tbuckley/cabot-search huggingface dataset:
Clinicopathological and genomic characteristics of <i>POLE</i>-mutated colorectal cancer in a Chinese population.
Authors: Xuhui Zhang, Xicheng Wang, Ying Xin, Yuezong Bai, Jian Li, Lin Shen
Journal: Journal of Clinical Oncology (2021)

e15531 Background: DNA polymerase ε (POLE) is essential for proofreading and fidelity in DNA replication and repair. Previous studies found that mutation in POLE associated with higher tumor mutational burden (TMB), which is an approved biomarker for immunotherpy in solid tumors. However, the clinicopathological and mutational analyses of POLE-mutated colorectal cancer in a large Chinese population have not yet been reported. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in 4628 samples of colorectal tumors and matched normal pairs in a CAP/CLIA-approved laboratory (3DMed). NGS testing for gene mutations, TMB and MSI was implemented. Results: Of 4628 colorectal cancer patients, POLE mutations were observed in 67 patients (1.45%). A total of 11 different POLE mutations were identified, mostly associated with exonucleas domain. P286R(32,0.69%), V411L(13,0.28%), A456P(7,0.15%), S459F(3,0.06%) and S297F(3,0.06%) were the most frequently mutated sites of POLE. We also detected 1 V758L and 1 W1130R mutation outside the exonuclease domain in separate cases. Among the 4628 patients, 2157 patients were detectable for TMB by NGS panel, including 2128 POLE wild type and 29 POLE mutation patients. The TMB of patients with POLE mutations was significantly higher than that in wide type POLE tumors (mean TMB 252.3 vs 13.4 muts/Mb, P ＜0.0001). All the 29 POLE-mutated patients were TMB-H (≥10 muts/Mb) and 28 of them were MSS. A MSS patient with metastatic colon cancer harboring A456P POLE mutation responsed well to the immunotherpy and achieved a partial response. Conclusions: Our results realved a remarkable positive correlation between POLE mutation and TMB level in a Chinese colorectal cancer population, which suggests POLE gene will be a promising biomarker of immunotherpy for MSS colorectal tumor.[Table: see text]
Long-term outcome of a phase III trial on neoadjuvant chemoradiation with capecitabine and irinotecan in patients with locally advanced rectal cancer: Updated results of the CinClare trial.
Authors: Ji Zhu, Xinchen Sun, Anwen Liu, Yaqun Zhu, Tao Zhang, Luying Liu, Jianhui Jia, Shisheng Tan, Junxin Wu, Xin Wang, Juying Zhou, Jialin Yang, Chen Zhang, Hongyan Zhang, Xinjia He, Gang Cai, Wei Zhang, Sanjun Cai, Zhen Zhang
Journal: Journal of Clinical Oncology (2021)

3603 Background: Adding UGT1A1-guided irinotecan to capecitabine-based neoadjuvant chemoradiotherapy (CRT) significantly increased the pathological complete response (pCR) rate nearly doubling [J Clin Oncol. 2020 Dec 20;38(36):4231-4239]. Here, results of long-term outcome are reported. Methods: Eligible patients with clinical stage II/III rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomized to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by a cycle of oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with *1*1 or 65 mg/m2 for patients with *1*28, followed by a cycle of irinotecan and capecitabine. Surgery was scheduled for 8 weeks after completion of CRT. Five cycles of adjuvant XELOX chemotherapy were administered regardless of the pathologic result. Patients were stratified by UGT1A1 genotype (*1*1 vs. *1*28) clinical T stage (cT3 vs. cT4) and tumor distance from the anal verge (≤5 cm vs. &gt; 5 cm). The primary end point of pCR was reached. Survival time was calculated from the date of randomization to the date of event or the last follow-up. Secondary endpoints were defined as local failure for local control (LC), tumor recurrence or death from any cause for disease-free survival (DFS), and death from any cause for overall survival (OS). Results: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). A total of 311 patients underwent surgery and pCR was achieved in 80 patients, another 10 patients undergo a watch-and-wait approach after achieving cCR. With a median follow-up time of 48 months (Q25-Q75, 41-55 months), 57 deaths (33 and 24), 17 local failures (11 and 6) and 69 distant metastases (37 and 32) were observed, respectively. Overall, the 4y LC rate were 93% and 96% in control and experimental groups, with estimated LC HR of 0.53 (95% confidence interval [CI], 0.20-1.43), the 4y DFS rates were 69% and 74% (HR = 0.74, 95% CI 0.49-1.10), and the 4y OS were 80% and 85%, (HR = 0.70, 95% CI 0.42-1.19), respectively. In the subgroup analysis, irinotecan showed a significant improvement in DFS (HR = 0.77, 95% CI 0.61-0.98) and OS (HR = 0.71, 95% CI 0.51-0.98) in UGT1A1 *1*1 patients. Conclusions: The addition of irinotecan to standard capecitabine-based CRT had a tendency towards improving LC, DFS, and OS, but without reaching statistical significance. UGT1A1 *1*1 patients seem to benefit the most from irinotecan. Molecular studies and subsequent therapies should be considered. Clinical trial information: NCT02605265.
Efficacy of olanzapine combined with the standard triplet antiemetic therapy for cisplatin-based chemotherapy: A sub-analysis of a randomized, double-blind, placebo-controlled trial (J-FORCE).
Authors: Yukiyoshi Fujita, Masakazu Abe, Takuhiro Yamaguchi, Hiroki Ueda, Koichi Kitagawa, Jun Okamura, Katsuya Hirano, Yukio Sakata, Hirotoshi Iihara, Yasuhiro Shimada, Takeshi Aoyama, Kazuhiko Shibata, Kensuke Hori, Haruko Daga, Toshiaki Nakayama, Yasuhiko Sakata, Sadamoto Zenda, Hironobu Hashimoto
Journal: Journal of Clinical Oncology (2021)

12098 Background: In a randomized, double-blind, placebo-controlled trial (J-FORCE), we previously reported the efficacy of olanzapine (OLZ) 5 mg plus triplet antiemetic therapy for cisplatin (CDDP)-based chemotherapy-induced nausea and vomiting (CINV) in the delayed phase (24–120 h after CDDP treatment). Here, we report the results of a pre-planned subgroup analysis of this trial (in which risk factors were used as the allocation factors). This analysis was designed to determine which patients benefit more from OLZ. Methods: Subgroup analysis was performed on complete response (CR: no emesis and no rescue medication) in the acute (within 24 h of CDDP treatment) and delayed phase and time to treatment failure (TTF: time from CDDP treatment to the first vomiting or use of rescue medication). Data from 705 patients in the efficacy analysis population (354 in the OLZ group and 351 in the placebo (PLA) group) were analyzed by sex (male/female), age (≥55 years/ &lt; 55 years), and CDDP dose (≥70 mg/m 2 / &lt; 70 mg/m 2 ). For CR, we calculated point estimates of differences between groups and 95% confidence intervals and performed a Mantel-Haenszel test. We used the Kaplan-Meier method for the analysis of TTF, and comparisons between groups were made using a log-rank test. Results: Delayed CR (OLZ versus PLA) and risk difference (RD) of delayed CR following OLZ treatment were significantly greater than following PLA in the following subgroups: male (83.1% versus 70.5%, RD 12.6%, p = 0.001), female (70.9% versus 56.4%, RD 14.5%, p = 0.021), age ≥55 years (78.7% versus 67.6%, RD 11.1%, p = 0.003), age &lt; 55 years (81.0% versus 57.4%, RD 23.6%, p = 0.005), and CDDP ≥70 mg/m 2 (78.8% versus 65.3%, RD 13.5%, p &lt; 0.001). TTF of all subgroups (male/female, ≥55 years/ &lt; 55 years, and ≥70 mg/m 2 / &lt; 70 mg/m 2 ) was significantly longer in the OLZ group than in the PLA group (HR 0.493, p &lt; 0.001; HR 0.612, p = 0.022; HR 0.586, p &lt; 0.001; HR 0.401, p = 0.005; HR 0.546, p &lt; 0.001; HR 0.543, p = 0.031, respectively). Conclusions: Our results suggest a benefit of OLZ 5 mg plus triplet therapy regardless of risk factors for CDDP-based CINV. Clinical trial information: UMIN000024676. [Table: see text]
Pyrotinib plus capecitabine for HER2-positive metastatic breast cancer patients with brain metastases (PERMEATE): A multicenter, single-arm phase II study.
Authors: Min Yan, Quchang Ouyang, Tao Sun, Limin Niu, Jin Yang, Li Li, Yuhua Song, Chunfang Hao, Zhanhong Chen
Journal: Journal of Clinical Oncology (2021)

1037 Background: HER2-positive metastatic breast cancer (BC) has a high risk of brain metastases (BM), leading to poor survival. Small molecule tyrosine kinase inhibitor (TKI) with enhanced penetrability to the blood brain barrier combined with capecitabine have demonstrated promising clinical outcomes in HER2-positive metastatic BC patients with untreated (such as lapatinib) or previously treated (such as neratinib) BM. The randomized phase III PHOEBE trial has proved better efficacy of pyrotinib, an irreversible pan-HER receptor TKI, versus lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic BC. This study was conducted to investigate the efficacy and safety of pyrotinib plus capecitabine in HER2-positive metastatic BC patients with BM. Methods: In this multicenter phase II trial (NCT03691051), eligible patients received pyrotinib 400 mg orally once daily without breaks and capecitabine 1000 mg/m 2 orally twice daily for 14 days followed by 7 days off. Treatment was continued until disease progression or intolerable toxicity. Prior HER2 TKIs were not allowed. Cohort A included patients with radiotherapy-naive BM, and cohort B included those with progressive BM after whole brain radiotherapy or stereotactic conformal radiotherapy. The primary endpoint was confirmed central nervous system (CNS) objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Results: Between January 2018 and July 2020, a total of 78 female patients were included (Table). For cohort A (n = 59), the CNS ORR was 74.6% (95%CI: 61.6%-85.0%). For cohort B (n = 19), the CNS ORR was 42.1% (95%CI: 20.3%-66.5%). By the cutoff date on 25 January 2021, the median progression-free survival was 12.1 months (95%CI: 9.0-14.7) in cohort A and 5.6 months (95%CI: 3.4-10.7) in cohort B. The most common grade ≥3 adverse events were diarrhea (23.1% [18/78]), neutrophil count decreased (12.8% [10/78]), white blood cell count decreased (12.8% [10/78]), anemia (9.0% [7/78]), hand-foot syndrome (7.7% [6/78]), hypertriglyceridemia (6.4% [5/78]), and hypokalemia (5.1% [4/78]). Conclusions: Pyrotinib plus capecitabine resulted as an effective and safe treatment for HER2-positive BC patients with radiotherapy-naive BM, but the efficacy was modest in those with radiotherapy-treated BM. Clinical trial information: NCT03691051 .[Table: see text]
OMIC-05. PHOSPHOPROTEOMIC ANALYSIS IDENTIFIES SUBGROUP ENRICHED PATHWAYS AND KINASE SIGNATURES IN MEDULLOBLASTOMA
Authors: Kristin Leskoske, Krystine Garcia-Mansfield, Aparna Krishnan, Ritin Sharma, Jessica Rusert, Jill Mesirov, Robert Wechsler-Reya, Patrick Pirrotte
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is classified into four molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3) and Group 4 (G4), each with different molecular profiles and patient outcomes. Subgroup heterogeneity and low mutational burdens have hindered the identification of actionable therapeutic targets, especially in G3 MB which has a particularly poor prognosis. Therefore, we took a (phospho)-proteomics approach to identify active pathways and potential therapeutic opportunities in twenty orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3 and G4 subtypes. Through our enrichment analysis, we identified processes and pathways specifically upregulated in each MB subgroup. We also utilized neural network derived kinase-substrate predictions and kinase activity scores inferred by a heuristic machine learning algorithm to further characterize phosphosignaling activity. We found that MB PDX models recapitulate many features of primary MB tumors including two distinct proteomic subtypes of G3. G3a was enriched for transcription, translation and MYC target genes while G3b was enriched for axon guidance and neurotrophin signaling pathways. Notably, both G3a and G3b contained higher abundance of mitochondrial proteins, suggesting altered tumor metabolism in G3 MB. SHH PDXs displayed increased NFκB and JNK-MAPK signaling. Group 4 MBs most closely resembled differentiated neuronal cells and were enriched for PKC and AMPK signaling as well as DNA repair pathways. In conclusion, we have provided a comprehensive proteomic and phosphoproteomic characterization of commonly studied MB PDX models and revealed new insights into subgroup enriched pathways and kinase activity in MB.
Acute Pulmonary Embolism
Authors: Stavros Konstantinides
Journal: New England Journal of Medicine (2008)

A 62-year-old man presented with a 5-day history of progressively worsening dyspnea and orthopnea after returning from a 3-day business trip to the Far East. On physical examination, the heart rate was 102 beats per minute and the blood pressure 110/60 mm Hg. The lungs were clear, and the extremities appeared normal. A computed tomographic scan showed multiple thrombi in the pulmonary arteries and a dilated right ventricle. How should this case be managed?
Impact of age and frailty markers on overall survival among hospitalized patients with lung cancer treated with immunotherapy.
Authors: Eric Olson, Gregory Russell, Jeffrey Lantz, Nathan Roberts, Andy Shipe Dothard, Thomas Lycan, Heidi D. Klepin
Journal: Journal of Clinical Oncology (2021)

e21151 Background: Although predictive of chemotherapy toxicity, geriatric assessment measures are not systematically collected in clinical practice and may or may not be predictive for immune-related adverse events. Furthermore, hospitalization during immune checkpoint inhibitor (ICI) treatment for advanced lung cancer has variable prognostic significance. This study aimed to evaluate whether age and documented patient characteristics mapped to geriatric assessment domains (frailty markers, FM) predict survival in this setting. Methods: A single-center retrospective cohort of advanced stage lung cancer patients who received &gt;1 dose of an ICI from 6/1/18 to 2/1/20, were later hospitalized, and received ≥ 1 dose of systemic corticosteroids (n=97) was analyzed. Chart review ascertained documentation of any of the following FMs prior to ICI initiation: inability to walk one block, unintentional weight loss, decreased social activities, recent falls, need for assistance with medications, visual or hearing impairments, living alone, and concern regarding social support. Patients were stratified according to age and three FM categories (0 FM [low risk], ≥1 FMs [at risk], and ≥2 FMs [high risk]). Overall survival (OS) analysis was calculated from first dose of ICI to date of death or last follow-up. Cox’s proportional hazards models were used to assess the relationship between FMs and age on OS; hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Results: Analysis of &lt; 75 and ≥ 75 yo revealed a median OS of 15.1 and 5.4 months respectively (HR 2.76, CI 1.62-4.72). Controlled for performance status (PS), older age (≥75 yo) was associated with a higher risk of death (HR 2.39, CI 1.32-4.31). FMs were associated with higher mortality, adjusted for PS and age (at risk patients HR 1.81, CI 1.03-3.16; high risk patients HR 2.02, CI 1.07-3.78). PS prior to starting ICI was not associated with OS. Conclusions: Age ≥ 75 yo is associated with short survival among lung cancer patients hospitalized while receiving ICI. Pre-treatment FMs documented as part of usual care were associated with worse OS, even after controlling for PS and age. This study shows promise for use of machine learning algorithms to stratify risk in hospitalized patients undergoing treatment for lung cancer with ICIs. These data would allow providers to better target serious illness conversations and end-of-life resources.[Table: see text]
Subgroup Analyses in Oncology Trials: Regulatory Considerations and Case Examples
Authors: Anup K. Amatya, Mallorie H. Fiero, Erik W. Bloomquist, Arup K. Sinha, Steven J. Lemery, Harpreet Singh, Amna Ibrahim, Martha Donoghue, Lola A. Fashoyin-Aje, R. Angelo de Claro, Nicole J. Gormley, Laleh Amiri-Kordestani, Rajeshwari Sridhara, Marc R. Theoret, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Shenghui Tang
Journal: Clinical Cancer Research (2021)

Abstract Subgroup analyses are assessments of treatment effects based on certain patient characteristics out of the total study population and are important for interpretation of pivotal oncology trials. However, appropriate use of subgroup analyses results for regulatory decision-making and product labeling is challenging. Typically, drugs approved by the FDA are indicated for use in the total patient population studied; however, there are examples of restriction to a subgroup of patients despite positive study results in the entire study population and also extension of an indication to the entire study population despite positive results appearing primarily in one or more subgroups. In this article, we summarize key issues related to subgroup analyses in the benefit–risk assessment of cancer drugs and provide case examples to illustrate approaches that the FDA Oncology Center of Excellence has taken when considering the appropriate patient population for cancer drug approval. In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective.
Endoscopic transpapillary gallbladder stenting for acute cholecystitis using a novel integrated inside biliary stent and nasobiliary drainage catheter system
Authors: Koichiro Mandai, Takuji Kawamura, Koji Uno, Kenjiro Yasuda
Journal: Endoscopy (2021)

A novel integrated inside biliary stent and dedicated nasobiliary drainage catheter system (UMIDAS NB stent; Olympus Medical Systems, Tokyo, Japan) has been recently developed in Japan. The 7-Fr biliary stent placed over a 4-Fr nasobiliary drainage catheter can be deployed simultaneously using a dedicated pushing catheter over the guidewire [1] ([Fig. 1]). Here, we describe a case of successful endoscopic transpapillary gallbladder stenting for acute cholecystitis using this drainage system.
Relationship between tumor size and metastatic site in patients with stage IV breast cancer: A large SEER-based study.
Authors: Qian Dong, Mi Zhang, Da Jiang
Journal: Journal of Clinical Oncology (2021)

e13065 Background: To analyze the correlation between tumor size and metastatic site in first-diagnosed stage IV breast cancer patients. Methods: Stage IV breast cancer patients diagnosed from 2010 to 2015 were screened by the Surveillance, Epidemiology, and End Results (SEER) database. The characteristics of clinical variables were represented by a frequency table, and the Chi-square test was used for comparison. At the same time, the Chi-square test was used to analyze the relationship between tumor size and organ metastasis. Correlation between tumor size and the prognosis of patients was contributed by KM curve and Log-rank test. Results: Regardless of tumor size, the proportion of bone metastasis was higher and brain metastasis was lower in breast cancer patients. There were significant differences in the site of metastases based on different subtype. Luminal A and Luminal B breast cancer had the highest proportion of bone metastases; brain metastasis accounted for the highest proportion in triple-negative breast cancer (TNBC); while the incidence of liver metastasis was the highest in Her-2(+) breast cancer. At the same time, the results indicated that Luminal A breast cancer with a tumor size &gt; 5 cm was more likely to develop multi-site metastasis and lung metastasis, while Luminal B breast cancer with a tumor size ≤ 5 cm was more likely to develop liver metastasis. The results also revealed that TNBC patients with a tumor size of 0 - 2cm were more likely to develop bone metastasis than those with a tumor size &gt; 5 cm, and the incidence of lung metastasis in triple-negative patients showed an increasing trend with the increase of tumor size. Conclusions: Based on subtype, we found that there was a significant difference between tumor size and metastatic site in patients with stage IV breast cancer, and the difference was statistically significant. This study provided evidence-based basis for decision-making of stage IV breast cancer treatment.
RARE-03 CENTRAL NERVOUS SYSTEM TUMORS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1, A COHORT FROM A NATIONAL PEDIATRIC ONCOLOGY CENTER
Authors: Kim Vandenput, Lisethe Meijer, Netteke Schouten-van Meeteren
Journal: Neuro-Oncology (2021)

Abstract Approximately 15% of the children with Neurofibromatosis type 1 (NF1) develop a central nervous system (CNS) tumor, predominantly optic pathway glioma. However, other brain tumor types are also frequent, resulting in a heterogenous population regarding tumor type, symptoms and treatment. Even though many tumors are indolent, clinical deterioration or radiological progression requires surveillance and treatment. Pediatric oncology care in the Netherlands has been centralized into the Princess Máxima Center since June 2018, providing care for the majority of Dutch NF1 CNS tumor patients. This retrospective cohort study describes the course of disease in NF1 patients with a CNS tumor diagnosed between 2005–2020, based on data from patient files. The population consisted of 95 patients (48 males), median age at diagnosis 4.3 (range 0.8–17.2) and 12.6 (range 2.9–19.9) years at follow up, 27% familiar NF1, mostly nonsense or frameshift mutations. Neurological and/or visual symptoms were present in 64 (67.4%) patients. 63.6% of the tumors was in the optic pathway, 9.1% in the cerebellum. Biopsy in 19/95 revealed 1 ependymoma and 18 low grade glioma, with rarely additional molecular changes besides NF1. Kaplan Meier median PFS was 24 months (range 3–174.5, n=65) in symptomatic presenting patients, 34 months (range 5–165, n=20) in asymptomatic patients with abnormal ophthalmological and/or neurological exam and 67.3 months (range 7–130, n=10) in asymptomatic patients without abnormalities at exam. Treatment was indicated in 53 (55.8%), predominantly chemotherapy (n=49), with substantial toxicity. Carboplatin allergy was seen in 29/44 (65.9%) patients, peripheral neuropathy in 21/46 (45.7%) patients receiving vincristine, and 5/10 patients receiving irinotecan and bevacizumab ended treatment early due to toxicity. In conclusion: analysis of our extensive cohort of NF1 patients with a CNS tumor indicates the relevance of regular screening of NF1 patients without complaints and critical surveillance and systematical documentation of treatment toxicity.