tbuckley/cabot-search huggingface dataset:
Prognostic impact of pSTAT3 on overall survival (OS) in gastrointestinal (GI) cancers: Data from 3 phase 3, randomized controlled trials (RCTs).
Authors: Emily Brooks, Claudia Lebedinsky, Tanios S. Bekaii-Saab, Manish A. Shah, Derek J. Jonker, Kamesh Kuchimanchi, Ewa Wybieralska, Marilyn Fontaine, Cindy Oh, Suha Sari, Emma Foos, Bo Xu, Matthew Hitron
Journal: Journal of Clinical Oncology (2021)

4147 Background: Retrospective studies of phosphorylated STAT3 (pSTAT3, a regulator of gene expression) in cancer-lineage cells have suggested it is a biomarker of poor prognosis. We analyzed data from 3 phase 3 RCTs (BRIGHTER [T1; NCT02178956], CO.23 [T2; NCT01830621], CanStem111P [T3; NCT02993731]) to evaluate the prognostic impact of pSTAT3 on OS in GI cancer patients (pts). Methods: pSTAT3 was evaluated in archival tumor tissue from pts with gastric or gastroesophageal junction adenocarcinoma (T1), colorectal cancer (T2), or pancreatic cancer (T3) who received standard of care in the control arms (CTL) of their respective trials. pSTAT3 positive (+) or negative (−) status was determined by detecting pSTAT3 in both tumor and tumor microenvironment (TME) cells in a laboratory-developed immunohistochemistry (IHC) assay (T1; T2), later developed into the investigational pSTAT3 IHC D3A7 assay (Agilent Technologies, Inc.) (T3). The positivity cutoff requires a sample have both a TME score of 2 and ≥5% of tumor cells staining positively for pSTAT3. Pre-analytical variables (eg, specimen collection, handling, and processing), tumor indication, and slight differences in the assays used for each study may contribute to relative differences in evaluable rates between studies. In an exploratory analysis, OS was compared in pSTAT3+ vs pSTAT3− pts via an unstratified log-rank test. Results: In each study, intent-to-treat pts with evaluable pSTAT3 results were considered pSTAT3-evaluable. This abstract includes pSTAT3-evaluable pts randomized to the CTL arms (T1: n/N=248/357, 69.5%; T2: n/N=110/144, 76.4%; T3: n/N=243/569, 42.7%). Baseline characteristics are presented in the table. Median (m) OS was shorter in pts with pSTAT3+ tumors across all studies (T1 hazard ratio [HR]=1.32 [95% confidence interval (CI): 1.00, 1.74]; T2 HR=2.40 [1.50, 3.83]; T3 HR=1.08 [0.77, 1.50]). Conclusions: In pSTAT3-evaluable populations from 3 RCTs across GI cancers, CTL pts with pSTAT3+ (vs pSTAT3−) tumors had shorter mOS. These results suggest that pSTAT3 positivity may be a biomarker of poor clinical outcome. Clinical trial information: NCT02178956; NCT01830621; NCT02993731. [Table: see text]
Deep learning of HIV field-based rapid tests
Authors: Valérian Turbé, Carina Herbst, Thobeka Mngomezulu, Sepehr Meshkinfamfard, Nondumiso Dlamini, Thembani Mhlongo, Theresa Smit, Valeriia Cherepanova, Koki Shimada, Jobie Budd, Nestor Arsenov, Steven Gray, Deenan Pillay, Kobus Herbst, Maryam Shahmanesh, Rachel A. McKendry
Journal: Nature Medicine (2021)
100 years of Bacillus Calmette–Guérin immunotherapy: from cattle to COVID-19
Authors: Niyati Lobo, Nathan A. Brooks, Alexandre R. Zlotta, Jeffrey D. Cirillo, Stephen Boorjian, Peter C. Black, Joshua J. Meeks, Trinity J. Bivalacqua, Paolo Gontero, Gary D. Steinberg, David McConkey, Marko Babjuk, J. Alfred Witjes, Ashish M. Kamat
Journal: Nature Reviews Urology (2021)

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.
Updates from ICARIA-MM, a phase 3 study of isatuximab (Isa) plus pomalidomide and low-dose dexamethasone (Pd) versus Pd in relapsed and refractory multiple myeloma (RRMM).
Authors: Paul G. Richardson, Aurore Perrot, Jesús F. San-Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A. Dimopoulos, Jeffrey SY. Huang, Jiri Minarik, Michele Cavo, H. Miles Prince, Cheng Zheng, Franck Dubin, Helgi Van De Velde, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2021)

8017 Background: Isa is an approved monoclonal antibody that binds to a specific epitope on the CD38 receptor. The Phase 3 ICARIA-MM study (NCT02990338) demonstrated significantly improved progression-free survival (PFS) with Isa-Pd vs Pd ( P= 0.001) and a manageable safety profile (Attal M, et al. Lancet 2019;394:2096-2107). Here we report updated ICARIA results. Methods: Pts with RRMM (N = 307) who have received ≥2 prior therapies, including lenalidomide (Len) and a proteasome inhibitor (PI), were randomized to Isa-Pd (n = 154) or Pd (n = 153). Isa was administered intravenously at 10 mg/kg weekly for 4 weeks, and every other week thereafter. This preplanned second interim analysis assessed longer term outcomes, including time to next treatment (TTNT), overall survival (OS), time from randomization to disease progression on first subsequent therapy or death (PFS2), and safety. Results: Pts had a median of 3 prior lines of therapy (IQR 2–4; table). As of Oct 1, 2020 (median follow-up, 35.3 months [mo]), 27 Isa-Pd pts (18%) vs 12 Pd pts (8%) were still on treatment; 60% vs 72% had proceeded to subsequent therapy. Median TTNT was 15.5 mo with Isa-Pd vs 8.9 mo with Pd (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.42–0.74; P&lt; 0.0001); 24% vs 58% of pts with subsequent therapy received daratumumab (dara). Overall response rate (ORR) in subsequent treatment with dara monotherapy was higher after Pd (38%) than Isa-Pd (14%), but was similar (32% vs 31%) with dara combination therapy (table). Median PFS2 in the intent-to-treat population was 17.5 mo with Isa-Pd vs 12.9 mo with Pd (HR 0.76; 95% CI 0.58–0.99; P= 0.0202). Median OS was 24.6 mo with Isa-Pd vs 17.7 mo with Pd (HR 0.76; 95% CI 0.58–1.01; one-sided P= 0.0280). Median treatment duration was 47.6 weeks (range 1.3–171.6) with Isa-Pd vs 24.0 weeks (range 1.0–168.6) with Pd. Serious treatment-emergent adverse event (TEAEs) were seen in 73% of Isa-Pd pts vs 60% of Pd pts. Most frequent non-hematologic TEAEs (any grade) with Isa-Pd were infusion reaction (38%), upper respiratory tract infection (34%), and diarrhea (30%). Grade 3–4 neutropenia (85% vs 71%) and thrombocytopenia (34% vs 25%) were more frequent with Isa-Pd than with Pd. Conclusions: Isa-Pd demonstrates a significant improvement in TTNT and PFS2 compared with Pd. A strong trend in OS benefit was also seen in the Isa-Pd arm, with approximately 7 mo improvement in median OS. The overall safety profile remains unchanged from prior analyses. Funding: Sanofi. Clinical trial information: NCT02990338. [Table: see text]
Analysis of LRP1B as a potential biomarker for colorectal cancer immunotherapy.
Authors: Ruiting Liu, Qianqian Duan, Qin Zhang
Journal: Journal of Clinical Oncology (2021)

e15521 Background: Low-density lipoprotein receptor-related protein 1B (LRP1B), a putative tumor suppressor, is one of the most frequently altered gene in cancer. Recently, there are emerging evidences that LRP1B is involved in sensitivity to melanoma and non-small cell lung cancer immunotherapy. Here we explored the relationship between LRP1B mutation and potential effect of immunotherapy for colorectal cancer (CRC) based on multidimensional data. Methods: Next-generation sequencing (NGS) data of CRC patients (n = 536) from TCGA and Chinese clinical dataset (n = 249) was used to evaluate tumor mutational burden (TMB) differences between LRP1B mutation group and wildtype group. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Neoantigens of CRC samples (n = 214) were obtained from The Cancer Immunome Atlas. In addition, we investigated the association of LRP1B mutation with 30 immune-related genes, which were classified into 3 categories: immune checkpoint, T-effector and interferon-γ gene signature, and T cell receptor. Results: 22.95% (123/536) patients in TCGA harbored LRP1B mutation. In the Chinese cohort, the LRP1B mutation ratio (24.50%, 61/249) was similar to TCGA. The TMB level of LRP1B mutation group in both TCGA and Chinese cohort was significantly higher than wild-type group (P &lt; 0.001). The TNB between two group is also showed a significant difference (P &lt; 0.001) in TCGA. Of the 30 immune-related genes, 27 (90.0%) genes are differentially expressed (P &lt; 0.05) and all 27 differentially expressed genes have higher expression levels in LRBP1-mutated samples in comparison with wild-type ones. Conclusions: LRBP1-mutated CRC patients have a higher TMB, TNB and show higher expression level with immune-related genes. These results indicated that LRP1B mutation may serve as a potential biomarker of ICI benefit in CRC patients. Moreover, further clinical insights and prospective validation studies are warranted.
Projected long-term impact of adjuvant trastuzumab emtansine (T-DM1) on metastatic breast cancer occurrence in Turkey.
Authors: David J. Press, Gözde Özcan, Ezgi Teksoy, Akanksha Tomar, Cedric Revil, Pavel Napalkov, Mellissa Williamson
Journal: Journal of Clinical Oncology (2021)

e12523 Background: Progression from early stage breast cancer (eBC) to metastatic breast cancer (mBC) constitutes a substantial disease burden in Turkey. At a population-level, investment in treatment with curative intent may contribute to long-term reductions or delays in mBC. Women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive eBC who do not achieve pathologic complete response (pCR) after neoadjuvant taxane and trastuzumab-based treatment may be indicated for adjuvant trastuzumab emtansine (T-DM1) monotherapy. For this clinical population, the KATHERINE trial (NCT01772472) demonstrated significantly higher invasive disease-free survival among women who received adjuvant T-DM1 relative to trastuzumab (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; p&lt;0.001). Methods: We developed epidemiology models based on data from cancer registries, observational studies, clinical trials, estimated population-level T-DM1 uptake, and extrapolations, by calendar year to predict the population-level number of women who will avoid mBC in Turkey over the next 10 years (i.e., 2022 to 2031). Weighted transitional probability averages were based on invasive disease-free and overall survival curves from the KATHERINE trial. Results: Over the next 10 years in Turkey, we projected that 22,597 women will be diagnosed with HER2-positive eBC and will not achieve pCR after neoadjuvant therapy. We projected that the total number of women who will experience mBC occurrence following adjuvant T-DM1 use from 2022-2031 will decrease annually from 0 to 249 relative to projections without introduction of T-DM1, with a cumulative total of 1,219 women not experiencing mBC occurrence, corresponding to 17% of total projected mBC occurrence over the next decade. At year 10 (2031), we projected that 29% fewer women would experience mBC occurrence in Turkey (604 with TDM-1 vs. 853 with trastuzumab). Conclusions: Population-level improvements in HER2-positive eBC to mBC disease progression are expected over the next 10 years in Turkey following adjuvant T-DM1 monotherapy. Further research will elucidate treatment-related improvements in costs to society as a result of population-level improvements in disease outcomes for women diagnosed with eBC.[Table: see text]
Effect of an antiracism intervention on disparities in time to lung cancer surgery.
Authors: Jacob Newton Stein, Samuel Cykert, Christina Yongue, Eugenia Eng, Isabella Kathryn Wood, Marjory Charlot
Journal: Journal of Clinical Oncology (2021)

101 Background: Racial disparities are well described in the management of early-stage lung cancer, with Black patients less likely to receive potentially curative surgery than non-Hispanic Whites. A multi-site pragmatic trial entitled Accountability for Cancer Care through Undoing Racism and Equity (ACCURE), designed in collaboration with community partners, eliminated racial disparities in lung cancer surgery through a multi-component intervention. The study involved real-time electronic health record (EHR) monitoring to identify patients not receiving recommended care, a nurse navigator who reviewed and addressed EHR alerts daily, and race-specific feedback provided to clinical teams. Timeliness of cancer care is an important quality metric. Delays can lead to disease progression, upstaging, and worse survival, and Black patients are more likely to experience longer wait times to lung cancer surgery. Yet interventions to reduce racial disparities in timely delivery of lung cancer surgery have not been well studied. We evaluated the effect of ACCURE on timely receipt of lung cancer surgery. Methods: We analyzed data of a retrospective cohort at five cancer centers gathered prior to the ACCURE intervention and compared results with prospective data collected during the intervention. We calculated mean time from clinical suspicion of lung cancer to surgery and evaluated the proportion of patients who received surgery within 60 days stratified by race. We performed a t-test to compare mean days to surgery and chi 2 for the delivery of surgery within 60 days. Results: 1320 patients underwent surgery in the retrospective arm, 160 were Black. 254 patients received surgery in the intervention arm, 85 were Black. Results are summarized in Table. Mean time to surgery in the retrospective cohort was 41.8 days, compared with 25.5 days in the intervention cohort (p&lt;0.01). In the retrospective cohort, 68.8% of Black patients received surgery within 60 days versus 78.9% of White patients (p&lt;0.01). In the intervention, the difference between Blacks and Whites with respect to surgery within 60 days was no longer significant (89.41% of Black patients vs 94.67% of White patients, p=0.12). Conclusions: Racial disparities exist in the delivery of timely lung cancer surgery. The ACCURE intervention improved time to surgery and timeliness of surgery for Black and White patients with early-stage lung cancer. A combination of real-time EHR monitoring, nurse navigation, and race-based feedback markedly reduced racial disparities in timely lung cancer care. [Table: see text]
Sub-centimeter lymphadenopathy in germ cell testicular cancer: An ongoing surveillance challenge.
Authors: Ruth Kieran, Iseult Browne, John McCaffrey
Journal: Journal of Clinical Oncology (2021)

e17011 Background: Correct identification of retroperitoneal disease is essential for proper staging and management in germ cell tumors. A size threshold of a 10mm diameter has high specificity in assessing nodal metastases, but sensitivity can be poor at this level and many patients have sub-centimeter lymphadenopathy on post-orchidectomy staging. As many staging scans are done soon after surgery, these may represent reactive lymph nodes. We aimed to assess the prevalence of sub-centimeter lymphadenopathy on baseline imaging in our patients, and its association with recurrence. Methods: Records of patients diagnosed with testicular germ cell cancer in a tertiary cancer center (n = 55, 2015-2020) were reviewed (median followup of 26 months, range 1-59). Lymphadenopathy size measurements were taken from the scan report, which had been authorized by a radiology consultant. Results: Patients had a median age of 34 (range 19-63). 37 (67%) had pure seminomas, 2 (4%) pure embryonal tumors, 12 (22%) mixed tumors with a primarily (&gt; 50%) embryonal component, and 4 (7%) other mixed types. 48 (87%) had stage 1 disease, 3 (6%) stage 2 and 4 (7%) stage 3 disease. 26 (47%) had CT staging preoperatively, of the remainder 69% (n = 20) were staged in the first 48 postoperative hours. 28 (51%) had no lymphadenopathy, 15 (27%) had sub-centimeter lymphadenopathy within the landing zone, 8 (15%) had lymphadenopathy measuring &gt; 1 cm within the landing zone, 4 (7%) had lymphadenopathy elsewhere. 7 had immediate chemotherapy, 48 entered surveillance. For the 14 with sub-centimeter lymphadenopathy within the landing zone who did not have immediate chemotherapy, 3 regressed, 8 were stable. 2 underwent a PET for further assessment, 1 a biopsy. 3 increased in size. 6 patients on surveillance had a recurrence – of these 2 had seminomas with no baseline lymphadenopathy, 4 had mixed primarily embryonal tumors (3 with sub-centimeter lymphadenopathy (0.6, 0.7 and 0.9 cm each), one with a 1.3cm para-aortic lymph node). Of those 4, only 1 had significantly elevated HCG pre-operatively, all recurred in the sites of previously noted lymphadenopathy. Those with mixed, primarily embryonal disease with lymphadenopathy (representing 50% of such patients on surveillance) had a higher recurrence risk than other patients on surveillance (OR: 153, 95% CI 6-3709, p= 0.002) Those undergoing preoperative/delayed postoperative imaging (n = 28) were equally likely to have lymphadenopathy to those having imaging in the first 7 postoperative days ( X 2 (3, N= 27) = 2.9, p= 0.4). 1 patient had died (unrelated causes), all others were disease-free at most recent followup. Conclusions: Sub-centimeter lymphadenopathy is more likely to be benign in those with seminomas, but even small volume lymphadenopathy in those with mixed tumors with a primarily embryonal component may represent metastatic disease, and should be monitored closely.
Gene-edited healthy donor CAR T cells show superior anti-tumour activity compared to CAR T cells derived from patients with lymphoma in an in vivo model of high-grade lymphoma
Authors: Charlotte Elizabeth Graham, Agnieszka Jozwik, Ruby Quartey-Papafio, Nikolaos Ioannou, Ana M. Metelo, Carlo Scala, Glenda Dickson, Orla Stewart, Maria Almena-Carrasco, Elisa Peranzoni, Alan G. Ramsay, Piers E. M. Patten, Thomas Pertel, Farzin Farzaneh, Sandra Dupouy, Andrea Pepper, Reuben Benjamin
Journal: Leukemia (2021)

CD19-targeted autologous chimeric antigen receptor (CAR) T-cell therapy has shown dramatic response rates in relapsed and refractory patients with B-cell malignancies [1][2][3][4].However, a growing body of literature has demonstrated T-cell dysfunction in some cancer patients, which impairs the effectiveness of the end CAR T-cell product [5][6][7].Healthy donor (HD) CAR T cells could potentially provide a source of more functional cells.Graft-versushost disease (GvHD) limits the use of non-HLA-matched HD CAR T cells, but gene-editing to remove the native alpha beta T-cell receptor (TCR) from HD CAR T cells has allowed HD TCR -CAR T cells to be given to HLA unmatched patients with B-acute lymphoblastic leukaemia or with B-cell lymphoma in clinical trials [8][9][10].This study sought to compare the functionality of HD and HD TCR -CAR T cells with B-cell lymphoma patient CAR T cells.In vitro functional assays were performed and in vivo activity was assessed using a xenograft model of high-grade B-cell lymphoma (NOD/SCID/IL2Rγ null (NSG) Raji luciferase), correlating efficacy with phenotypic features of the CAR T-cell product.Peripheral blood mononuclear cells were collected from consenting B-cell lymphoma patients (n = 7) who underwent apheresis for a commercial CAR T-cell product, and from young adult HDs (age 18-30 years, n = 13) (Human Tissue Authority Licence number 12223 and King's College London Research Ethics Committee Ref: HR-17/18-5515).Young adults were chosen because aged T cells are thought to be more terminally differentiated with reduced proliferative capacity [11].Using the same CAR construct (anti-CD19 4G7 scFv 4-1BB CD3ζ lentiviral CAR) (Fig. 1a) and manufacturing process, research grade lymphoma patient and HD CAR T cells were produced.HD TCR - CAR T cells were made by electroporating HD CAR T cells with TALEN ® mRNA targeting the TRAC locus (TCR alpha constant).Residual unedited CAR T cells were removed by magnetic bead depletion [12].Manufacturing lasted 14 days for all CAR T-cell groups prior to cryopreservation and storage.
A phase II study of palbociclib for recurrent or refractory advanced thymic epithelial tumor (KCSG LU17-21).
Authors: Myung-Ju Ahn, Hyun Ae Jung, Miso Kim, Joo-Hang Kim, Yoon Hee Choi, Jinhyun Cho, Ji Hyun Park, Keon Uk Park, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park
Journal: Journal of Clinical Oncology (2021)

8576 Background: Thymic epithelial tumors (TETs) are rare but the most common tumor of the anterior mediastinum. Platinum-based combination chemotherapy is standard of care which is associated with a 50%-90% overall response rate (ORR) in metastatic disease. However, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with cell cycle including pRB, p16 INK4A , and cyclin D1 are commonly observed in TETs. Based on these results, we conducted a phase II trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. Methods: This is a phase II multicenter, open-label, single arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapy. Patients receive oral palbociclib 125mg daily for 21 days followed by a 7-day break. The primary endpoint was the progression-free survival (PFS) rate at 6 months (H0 = 30% vs H1 = 48%). Results: Between August 2017 and October 2019, 48 patients were enrolled. The median number of previous chemotherapy was 1 (range: 1-4) and 21 (43.7%) of 48 patients received thymectomy. By WHO classification, Type A (n = 1), Type B1 (n = 2), Type B2 (n = 8), Type B3 (n = 13), Type C (n = 23), and unknown (n = 1). With medial follow-up of 14.5 months (range 0.8-38.2), the median cycle of palbociclib was 10 (range 1-40). The PFS at 6 months was 60% and the median PFS was 11.0 months (95% CI: 4.6-17.4). Six of 48 patients (12.5%) achieved partial response. The median overall survival was 26.4 months (95% CI: 17.4-35.4). The most common adverse events of any grade included neutropenia (62.5%), anemia (37.5%) and thrombocytopenia (29.1%). Conclusions: Palbociblib monotherapy is well tolerable and encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy. Updated results will be presented. Clinical trial information: NCT03219554.