tbuckley/cabot-search huggingface dataset:
Outcomes of ovarian cancer patients treated with platinum or non-platinum based chemotherapy after PARP inhibitor maintenance.
Authors: Ralynn Brann, Kevin Michael Kremer, Matthew Carlson, Salvatore LoCoco, Jayanthi Sivasothy Lea, David Scott Miller, Jessica Lee
Journal: Journal of Clinical Oncology (2021)

5563 Background: PARP inhibitors (PARPi) are approved for maintenance treatment of platinum sensitive ovarian cancers either after front-line therapy or after treatment for recurrence. Current recommendations include retreatment with platinum-based chemotherapy (PC) after progression on maintenance PARPi. There exists a theoretical concern that progression of disease (POD) on PARPi is indicative of the development of platinum resistance due to similar DNA targets of platinum chemotherapy and PARPi. Our objective was to evaluate the response to subsequent chemotherapy in patients who progressed on PARPi maintenance. Methods: All patients with ovarian, fallopian tube, or primary peritoneal cancer treated with PARPi treatment from 2017 to 2021 at two academic tertiary care centers were retrospectively identified. Patients were assessed for treatment time on PARPi, time to POD on PARPi (PFS), type of chemotherapy regimen following PARPi maintenance, and time to disease progression on subsequent therapy following PARPi (PFS2). Comparative statistical analyses were performed with appropriate two-sided statistical tests. Time to progression on chemotherapy after PARPi was calculated using the Kaplan-Meier method. Results: A total of 83 ovarian cancer patients treated with PARPi were identified, and of these, 61 (73.5%) were treated with PARPi in the maintenance setting. Among the patients treated with PARPi maintenance, 22 (36.1%) remain on treatment. 19 (31.1%) patients were started on PARPi maintenance after front-line chemotherapy. While on PARPi maintenance, 63.9% discontinued PARPi, the majority due to POD, and 26.2% due to patient intolerance of side effects. Following POD, 21/29 (72.4%) received subsequent PC and 8/29 (27.6%) received non-platinum based chemotherapy (NPC). Treatment time, PFS, and PFS2 are listed in Table. Of the patients who received PC, 14/21 (66.7%) had a PFS2 of over six months and 5/21 (23.8%) had a PFS2 of over 12 months. Of the patients who received NPC, 7/8 (87.5%) had a PFS2 of over six months and 2/8 (25.0%) had a PFS2 of over 12 months. Conclusions: Following POD on PARPi, patients responded to both PC and NPC. Time to progression on subsequent chemotherapy after treatment with PARPi does not differ significantly between PC and NPC regimens. Many patients continue to see benefit from PC after PARPi maintenance. Retreatment with PC following POD on PARPi maintenance should still be considered.[Table: see text]
EMBR-07. MYC BUT NOT MYCN GENERATES AGGRESSIVE GROUP 3 MEDULLOBLASTOMA BY ARF PATHWAY SUPPRESSION
Authors: Oliver Mainwaring, Holger Weishaupt, Sonja Hutter, Miao Zhao, Gabriela Rosén, Laura Breinschmid, Annemieke Verbaan, Anders Sundström, Karl Annusver, Maria Kasper, Fredrik Swartling
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, often harbor MYC amplifications and arise in the presence of a functional p53 suppressor protein. To elucidate the mechanism behind this inexplicable tumor development we generated an inducible, immunocompetent transgenic mouse model of MYC-driven MB. Tumors driven from the glutamate transporter promoter molecularly resembled aggressive Group 3 MB driven by an enriched photoreceptor program. They developed embryonically in a monoclonal fashion in the presence of a functional unmutated p53 gene. Compared to MYCN-expressing MB driven from the same promoter, we discovered pronounced silencing of the ARF suppressor upstream of p53. We similarly found significant methylation of the ARF promoter in MYC-amplified as compared to MYCN-amplified human MB samples. While MYCN-driven tumor malignancy was more sensitive to ARF depletion, it dramatically increased metastatic spread of MYC-driven tumors. DNMT inhibition could restore ARF levels in MYC-expressing tumors but did not show any therapeutic advantage in tumors in vivo. Computational modeling suggested the HSP90 protein to act as a more specific target and ARF could indeed be restored by the HSP90 inhibitor onalespib that promoted increased survival in our inducible animal model suggesting that HSP90 inhibition could be potentially used in patients affected by MYC-driven ARF-silenced cancer.
SARS-CoV-2 vaccination for patients with inflammatory bowel disease – Authors' reply
Authors: James L Alexander, Nicholas A Kennedy, Charlie W Lees, Tariq Ahmad, Nick Powell
Journal: The Lancet. Gastroenterology & hepatology (2021)

We thank Garcia Garrido and colleagues for their comments on the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) and IBD Clinical Research Group section position statement1 and the studies cited in their Correspondence, including the valuable meta-analysis of the impact of immunosuppression on pneumococcal vaccination.2 However, the results of this meta-analysis should be interpreted with caution in patients with IBD, as most of the studies included (18 of 22) were from patients with other immune-mediated inflammatory diseases (mostly rheumatoid arthritis), in which the only conventional immunomodulator reported was methotrexate.
Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of ESKD in Diabetes
Authors: Eiichiro Satake, Pierre-Jean Saulnier, Hiroki Kobayashi, Manoj K. Gupta, Helen C. Looker, Jonathan M. Wilson, Zaipul I. Md Dom, Katsuhito Ihara, Kristina O’Neil, Bozena Krolewski, Caterina Pipino, Meda E. Pavkov, Viji Nair, Markus Bitzer, Monika A. Niewczas, Matthias Kretzler, Michael Mauer, Alessandro Doria, Behzad Najafian, Rohit N. Kulkarni, Kevin L. Duffin, Marcus G. Pezzolesi, C. Ronald Kahn, Robert G. Nelson, Andrzej S. Krolewski
Journal: Journal of the American Society of Nephrology (2021)

Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood.
Immune checkpoint inhibitors (ICI) in advanced sarcomatoid renal cell carcinoma (sRCC): A multicenter study.
Authors: Dharmesh Gopalakrishnan, Katharine Collier, Joseph J Park, Jacob P Zaemes, Elaine Tat Lam, Sabah Alaklabi, Ellen Jaeger, Rahul Atul Parikh, Pedro C. Barata, Eric Kauffman, Michael B. Atkins, Ajjai Shivaram Alva, Yuanquan Yang, Saby George
Journal: Journal of Clinical Oncology (2021)

4568 Background: Advanced sRCC is an aggressive disease with limited responsiveness to chemotherapy and VEGF-targeted therapies. Subgroup analyses from randomized trials showed improved outcomes with ICI, though sample sizes were relatively small. Methods: We conducted a multi-institutional retrospective analysis of consecutive patients (pts) who had RCC with any sarcomatoid component and received systemic therapy for advanced disease. The pts were classified into ICI + and ICI - groups (gp) based on whether they had received ICI in any treatment line. Overall survival (OS) was measured from the initiation of first systemic therapy. Time to ICI failure (TIF) was defined as the interval from initiation of ICI to subsequent therapy or death. Survival distributions were estimated using the Kaplan-Meier method. Association between covariates and survival was analyzed using multivariate Cox regression. Two-tailed P &lt; 0.05 was considered statistically significant. Results: 203 pts from 6 US academic cancer centers met the inclusion criteria – 155 in ICI + gp and 48 in ICI - gp. Overall, 137 (67%) pts were male and 181 (89%) were white; median age at mRCC diagnosis was 59.7 (IQR 52.4-67.7) years; 129 (63%) pts presented de novo with distant metastases, 154 (76%) had clear cell (CC) histology, and 182 (90%) had intermediate/poor risk by IMDC criteria. ICI + had a higher proportion of purely CC tumors (81% vs 64%, P =.02); other demographic and clinical features were similar between the two gps. After a median follow-up of 48.1 (95% CI 40.7-55.5) months (mos), median OS and response rates were significantly higher in the ICI + gp (Table). OS benefit, compared to ICI - , was maintained in pts who received ICI in ≥ second line (39.6 vs 7.6 mos, HR 0.33, 95% CI 0.22-0.51, log-rank P &lt;.001). TIF was comparable between pts treated with ICI upfront vs in ≥ second line (6.0 vs 5.3 mos, HR 1.27, 95% CI 0.87-1.85, P =.21). On multivariate analysis, ICI - (HR 2.50, 95% CI 1.61-3.88, P &lt;.001), non-CC histology (HR 3.14, 95% CI 1.98-5.00, P &lt;.001) and sarcomatoid component ≥20% (HR 1.92, 95% CI 1.28-2.90, P =.002) were predictive of all-cause mortality. Among pts with non-CC or mixed histology (n=45), ICI + had higher OS (18.0 vs 5.5 mos, HR 0.20, 95% CI 0.09-0.44, P &lt;.001) and ORR (44% vs 12%, P =.03), compared to ICI - . Conclusions: Treatment with ICI led to markedly higher survival and response rates in advanced sRCC. OS benefit was maintained with ICI in the second line and beyond. Significant benefit was also noted among pts with non-CC or mixed histology sRCC.[Table: see text]
Dyslexia
Authors: Sally E. Shaywitz
Journal: New England Journal of Medicine (1998)

Developmental dyslexia is characterized by an unexpected difficulty in reading in children and adults who otherwise possess the intelligence, motivation, and schooling considered necessary for accurate and fluent reading. Dyslexia (or specific reading disability) is the most common and most carefully studied of the learning disabilities, affecting 80 percent of all those identified as learning-disabled.1 Although the diagnosis and implications of dyslexia were once quite uncertain, recent advances in our knowledge of its epidemiology, neurobiology, and genetics, as well as of the cognitive influences on this disorder, now allow physicians to approach dyslexia within the framework of a traditional medical . . .
Primary Renal Tumour Response in Patients Treated with Nivolumab for Metastatic Renal Cell Carcinoma: Results from the GETUG-AFU 26 NIVOREN Trial
Authors: Jean Courcier, Cécile Dalban, Brigitte Laguerre, Sylvain Ladoire, Philippe Barthélémy, Stéphane Oudard, Florence Joly, Gwénaëlle Gravis, Christine Chevreau, Lionel Geoffrois, Élise Deluche, Frédéric Rolland, Delphine Topart, Stéphane Culine, Sylvie Négrier, Hakim Mahammedi, Florence Tantot, Antoine Jamet, Bernard Escudier, Ronan Flippot, Laurence Albigès
Journal: European Urology (2021)
Outcomes of immunotherapy (ICI) alone vs tyrosine kinase inhibitors (TKI) alone versus ICI and TKI combined in renal cell carcinoma brain metastasis.
Authors: Patrick Joseph O'Shea, Vineeth Tatineni, Yasmeen Rauf, Xuefei Jia, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2021)

2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]
Prognostic factors of survival in patients with Burkitt lymphoma treated at the National Institute of Neoplastic Diseases in Peru: A 14-years’ experience.
Authors: Rossana Solf, Rolig Aliaga, Francisco Vallenas, Claudio J. Flores, Luis Malpica, Jule Franve Vasquez Chavez
Journal: Journal of Clinical Oncology (2021)

e19570 Background: Burkitt lymphoma (BL) is one of the most aggressive B-cell lymphoma types. However, it has a high cure rate which varies depending on the different clinical pathological characteristics. We aimed to evaluate the prognostic factors for survival in patients with BL. Methods: We performed a retrospective study at the National Institute of Neoplastic Diseases in Peru from 2000 to 2014. We reviewed medical records of patients with BL aged 15 years and above. The data collected were based on clinical characteristics, treatment and survival. Patients with human immunodeficiency virus (HIV) infection were considered for analysis. The overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method, the survival curves according to the clinical characteristics were compared using the log-rank test. Prognostic factors were determined using Cox regression modeling. Results: A total of 55 patients had sufficient data for analysis. The median age was 34 years (range 15-73), 78% were male and 73% had B symptoms. Lymph node involvement (LNI) as primary site was present in 89% of patients, of which 43% and 39% were retroperitoneal and cervical LNI, respectively. Bulky mass ( &gt; 10cm) was reported in 73% of the patients. Advanced disease was found in 78% (stage III 31%, IV 47%). Elevated serum LDH level was seen in 60% of cases; and 33% had HIV infection. Intensive chemotherapy was given to 80% (44) of patients, with 34% receiving multi-agent acute lymphoblastic leukemia protocol, 22.8% DA-EPOCH, 18% CODOX-M IVAC, and 11.4% Hyper-CVAD. No patient received rituximab in the front-line setting. The complete response rate was 39%. With a median follow-up of 9 years, the median OS for the entire cohort (N = 55) was 6.9 months (range 1.9-11.9) with a 5-year survival rate of 26.3%. The median OS for the treated patients (N = 44) was 11.3 months (range 3.2-19.4) with a 5-year survival rate of 30.6%. The median PFS was 7.3 months, and the 5-year OFS rate was 30.8%. 5-year OS rates were worse in those with B symptoms (66% vs. 12.5%, p = 0.003), elevated serum LDH level (44.1% vs. 15.2%, p = 0.043), albumin &lt; 3.5 g/dL (36.5% vs. 15.4%, p = 0.023), beta-2 microglobulin &gt; 2.5 mg/L (41.4% vs. 20%, p = 0.029), and HIV infection (31% vs. 16.7%, p = 0.006). In the multivariate analysis, the presence of B symptoms (HR 5.4 [2.2, 13.4], p &lt; 0.001) and HIV infection (HR 2.8 [1.5, 5.4], p = 0.002) were both factors associated with worse survival. Conclusions: In our study, the 5-year OS rate of patients with BL treated with chemotherapy was shorter (30.6%) than in developed countries. The response rates were also lower than in other studies. Inclusion of rituximab is needed to improve response rates. Presence of B symptoms and HIV infection were associated to worse survival.
無作為第II相試験にある日本の悪性リンパ腫および急性白血病患者におけるラスブリケース(尿酸オキシダーゼ)の効果と新たな安全性プロフィール(ARD5290)
Authors: Ogura M, Ishizawa K, Hamaguchi M, Hotta T, Ohnishi K, Sasaki T, Sakamaki H, Tamura K, Usui N, Morishima Y
Journal: Journal of Clinical Oncology (2006)
Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.
Authors: Surender Kharbanda, Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Sireesh Appajosyula, Sandeep Laumas, Harpal Singh
Journal: Journal of Clinical Oncology (2021)

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC 50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC 50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.
Long-term survival and toxicity in patients with progressive advanced neuroendocrine tumors treated with lutetium peptide radiolabelled radiotherapy: A Western Australian long-term follow-up study.
Authors: Kim Robyn Kennedy, Phillip Claringbold, William Macdonald, Glenn Boardman, David Turner Ransom, Harvey Turner
Journal: Journal of Clinical Oncology (2021)

e16202 Background: There are limited treatment options for advanced neuroendocrine tumours, and radiolabelled somatostatin analogues have shown favourable safety and efficacy over other existing treatments. Lutetium Octreotate has been shown to be the somatostatin analogue of choice in Peptide Radiolabelled Radiotherapy (PRRT) for advanced neuroendocrine tumours (NETs). Methods: We conducted a retrospective review of the long term safety and survival outcomes of 104 patients prospectively treated on the CLEMENT1, CLEMENT2, NETTLE, and NETT VALuE trials where patients with advanced progressive NETs were treated with Lutetium Octreotate PRRT in Perth, Western Australia. With a median follow-up time of 68 months, this is the longest follow-up study of advanced NETs treated with Lutetium PRRT in the literature to date. Results: Results showed comparable periods of disease stability as other studies, with median progression free survival of 43 months, and superior survival to other series, with a median survival of 71 months. There were patients who had very durable responses, with five year overall survival 61.5%, five year progression free survival 30.1%, 10 year overall survival 30.1%, and 10 year progression free survival of 29.3%, demonstrating Lu 177 can provide a very long duration of response in some patients. PRRT treatment was well tolerated with 1.9% of patients suffering long term renal impairment, and 1% with long term mild thrombocytopenia attributed to PRRT. Importantly, there was a higher rate of MDS and leukaemia in our series (6.7%), which is likely attributed to the longer period of follow-up with all except one case occurring 48 months after PRRT treatment, which is later than the median follow up in most other studies. Conclusions: Overall, this study showed that Lutetium PRRT remains an efficacious and well tolerated treatment in long term follow-up. For clinicians deciding on the timing of PRRT for individual patients the 6.7% long term risk of MDS/leukaemia needs to be balanced against the 29.3% PFS at 10 years. Clinical trial information: ACTRN12610000440022.
Iron deficiency and risk of early readmission following a hospitalization for acute heart failure
Authors: Julio Núñez, Josep Comín‐Colet, Gema Miñana, Eduardo Núñez, Enrique Santas, Anna Mollar, Ernesto Valero, Sergio García‐Blas, Ingrid Cardells, Vicent Bodí, Francisco J. Chorro, Juan Sanchis
Journal: European Journal of Heart Failure (2016)