt were detected, including 1 pt with an FGFR3-TACC3 fusion and hotspot mutations found only in cfDNA. FGFR3 MAF decreased in 7 of 9 pts on erda, 2 of whom declined to undetectable levels. Conclusions: A high degree of concordance of FGFR3 alt was observed between primary tumors and cfDNA. Most erda responders displayed reduction of FGFR3 cfDNA MAF. FGFR3 alts exclusive to cfDNA were found in a small subset of pts. Further pt accrual and follow-up are ongoing to assess for correlations between erda response/progression and changes in FGFR3 cfDNA MAF, and to assess whether cfDNA can identify resistance mechanisms.[Table: see text]
Novel magnetic silk fibroin scaffolds with delayed degradation for potential long-distance vascular repair
Authors: Xin Liu, Yuxiang Sun, Bo Chen, Yan Li, Peng Zhu, Peng Wang, Sen Yan, Yao Li, Fang Yang, Ning Gu
Journal: Bioactive Materials (2021)

Although with the good biological properties, silk fibroin (SF) is immensely restrained in long-distance vascular defect repair due to its relatively fast degradation and inferior mechanical properties. It is necessary to construct a multifunctional composite scaffold based on SF. In this study, a novel magnetic SF scaffold (MSFCs) was prepared by an improved infiltration method. Compared with SF scaffold (SFC), MSFCs were found to have better crystallinity, magnetocaloric properties, and mechanical strength, which was ascribed to the rational introduction of iron-based magnetic nanoparticles (MNPs). Moreover, in vivo and in vitro experiments demonstrated that the degradation of MSFCs was significantly extended. The mechanism of delayed degradation was correlated with the dual effect that was the newly formed hydrogen bonds between SFC and MNPs and the complexing to tyrosine (Try) to inhibit hydrolase by internal iron atoms. Besides, the β-crystallization of protein in MSFCs was increased with the rise of iron concentration, proving the beneficial effect after MNPS doped. Furthermore, although macrophages could phagocytose the released MNPs, it did not affect their function, and even a reasonable level might cause some cytokines to be upregulated. Finally, in vitro and in vivo studies demonstrated that MSFCs showed excellent biocompatibility and the growth promotion effect on CD34-labeled vascular endothelial cells (VECs). In conclusion, we confirm that the doping of MNPs can significantly reduce the degradation of SFC and thus provide an innovative perspective of multifunctional biocomposites for tissue engineering.
Differential immune-related microenvironment determines PD-1/PD-L1 blockade efficacy in advanced non-small cell lung cancer patients.
Authors: Masayuki Shirasawa, Tatsuya Yoshida, Yukiko Shimoda, Daisuke Takayanagi, Kouya Shiraishi, Takashi Kubo, Sachiyo Mitani, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Hitoshi Ichikawa, Takashi Kohno, Noboru Yamamoto, Shun-ichi Watanabe, Noriko Motoi, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2021)

9044 Background: Programmed death ligand-1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/anti-PD-L1 therapy in advanced non-small cell lung cancer patients (NSCLC). Immune-related tumor microenvironment (TME) is classified into four different types based on the status of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Methods: We retrospectively reviewed advanced NSCLC patients treated with anti-PD-1/anti-PD-L1 therapy between 2015 and 2019, and investigated the association between the efficacy of anti-PD-1/anti-PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, and the density of CD8-positive TILs by immunohistochemistry (/mm 2 ), and mutational profiles assessed by next-generation sequencing. Results: Overall, 228 patients without driver mutation ( EGFR, ALK, ROS1, and RET) were included in the analysis. The patients were classified into four following groups: Type I: PD-L1 High (tumor proportion score [TPS]≥50%)/TIL High (≥85/mm 2 ; n = 73), Type II: PD-L1 Low (TPS &lt; 50%)/TIL Low ( &lt; 85/mm 2 ; n = 70), Type III: PD-L1 High /TIL Low (n = 37), and Type IV: PD-L1 Low /TIL High (n = 48). The progression-free survival (PFS) and objective response rate (ORR) of anti-PD-1/anti-PD-L1 therapy clearly differed according to the different tumor microenvironment (TME) types (ORR and median PFS; Type I: 64%, 14.5 months, Type II: 12%, 2.1 months, Type III: 24%, 3.6 months, Type IV: 41%, 10.8 months). In patients with PD-L1 High tumors, Type I tumors had significantly better ORR and PFS than Type III (ORR: p &lt; 0.001, and PFS: p &lt; 0.001) tumors. Regarding the association between mutational profiles, histology and the TME types, the presence of TP53 mutation and KRAS mutation significantly related to TIL High (Type I and IV) and PD-L1 High tumors (Type I and III), respectively. Pleomorphic and NSCLC- not otherwise specified histology were associated with Type I tumors, while LCNEC was associated with PD-L1 low tumors (Type II and IV). Conclusions: Various factors (mutational profile and histology) are related to TME classification based on the status of TILs and PD-L1 expression. Differential types of TME, including PD-L1 expression and TILs status, can accurately predict the efficacy of anti-PD-1/anti-PD-L1 therapy.[Table: see text]
Final results of phase 1 evaluation of the safety and clinical activity of sapanisertib in combination with serabelisib and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.
Authors: David Starks, Luis Alexander Rojas-Espaillat, Nandini Dey, Pradip De, Brian Leyland-Jones, Casey B. Williams
Journal: Journal of Clinical Oncology (2021)

5569 Background: Evidence suggests that activation of the PI3K/AKT/mTOR pathway by paclitaxel may play a role in the development of taxane resistance. Conversely, PI3K inhibitors have been shown to sensitize tumors to the effects of paclitaxel. Therefore, the link between taxane resistance and activation of the PI3K/AKT/mTOR signaling pathway suggests inhibition of this pathway in combination with antimitotic drugs like paclitaxel may improve treatment outcomes in many malignancies. To further investigate this hypothesis we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial of heavily pretreated patients to determine the safety, efficacy, and RP2D. Methods: This is an open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. A traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts was used. All 5 cohorts plus an expansion cohort are presented. Results: Enrollment has been completed and the overall results are summarized. Nineteen patients were enrolled; the majority were heavily pretreated with the average number of prior regimens exceeding 4. Based upon ITT, the ORR is 37%. The ORR is 47% in patients that completed at least 3 cycles. The clinical benefit rate is 73% and the PFS currently stands at approximately 11 months. Two patients with endometrioid endometrial adenocarcinoma achieved a complete response. All patients received comprehensive genomic profiling and 7 patients received prior mTOR inhibitor. Overall, the combination was well tolerated, except by patients in cohort 5. One DLT occurred in the last patient enrolled. The most common non-laboratory AEs were nausea (6%), fatigue (5%), and mucositis (5%). There were 45 (9%) grade 3 or 4 events, and the most common were decreased WBC and non-febrile neutropenia. Hyperglycemia was common in patients with a history of diabetes mellitus. Conclusions: Overall, the combination of sapanisertib, serabelisib, and paclitaxel was safe and efficacious throughout the first 4 cohorts. There were few serious adverse events, and most side effects were managed with routine supportive care interventions. Preliminary clinical results appear very promising, especially for patients with PI3K/AKT/mTOR pathway mutations. The positive effects of the combination were routinely seen in the lowest dosing cohorts and clinical benefit was even seen in patients that had previously failed everolimus or temsirolimus. All patients were either resistant or refractory to paclitaxel at time of enrollment, so further exploration of this combination to elucidate the mechanism of benefit is warranted. Clinical trial information: NCT03154294.
Discovery and Features of an Alkylating Signature in Colorectal Cancer
Authors: Carino Gurjao, Rong Zhong, Koichiro Haruki, Yvonne Y. Li, Liam F. Spurr, Henry Lee-Six, Brendan Reardon, Tomotaka Ugai, Xuehong Zhang, Andrew D. Cherniack, Mingyang Song, Eliezer M. Van Allen, Jeffrey A. Meyerhardt, Jonathan A. Nowak, Edward L. Giovannucci, Charles S. Fuchs, Kana Wu, Shuji Ogino, Marios Giannakis
Journal: Cancer Discovery (2021)

Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression. SIGNIFICANCE: Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D.This article is highlighted in the In This Issue feature, p. 2355.
Does timing of chemotherapy impact breast satisfaction after breast conservation therapy and mastectomy with immediate reconstruction?
Authors: Kate R. Pawloski, Tracy-Ann Moo, Varadan Sevilimedu, Jonas A. Nelson, Paula Garcia, Laurie J. Kirstein, Monica Morrow, Audree B. Tadros
Journal: Journal of Clinical Oncology (2021)

589 Background: Receipt of chemotherapy is associated with decreased postoperative breast satisfaction, but whether timing as neoadjuvant (NAC) versus adjuvant (AC) affects this outcome after breast conservation therapy (BCT) and mastectomy with immediate reconstruction (M-IR) is unclear. Methods: We retrospectively identified patients treated with chemotherapy and breast surgery (BCT and M-IR), from 1/2017-12/2019, who completed ≥ 1 BREAST-Q survey through 12/2020. Mean (standard deviation [SD]) Q-scores for satisfaction with breasts (SATBR) were compared between NAC versus AC groups in BCT and M-IR cohorts, respectively. Higher Q-scores on a 0-100 scale indicate superior satisfaction. A minimum 4-point difference was considered clinically important. Chemotherapy timing and significant covariates on univariate analyses were entered in multivariable linear regressions of 1- and 2-year SABTR. Results: 640 patients had BCT and 602 had M-IR; 210 (33%) BCT patients and 294 (49%) M-IR patients had NAC. Compared with M-IR, SATBR was higher after BCT in both NAC and AC groups, at all postoperative timepoints (Table). Following BCT, SABTR was highest in both NAC and AC groups at 6 months and returned to baseline in the NAC group by year 3. In the M-IR cohort, 331 (55%) patients had radiation and 120 (20%) had complications requiring re-operation or hospitalization. Compared with baseline, mean (SD) Q-scores were substantially lower at 6 months but improved to near baseline at 3 years in both NAC and AC groups. On multivariable analysis, radiation was associated with decreased SABTR at 1 year (Beta, -11; 95% CI, -17, -5.0; p&lt;0.001) and 2 years (Beta, -12; 95% CI, -19, -5.5; p&lt;0.001), as were complications at 1 year (Beta, -6.1; 95% CI, -12, -0.34; p=0.038) but not 2 years (Beta, -5.5; 95% CI, -12, 0.92; p=0.09). After multivariable adjustment, NAC was not significantly associated with 1- or 2-year SABTR after M-IR or BCT. Conclusions: SABTR was higher in BCT compared with M-IR cohorts, independent of chemotherapy timing. Following BCT, SABTR was lower in the NAC group at years 2-3 but remained at baseline or higher at all timepoints. In the M-IR cohort, both groups endorsed lower than baseline SABTR in years 0-2 but returned to near baseline at 3 years. Radiation and complications were independent predictors of decreased SABTR, but our findings suggest that patients who experience complications after M-IR can expect return to baseline breast satisfaction by 2 years.[Table: see text]
Determinants of Lung Fissure Completeness
Authors: Marieke C. van der Molen, Jorine E. Hartman, Cornelis J. Vermeulen, Maarten van den Berge, Alen Faiz, Huib A. M. Kerstjens, Jean-Paul Charbonnier, Lowie E. G. W. Vanfleteren, Dirk-Jan Slebos
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

New advanced bronchoscopic treatment options for patients with severe chronic obstructive pulmonary disease (COPD) have led to increased interest for COPD phenotyping, including fissure completeness.
The use of external control data for predictions and futility interim analyses in clinical trials
Authors: Steffen Ventz, Leah Comment, Bill Louv, Rifaquat Rahman, Patrick Y Wen, Brian M Alexander, Lorenzo Trippa
Journal: Neuro-Oncology (2021)

External control (EC) data from completed clinical trials and electronic health records can be valuable for the design and analysis of future clinical trials. We discuss the use of EC data for early stopping decisions in randomized clinical trials (RCTs).
First long-term results on efficacy and safety of long-acting pasireotide in combination with everolimus in patients with advanced carcinoids (NET) of the lung/thymus: Phase II LUNA trial.
Authors: Eric Baudin, Alfredo Berruti, Mario Giuliano, Wasat Mansoor, Catalin Bobirca, Erik Houtsma, Niamh Fagan, Kjell E. Oberg, Piero Ferolla
Journal: Journal of Clinical Oncology (2021)

8574 Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI &lt;70%. PAS +EVE combination showed clinical benefit in terms of PFS and BPFS compared to PAS and EVE alone as shown in Table. At least one dose reduction of PAS or EVE was reported in &gt;50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. [Table: see text]
Investigation of immune microenvironment in EGFR mutant NSCLC.
Authors: Yi Hu, Longgang Cui, Xiaochen Zhao, Yuezong Bai, Fan Zhang
Journal: Journal of Clinical Oncology (2021)

e20517 Background: Immune checkpoint inhibitor therapy has made great achievements in NSCLC, but patients with EGFR mutations have poor efficacy with immunotherapy. Previous studies have explored the expression of PD-L1, neo-antigen, co-mutation and regulatory pathways in EGFR mutate NSCLC. This work compared the immune microenvironment of EGFR mutant and wild-type NSCLC. Methods: Patients: NSCLC. Using multi-color immunohistochemistry (multi-IHC) to evaluate the expression of 2 indicators in tumors and tumor stroma, namely CD8 + T cell and macrophage. Shapiro-Wilk was used for normality test, and t-test or Mann-Whitney U test was used according to the results. Two-sided P &lt; 0.05 was considered a significant difference. Results: The study included 119 NSCLC patients, including 59 women (49.6%) and 60 men (50.4%), with a median age of 57. There were 68 patients (57.1%) with EGFR mutations, 19 patients (16%) with KRAS mutations, and 58 patients (48.7%) with TP53 mutations. multi-IHC results showed that, EGFR mutation Vs EGFR wild type samples, (1) the number and proportion of CD8 + T cells in tumor were not statistically different. The median number of CD8 + T cells in tumor stroma was 231.5 vs 359, p = 0.05 and the proportion of CD8 + T cells was 3.92% vs 5.64%, p = 0.02; (2) The median number of macrophage in tumors was 1522 vs 110, p &lt; 0.01, and the proportion of macrophage cells was 24.93% Vs 1.38%, p &lt; 0.01. The median value of macrophages in tumor stroma was 617.5 Vs 208, p &lt; 0.01, and the proportion of macrophages cells was 10.88% vs 3.03%, p &lt; 0.01. Conclusions: Compared with EGFR wild-type patients, EGFR mutation patients have a lower proportion of CD8 + T cells and a higher proportion of macrophages in the immune microenvironment.
Evaluation of immunohistochemical expression of mismatch repair proteins in endometrioid and seromucinous borderline ovarian tumors a 10-year experience in a large health care institution.
Authors: Hector Chavarria, Marina Frimer, Noah D. Kauff, Veena S. John, Seema Khutti
Journal: Journal of Clinical Oncology (2021)

e17557 Background: Borderline tumors (BT) are atypical proliferation of epithelium in the ovary in the absence of destructive stromal invasion, representing for 15% of all epithelial ovarian cancers. [1] Around 10% of the ovarian tumors are hereditary, and approximately 10% of all the hereditary forms of epithelial ovarian tumors are result of a loss of DNA mismatch repair (MMR). [2] Endometrioid borderline tumor (EBT) and Seromucinous borderline tumors (SMBT) are rare tumors in ovary and there is limited literature available on immunohistochemical (IHC) expression of Mismatch repair proteins(MMRP)in these tumors.[3, 4] The aim of this study is to evaluate IHC expression of MMRP in EBT and SMBT of ovary. Methods: Pathology database was searched for ovarian Endometrioid borderline tumor (EBT) and Seromucinous borderline tumor (SMBT) for a 10-year period (2010-2020). The cohort consisted of 10 EBT (6 of which had focal microinvasion or carcinoma) and 12 SMBT(2 of which had focal carcinoma ). For comparison, 1 borderline Brenner. 15 serous borderline tumors (SBT) and 15 mucinous borderline tumors (MBT) were also included. After reviewing slides, a block with adequate borderline tumor was selected for IHC stains. For the cases with carcinoma, two different blocks with each component were selected. In all selected blocks, IHC stains for four MMRP (MLH1, PMS2, MSH2, MSH6) were performed. The complete absence of nuclear staining in tumor cells was considered as “loss” of the MMRP expression. Any “weak” or “focal” nuclear staining was considered intact. Results: Total 53 cases were evaluated for MMRP IHC. All cases had intact MMRP expression. In cases with carcinoma, both components (BT and carcinoma) have intact MMR IHC expression. See table. Conclusions: Our study did not show loss of MMRP IHC expression in EMT or SMBT. However, our study consisted of a small number of cases. Multi Institutional study with a large number of cases can be helpful in future to further evaluate the role of MMRP IHC in EMT and SMBT. [Table: see text]