tbuckley/cabot-search huggingface dataset:
A phase Ib study of the anti-CD47 antibody magrolimab with the PD-L1 inhibitor avelumab (A) in solid tumor (ST) and ovarian cancer (OC) patients.
Authors: Nehal J. Lakhani, Amita Patnaik, John B. Liao, John William Moroney, David S. Miller, Gini F. Fleming, Matt Axt, Yan V. Wang, Balaji Agoram, Jens-Peter Volkmer, Roy Maute, Andreas Schroeder, Isagani Chico, Mark Chao, Chris H.M. Takimoto, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2020)

18 Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a “don’t eat me” signal for macrophages that enhances ovarian cancer cell phagocytosis in preclinical models in combination with the PD-L1 inhibitor avelumab. CD47 blockade can also enhance cross-priming of T cells. Methods: In Part 1 (P1) M+A doses were escalated in ST patients (pts) while Part 2 (P2) enrolled platinum-resistant or refractory OC pts. All received a 1 mg/kg Day 1 priming dose of M to mitigate on-target anemia due to macrophage-mediated extravascular hemolysis followed by 30 or 45 mg/kg maintenance doses in P1 or 45 mg/kg in P2, in combination with 800 mg of A Q2 wks. Results: In the 34 total pts (13 in P1 and 21 in P2), median age was 66 years (range 47-88), and median # of prior therapies was 5 (range 1-10). In P1, no dose limiting toxicities occurred. In P1+P2, no Grade (G) 4 or 5 treatment-related adverse events (TRAEs) occurred. TRAEs of any G in &gt; 20% pts included headache 62%, fatigue 47%, infusion related reaction 44%, pyrexia 38%, chills 35%, nausea 35%, anemia 24%, and vomiting 21%. In P1, a patient (pt) with metastatic papillary adenocarcinoma of the finger on 45 mg/kg of M had a confirmed partial response (PR) lasting for 4 months before progressing. In P2, 1 pt had an unconfirmed PR but progressed per RECIST v1.1 on the next scan achieving a best response of stable disease (SD). In the 18 OC P1+P2 pts with at least one response evaluation, 56% had SD and 44% had progression. Analysis of tumor biopsies for immune cells infiltration and CD47, PD-L1, and other marker expression is ongoing. In the 13 OC tumors analyzed to date, only 2 were PD-L1 positive. One PD-L1+ tumor had PD-L1 expression only on infiltrating immune cells. The other PD-L1+ had tumor cell expression and was the only OC pt with tumor shrinkage. This supports the potential importance of PD-L1 expression for this combination. Pharmacokinetic profiles will be presented. Conclusions: M+A is a novel, well-tolerated combination treatment regimen with 1 observed PR in a ST pt and a 56% SD rate in OC pts. Tumor shrinkage was noted in the only OC pt with tumor cell expression of PD-L1 which warrants further evaluation in PD-L1+ OC pts. Clinical trial information: NCT03558139.
Per oral vitamin B12 replacement therapy after gastrectomy and its optimal dose (retrospective study) and our protocol of a prospective clinical trial.
Authors: Yasushi Rino, Toru Aoyama, Norio Yukawa, Haruhiko Cho, Takashi Oshima, Takanobu Yamada, Yosuke Atsumi, Kentaro Hara, Masakatsu Numata, Keisuke Kazama, Hiroshi Tamagawa, Tsutomu Sato, Takaki Yoshikawa
Journal: Journal of Clinical Oncology (2020)

338 Background: Postgastrectomy vitamin B12 deficiency is common metabolic sequel and worsens the quality of life of gastric cancer survivors. Recently, oral vitamin B12 replacement is reported. Therefore, we investigated retrospectively the efficacy of oral vitamin B12 replacement for gastric cancer patients with vitamin B12 deficiency after total gastrectomy. Methods: We reviewed 73 patients with gastric cancer who underwent total gastrectomy and were treated vitamin B12 replacement. Patients were consisted of 56 males and 17 females and median age was 70 y/o. We investigated initial treatment of vitamin B12 replacement and improvement of vitamin B12 deficiency. Results: Initial treatment of vitamin B12 replacements were intramuscular injection for 42 patients, per oral replacement for 28 patients and intravenous injection for 3 patients. Finally, all patients were treated with per oral replacement and the serum vitamin B12 levels became within normal range. Final vitamin B12 doses of replacement therapy were 500 µg of 20 out of 73 pts, respectively. Conclusions: Vitamin B12 replacement therapy should be necessary and continued. According to our results, one vitamin B12 tablet a day is enough. The vitamin B12 deficiency symptoms could be prevented. 500 micrograms vitamin B12 replacement orally is maybe effective and necessary. Our prospective clinical protocol (UMIN000030727): In this study, an oral vitamin B12 preparation (1500 μg/day, administered daily) was set as the control treatment, and a specific clinical trial was started to determine whether 500 μg/day daily administration would be sufficient for replacement therapy. Clinical trial information: UMIN000030727.
Survival rates in elderly patients with heart failure: reply
Authors: Nicholas R. Jones, Andrea K. Roalfe, Ibiye Adoki, Clare J. Taylor, F.D. Richard Hobbs
Journal: European Journal of Heart Failure (2020)

We thank Dr Khan for the interest in our systematic review of survival in patients with chronic heart failure,1 and agree that prescribing data are important for contextualising heart failure survival. We were precluded from including these analyses in our review due to space limitations but plan to report prescribing data in an upcoming paper. We believe that Dr Khan's letter highlights three important points. Firstly, the comparatively poor survival rates seen in older patients may not be due to co-morbidities alone. Individual studies demonstrate that older people with heart failure have a significantly worse prognosis than age and sex-matched controls, even when co-morbidity is common in both groups. A recent observational study found the 1, 5 and 10-year survival rates amongst people with chronic heart failure aged between 75 and 84 years were 81.9% (95% confidence interval 81.3–82.4), 49.5% (48.7–50.3) and 23.8% (22.8–24.9) compared to respective survival in age and sex-matched controls of 94.2% (94.0–94.3), 71.9% (71.6–72.2) and 46.0% (45.5–46.6).2 Secondly, prescribing of medications with proven prognostic benefit in heart failure remains suboptimal across all age groups, although treatment rates are improving over time.3 Many patients also do not receive the recommended combination or optimal dose of medications.3 Older people may be at particular risk of not receiving these medications due to individual patient factors such as treatment intolerance, impaired renal function, or medication interactions. Under-prescribing may, in part, account for the poor survival rates seen in older people. Although there are few dedicated trials of heart failure treatment in older populations, subgroups analyses from studies such as CONSENSUS and PARADIGM-HF suggest older people derive a similar benefit to younger people from key heart failure medications. Given the prevalence of heart failure is above 10% in people aged over 70 years, improving prescribing in this age group is of particular importance.4 Finally, Dr Khan highlights the potential future importance of sodium–glucose cotransporter 2 (SGLT2) inhibitors in heart failure treatment. In a recent randomised controlled trial, people with heart failure and reduced ejection fraction treated with dapagliflozin compared to placebo had a 25% reduced risk of worsening heart failure or cardiovascular mortality (hazard ratio 0.74, 95% confidence interval 0.65–0.85).5 Thus far, SGLT2 inhibitors have shown a reassuring safety profile and may improve outcomes in both diabetes and renal failure, meaning many older people with heart failure could benefit. Real-world studies including older patients are needed to confirm the prognostic benefit of these treatments across age groups.
Prognostic implications of tumor sidedness in colorectal cancer patients in South Dakota, 2006-2015.
Authors: Jonathan Scott Bleeker, Muslim Atiq, Morgan Nelson, Kay Dosch
Journal: Journal of Clinical Oncology (2020)

46 Background: Tumor “sidedness” is emerging as an important prognostic and predictive factor in patients with metastatic colorectal cancer (CRC), with right sided colon cancer (RC) associated with poorer overall survival (OS) than left sided colon cancer (LC). This distinction has been noted in clinical trials and large databases, where American Indian (AI) populations are generally underrepresented. This project aims to investigate the prognostic implications of CRC sidedness in the state of South Dakota, focusing on the AI population. Methods: Data from patients diagnosed with CRC in the South Dakota cancer registry from January 1, 2006 to December 31, 2015 were analyzed for demographic and presenting features as well as survival outcomes. A total of 3,637 cases were included in the analysis, of which 191 (5%) were AI. Tumors arising from the cecum, ascending colon, hepatic flexure and transverse colon were considered RC while those arising from the splenic flexure, descending colon, sigmoid colon and rectum were considered LC. Results: In all patients, 47.1% of cases were RC; Caucasians (C) were significantly more likely to have RC, as 47.7% of cases in Caucasians were RC, whereas in the AI population, 35.6% cases were RC (p=0.005). Patients with RC were more likely to be female and older and less likely to present with metastatic disease than LC. Tumor sidedness was not associated with OS when analyzing all patients regardless of stage or in patients with non-metastatic disease. In patients with metastatic disease, RC was associated with inferior OS compared to LC [Median OS (mo): 9.9 v. 23.6, p&lt;0.001]. When analyzed by race, RC was associated with inferior OS in C [Median OS (mo): 9.6 v. 23.6, p=0.002] but not in AI [Median OS (mo): 10.2 v. 10.4, p=0.082]. Conclusions: Although limited by small sample size, this analysis is hypothesis generating, as AI patients with CRC were more likely to have LC than Caucasians and the well described prognostic implications of RC were not noted in the AI population. Larger population studies and further investigation as to potential explanations for this finding are recommended.
A Neuroethics Framework for the Australian Brain Initiative
Authors: Adrian Carter, Linda J. Richards, Deborah Apthorp, Mostafa Rahimi Azghadi, David R. Badcock, Bernard Balleine, John M. Bekkers, Michael Berk, James A. Bourne, Andrew P. Bradley, Michael Breakspear, Alan Brichta, Olivia Carter, Anne Castles, Khaled Chakli, Sarah Cohen-Woods, Simon J. Conn, Jennifer Cornish, Kim Cornish, Greg de Zubicaray, Gary F. Egan, Peter G. Enticott, Bernadette M. Fitzgibbon, Cynthia Forlini, Alex Fornito, Lyn Griffiths, Judith Gullifer, Wayne Hall, Glenda Halliday, Anthony J. Hannan, Stefan Harrer, Alan Harvey, Chris Hatherly, Ian B. Hickie, Jeanette Kennett, Matthew Kiernan, Trevor Kilpatrick, Isabell Kiral-Kornek, Mayuresh S. Korgaonkar, Andrew J. Lawrence, Rick Leventer, Neil Levy, Julio Licinio, Nigel Lovell, Geoff Mackellar, Lynne Malcolm, Alice Mason, Jason B. Mattingley, Sarah E. Medland, Patricia T. Michie, Jess Nithianantharajah, John Parker, Jonathan M. Payne, Laura Poole-Warren, Pankaj Sah, Zoltan Sarnyai, Peter R. Schofield, Olga Shimoni, David H.K. Shum, Tim Silk, Mark Slee, Ashleigh E. Smith, Tina Soulis, Sharath Sriram, Greg J. Stuart, Jonathan Tapson, Matthew B. Thompson, André van Schaik, Nicole A. Vincent, Bryce Vissel, Allison Waters
Journal: Neuron (2020)
Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy
Authors: Jing Li, Weichao Wang, Yajia Zhang, Marcin Cieślik, Jipeng Guo, Mengyao Tan, Michael D. Green, Weimin Wang, Heng Lin, Wei Li, Shuang Wei, Jiajia Zhou, Gaopeng Li, Xiaojun Jing, Linda Vatan, Lili Zhao, Benjamin Bitler, Rugang Zhang, Kathleen R. Cho, Yali Dou, Ilona Kryczek, Timothy A. Chan, David Huntsman, Arul M. Chinnaiyan, Weiping Zou
Journal: Journal of Clinical Investigation (2020)

Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
Started dose of regorafenib and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): A systematic review and meta-analysis.
Authors: Mikhail Fedyanin, Elizaveta Polyanskaya, Ilya Pokataev, Alexey Tryakin, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2020)

131 Background: Regorafenib is one of the standards of care in pts with chemorefractory mCRC. However, high toxicity is a common reason of treatment discontinuation, interruption and dose reduction. There are conflicting results how started dose of regorafenib influence OS (REBECCA, ReDOS and ARRANGE trials). Therefore, we performed systemic review and meta-analysis to evaluate association between started dose of regorafenib and OS in pts with mCRC. Methods: We performed a search of all retrospective and prospective studies in PubMed, Embase, and Cochrane library. The search criteria included all articles and abstracts for all years before 20.08.2019. We compared the pts with standard dose (160 mg) and &lt;160 mg at the first cycle. Primary outcome was hazard ratio (HR) for OS and 95% confidence interval (CI). Random effects were used for analysis due to potential heterogeneity of the studies. Meta-analysis was conducted by "Review Manager" Ver. 5.3. Results: We identified 6 trials – 3 prospective and 3 retrospective ones, which included 1955 pts (160 mg – 1584 and &lt;160 mg – 571 pts). Two trials showed worsening OS in pts with dose &lt;160 mg (Adenis et al., 2016 – HR 1.26, 95%CI 1.01-1.56 and Aljubran et al., 2019 – HR 2.25, 95%CI 0.93-5.43). Two studies showed improving OS in pts with dose &lt;160 mg (Bekaii-Saab et al., 2018 – HR 0.72, 95%CI 0.47-1.11; Gotfrit et al., 2017 – HR 0.46, 95%CI 0.17-1.22). And two studies didn’t show any difference (Yamaguchi et al., HR 0.95, 95%CI 0.82-1.1 and Argiles et al., 2019 - HR 0.86, 95%CI 0.65-1.13). According to results of the meta-analysis there was not any difference in OS between groups with the dose 160 mg and &lt;160 mg at the first cycle: HR 0.97, 95% CI 0.78-1.21; p = 0.79; I 2 = 64. Conclusions: Started dose of regorafenib &lt;160 mg in the pts with chemorefractory mCRC does not worsen the OS and this approach can be safely used in the daily clinical practice.
Comparison of gemcitabine delivery and tumor response in a pressurized pancreatic retrograde venous infusion versus systemic infusion in an orthotopic murine model.
Authors: Diego Vicente, Jayanth Shankara Narayanan, Partha Ray, Louis F. Chai, Suna Erdem, Matthew Carr, Benedict Capacio, Bryan Cox, David Jaroch, Steven C. Katz, Rebekah Ruth White
Journal: Journal of Clinical Oncology (2020)

737 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with limited response to systemic therapy (ST). Elevated tumor interstitial fluid pressures (IFP) inhibit penetration of ST. Regional Pressure Enabled Drug Delivery has recently demonstrated improved response for liver tumors in a clinical trial. However, this delivery method has not been evaluated in PDAC. We compared gemcitabine (Gem) by systemic delivery vs. a novel pressurized Pancreatic Retrograde Venous Infusion (PRVI) method in an orthotopic PDAC mouse model. Methods: PDAC murine cell line (KPC4580P) tumors were transplanted onto the pancreatic tail of C57BL/6J mice. Groups of 15 mice were randomly assigned to PRVI Gem, PRVI saline (Control), or intraperitoneal Gem (Systemic) groups. Five mice from the PRVI and Systemic groups were randomly selected after one hour post infusion to evaluate Gem tumor concentrations by liquid chromatography - tandem mass spectrometry (ng/mg), and the remainder of mice were euthanized after 7 days to evaluate treatment response. Results: Tumor concentrations of Gem were significantly higher following PRVI compared to Systemic (128 vs. 19, p &lt; 0.01) at one hour after treatment. Seven days after treatment, PRVI Gem mice demonstrated lower mean tumor volume (mm 3 ) than Systemic Gem and Control mice (274 vs. 857 vs. 629, p &lt; 0.01), respectively. Histologic evaluation of tumors demonstrated decreased cellularity in the PRVI Gem mice compared to Systemic and Control mice (35 vs. 78 vs. 71%, p = 0.01), respectively. No differences were seen in Ki67% or immune cell infiltrate between groups. Conclusions: PRVI delivery resulted in increased PDAC Gem concentrations and improved treatment responses with decreased tumor burden and cellularity. These findings suggest that pressurized regional chemotherapy infusion overcomes the elevated PDAC IFP and justifies additional translational pre-clinical studies with other chemotherapeutics (including immunomodulating antibodies) with different physicochemical properties.
SALVO: Single-arm phase II study of ipilimumab and nivolumab as adjuvant therapy for resected mucosal melanoma.
Authors: Robert R. McWilliams, Shernan Holtan, Gregory Russell Pond, Yousef Zakharia, Brendan D. Curti, Evidio Domingo Musibay, Anthony J. Olszanski, Lisa A. Kottschade, Ralph J. Hauke
Journal: Journal of Clinical Oncology (2020)

TPS65 Background: Mucosal melanoma is a rare and, therefore, poorly studied malignancy. Patients with resected primary tumors have a median time to recurrence of 5.5 months. While no one adjuvant therapy is of proven benefit for patients, immunotherapy has shown activity in metastatic mucosal melanoma. Methods: We are performing a single arm, phase II clinical trial through the Midwest Melanoma Partnership/Hoosier Cancer Research Network (6 sites) for resected mucosal melanoma. The primary endpoint is recurrence free survival (RFS), and it will include 36 subjects. Patients must have had an R0 or R1 resection of a mucosal melanoma (sinonasal, anorectal, vulvar, or other), and register within 90 days of surgery. Adjuvant radiation is allowed prior to registration but not required. Therapy consists of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) IV q3w x 4, then 480 mg nivolumab x 1 year. Statistical power is calculated to be 85% to detect a change in RFS from 5.5 months to 9.5 months, with a one sided alpha of 0.05. Enrollment began Sept 2017, with current participation from 6 large volume centers in the United States, with 17 patients enrolled as of Sept 2019. Full accrual is anticipated to complete by year end 2020. Patients will be followed for RFS and OS. Translational studies will include mutational burden, c-kit, BRAF, NRAS status, and serum markers of immunity -- including soluble PD-L1 and Bim. Clinical trial information: NCT03241186.
Novel coronavirus: Australian GPs raise concerns about shortage of face masks
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Cytotoxic drugs administered in high dosage have a much greater effect on tumour cells than on normal cells.<sup>1</sup> In recent years great advances have been made using combinations of cytotoxic drugs: combinations in high dosage given intermittently can often produce high anti-tumour activity with low toxicity and, during periods between treatment, the normal cells recover more rapidly than the malignant cells. Major successes have been achieved in acute lymphoblastic leukaemia in children<sup>2</sup> and in lymphomas, particularly in Hodgkin’s disease<sup>3</sup> and in Burkitt’s tumour. This article reviews chemotherapy in other malignant tumours. As optimum treatment schedules have not yet been developed in most of these diseases, dosages are not quoted, but references are given.
Access to care and outcomes for noncurative esophagogastric cancer: A population-based geographic study.
Authors: Elliott Kenneth Yee, Natalie Coburn, Victoria Zuk, Laura E Davis, Alyson Mahar, Ying Liu, Vaibhav Gupta, Gail Elizabeth Darling, Julie Hallet
Journal: Journal of Clinical Oncology (2020)

284 Background: Esophagogastric cancer (EGC) carries a heavy mortality burden owing largely to high rates of unresectable disease at diagnosis. Among patients not undergoing curative-intent therapy, access to care may vary. We examined the geographic distribution of care delivery and survival across a jurisdiction, and its relationship with distance to cancer centres (CCs), for non-curative EGC. Methods: We conducted a population-based analysis of adults with non-curative EGC from 2005-2017 using linked administrative healthcare datasets in Ontario, Canada. Outcomes were medical oncology consultation, receipt of chemotherapy, and overall survival (OS). We used geographic information system analysis to map locations of CCs and outcomes across census divisions. Regions of discordance between care use and OS were identified with bivariate choropleth maps. Multivariable modified Poisson models assessed the relationship between distance to the nearest CC and outcomes, adjusting for demographic, clinical, and socioeconomic factors. Results: Of 10,228 patients surviving a median of 5.1 months (IQR: 2.0-12.0), 68.6% had medical oncology consultation and 32.2% received chemotherapy. Regions of comparable OS and care delivery were clustered throughout the province. CCs were distributed unevenly, with higher levels in Southern Ontario. Higher-level CCs clustered in regions with higher rates of consultation, chemotherapy use, and OS. Each increment in distance from location of residence to the nearest CC (11-50, 51-100, and ≥101 km) was associated with lower likelihood of seeing medical oncology and receiving chemotherapy, and inferior OS, compared to ≤10 km. Conclusions: A third of patients with non-curative EGC did not see medical oncology, and the majority did not receive chemotherapy. Care delivery and OS exhibited high geographic variability. Location of residence influenced access to care and OS, with inferior outcomes for those living further from a CC. These findings are important for designing interventions and policies to reduce disparities in access to care and outcomes for non-curative EGC.