tbuckley/cabot-search huggingface dataset:
Forecasting the global need for high-dose methotrexate to prevent and mitigate shortages.
Authors: Scott C. Howard, Andre Michel Ilbawi, Brian Lewis, Catherine Lam
Journal: Journal of Clinical Oncology (2019)

6571 Background: Causes of drug shortages in low-income and middle-income countries are numerous and often more than one cause contributes. Shortages are especially problematic when they involve drugs like high-dose methotrexate (HDMTX), which is required for several highly curable cancers and has no good substitute. Morocco is currently experiencing a national shortage of high-dose methotrexate that has so far lasted several months and has impacted the care of all patients whose protocol includes HDMTX. In this case, a single supplier left the market due to government-imposed pricing that made continued sales increasingly unprofitable. Practicing hematologist/oncologists in Myanmar, the Philippines, Vietnam, and Cambodia also reported shortages that reached patients during 2018. Methods: We created a forecasting model to identify the total annual national need for HDMTX and number of patients based on incidence by age, age distribution, and numbers of doses in typical protocols for osteosarcoma, primary CNS lymphoma, pediatric B-cell NHL, and ALL, curable cancers for which HDMTX is essential. Results: More than 200,000 patients per year need HDMTX (approximately 950,000 doses, see Table). 86% of these live in low- and middle-income countries, where access to inexpensive generic drugs is especially important. Conclusions: This forecasting tool will facilitate national purchasing and negotiating to assure continuous supply of HDMTX. It can be adapted for other drugs, and is especially relevant for low-cost generic drugs, which are disproportionately affected by shortages. [Table: see text]
Induction chemotherapy with docetaxel, cisplatin and cetuximab versus docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced or inoperable squamous cell carcinoma of the head and neck: Promising results of a randomized phase II AGMT-trial.
Authors: Felix Keil, Maximilian Hartl, Gabriela Altorjai, Martin Pecherstorfer, Beate Mayrbäurl, Alexander de Vries, Andrea Berghold, Regina Riedl, Michael A. Fridrik, Thorsten Fuereder, Martin Burian, Richard Greil
Journal: Journal of Clinical Oncology (2019)

6027 Background: Induction chemotherapy (ICT) with Cisplatin (P), 5-FU (F) and Taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial and toxicity and/or delay of radiotherapy may reduce the potential benefit of this treatment regimen. Here we report promising results of a randomized phase II trial comparing TPF with TP and Cetuximab (C) replacing F. Methods: In our trial, N= 100 patients with locally advanced or unresectable stage III or IV SCCHN were randomly assigned to either Arm A ( N= 49), receiving TPF, or Arm B ( N= 51), receiving TPC, both followed by radiotherapy (RT) + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. Results: We observed a remarkable response rate (CR + PR) of 86.4% in the TPC-arm that compared favorably with 77.5% responding patients in the TPF-arm three months after RT + C was completed. OS and PFS were similar in both arms. After 400 days we observed an OS rate of 79% in the TPF and 86% in the TPC arm, and a PFS rate of 67% in the TPF and 70% in the TPC arm. TPC containing ICT led to less serious adverse events (SAEs), including blood and lymphatic disorders (40.8% in TPF arm, 27.5% in TPC arm) and metabolism and nutrition disorders (22.4% in TPF arm, 9.8% in TPC arm) during ICT. Interestingly, in HPVp16 positive patients, 88.24% in the TPF-arm and 93.33% in the TPC-arm showed CR or PR three months after RT + C, whereas only 69.57% in the TPF-arm and 82.76% in the TPC-arm showed CR or PR. We only lost one patient because of treatment-related mortality (TRM) and no delay from the end of ICT to local radiotherapy was observed in any patient. All patients received RT + C within three weeks after ICT was completed. Conclusions: In conclusion, TPC is a feasible and tolerable therapy regimen and can be applied within one day with less hematological toxicities. In contrast, more local reactions were observed after TPC. TPC containing ICT leads to improved response rates, while OS and PFS were similar in both arms. TRM was extremely low with 1%. Therefore, we conclude, that TPC containing ICT could be a considerable therapeutical alternative for patients with locally advanced or unresectable stage III or IV SCCHN, who are eligible for ICT. Clinical trial information: 2011-005540-99.
Patient factors that drive unplanned acute care utilization in oncology care.
Authors: Tara L. Kaufmann, Erin Aakhus, Andrea Bilger, Peter Edward Gabriel, Vivek Nimgaonkar, Katharine A. Rendle, Arnav Shah, Rebecca Trotta, Justin E. Bekelman, Frances Barg
Journal: Journal of Clinical Oncology (2019)

e18011 Background: There is a critical need to develop oncology care delivery models that help cancer patients avoid preventable acute hospital care. We are conducting a mixed methods study to assess patient- provider- and system-level factors that drive unplanned acute care utilization in order to implement evidence-based practices (EBPs) at a large health system. Here we present data from patient perspectives on the factors that influence their decision to seek acute care. Methods: We used a purposive sampling approach to identify cancer patients with solid tumors on active treatment with unplanned acute care events at an academic cancer center or its two affiliated community practices from August 2018-January 2019. We conducted semi-structured interviews designed to elicit patient factors that drive unplanned acute care utilization and to understand strategies patients use to manage unexpected symptoms at home. Interviews were analyzed using the constant comparative method to identify key themes. Results: Forty-three patients participated in this study. We identify several patient factors that intersect with the decision to seek care: self-management behaviors, guilt, negative ED perception, safety concerns, and trust. Patients attempt self-management prior to contacting their oncology team, which introduces variability in the duration and severity of reported symptoms. Delay is related to patients’ sense of guilt for burdening their oncology team and to differences in provider accessibility. Patients describe a high symptom threshold to seek care that is often coupled with a negative perception of the ED. However, due to safety concerns, patients do prefer in-person evaluation for new and distressing symptoms. They also express a high level of trust in the oncology team and relative distrust of non-oncology providers. Conclusions: Our data suggest a conceptual model for patient factors that drive unplanned acute care and identify the following targets for implementation of EBPs: 1) symptom management 2) provider accessibility 3) alternate triage pathways for in-person evaluation. Strategies to target these needs should address patients’ emotional concerns and be well integrated within the oncology team.
Abstract 12346: Reduced Diuretic Response With Fluid Retention is a Poor Prognostic Factor in Patients With Acute Decompensated Heart Failure
Authors: Soichiro Aoki, Takahiro Okumura, Masaki Sakakibara, Akinori Sawamura, Ryota Morimoto, Yasuko Bando, Toyoaki Murohara
Journal: Circulation (2015)

Introduction: Diuretic response (DR) has been proposed as a prognostic factor in heart failure patients. The presence of leg edema or jugular venous distention reflects fluid retention (FR) and patients are treated with diuretics under the guide of FR. However, the prognostic value of DR and FR has not been clarified. The aim of this study was to investigate the relation of DR and FR to the mortality in patients with acute decompensated heart failure. Methods: We enrolled 188 consecutive acute heart failure inpatients survived to discharge (mean age of 78 years, 101 females). DR was calculated by the formula; in-hospital Δbody weight kg / 80mg oral furosemide (or equivalent loop diuretic dose). FR on admission was simply evaluated by the presence of leg edema or jugular venous distention. All patients were divided into 4 groups based on the median of DR and FR; Group-A (DR≤-0.49 with FR, n=65), Group-B (DR≤-0.49 without FR, n=29), Group-C (DR&gt;-0.49 with FR, n=47) and Group-D (DR&gt;-0.49 without FR, n=47). We followed all patients up to one year after discharge. Cardiac events were defined as cardiac deaths and re-hospitalization for worsening heart failure. Results: The mean of LVEF was 44% and plasma BNP level was 960 pg/mL. The median length of stay was 18 days, the dose of furosemide was 570 mg, and the Δbody weight was -3.6 kg. The blood urea nitrogen level (p=0.001), creatinine level (p=0.004) and the prior exposure to loop diuretics (p&lt;0.001) was significantly higher in the Group-C and D. The probability of cardiac events in the Group-C was significantly higher than that in any other groups (Figure). Adjusted multivariate analysis identified the Group-C as an independent predictor of cardiac events (HR: 2.32; 95% CI: 1.43-3.78; p=0.001). Conclusion: Reduced DR with FR is a poor prognostic factor in patients with acute decompensated heart failure.
Nivolumab and Pembrolizumab in advanced cutaneous melanoma : Results from real-life data in patients from France— Evaluation of use, current practices and medico economic approach.
Authors: Francoise Grude, Muriel Travers, Brice Moiteaux, Nathalie Beneton, Caroline Jacobzone, Yannick Le Corre, Delphine Legoupil, Patrice Plantin, Marc Porneuf, Bruno Sassolas, Fanny Marhuenda, Delphine Deniel Lagadec, Marc Pracht
Journal: Journal of Clinical Oncology (2019)

e21009 Background: In 2016, Nivolumab (N) and Pembrolizumab (P) have been registred for first line ECOG PS 0-1 adult patients with non-resecable or metastatic melanoma. The Brittany and Pays de la Loire Cancer Observatory has collected data on their real-life indications, current management, safety, efficacy and medico-economics Methods: All non opposing adult patients (pts) with advanced cutaneous melanoma who initiated a treatment with N (3 mg/kg q2w) or P (2 mg/kg q3w) in 2016 and 2017 were included. Minimum follow-up for survival was 12 months. Sex, age, mutation profile, lines of treatment, toxicities, response rate, survival and treatment cost have been collected. Results: 149 pts were treated by N and 201 pts by P with a median age of respectively 68 [21-88] and 69 years [28-96]. Of the 350 patients, 34% were at least 75 years and around 30% presented a BRAF mutation. The median duration of treatment was 4.9 months [0-34.6] for N and 4.2 [0-35.8] for P (Not Significant NS). 65% of pts were treated in 1 st line for N and 69% for P. 24% of the pts were treated in 2 nd line for both treatments. 81% of the pts had a baseline PS of 0 or 1. All lines combined (first line for wt BRAF and first or second line for m BRAF melanoma), clinical benefit was 53% for N and 47% for P. Median OS was respectively 21.7 m for N and 22.8 m for P (NS). mPFS were respectively 6.4 m and 4.6 m (NS). 18% of pts presented grade III/IV toxicities with N and 17% with P. wt BRAF pts showed more grade III/IV toxicities than m BRAF pts (p = 0.046). For N, pts with grade III/IV toxicities showed better PFS (p = 0.051) and OS (p = 0.064). For both cohorts, PS ≥2, BRAF status and treatment line identified subgroup of pts with worsened PFS and OS 55% (24/44) of pts who stopped N or P because of death had a baseline PS of 0-1 showing PS alone is not sufficient to predict survival. Aggressive diseases (high metastasis rate, cerebro-meningeal metastasis, high tumor growth rate with any previous treatment) appear to be the worse candidates for immunotherapy. N and P courses during the 2 years costed 6.6 and 9.7 millions of euros respectively with approximatively 84% or 79% of this cost for N and P clinically benefitting pts. Conclusions: Immunotherapy in real-life setting in cutaneous advanced melanomas confirms literature’s data regarding clinical benefit, survival rate and safety profile and suggests to think about a composite predictive biomarker including BRAF status, ECOG PS, toxicity and treatment line.
Vitamin D insufficiency and risk of paclitaxel-induced peripheral neuropathy.
Authors: Theodore Salvatore Jennaro, Ellen M. Lavoie Smith, Kiran Vangipuram, Kelley M. Kidwell, Monika Leigh Burness, Jennifer J. Griggs, Catherine H. Van Poznak, Daniel F. Hayes, Norah Lynn Henry, Daniel Louis Hertz
Journal: Journal of Clinical Oncology (2019)

e12027 Background: Peripheral neuropathy (PN) is a severe, dose-limiting toxicity of paclitaxel that occurs in up to 25% of patients and can lead to permanent loss of balance and manual dexterity. Due to the lack of effective strategies for PN prevention or treatment, there is a critical need to identify predictive risk factors for paclitaxel-induced PN. Vitamin insufficiencies are known risk factors for PN in other disease states. However, the effect of vitamin insufficiency on paclitaxel-induced PN has not been adequately investigated. Methods: Baseline levels of vitamin D and other nutrients (vitamin B, homocysteine, folate) were measured, and PN was assessed weekly in an observational trial of patients receiving paclitaxel 80 mg/m 2 for 12 weeks for non-metastatic breast cancer (NCT0233811). Nutrient levels were measured by Michigan Medicine and insufficiency defined by institutional standards (vitamin D insufficiency &lt; 20 ng/mL). In the primary analysis, the maximum increase from baseline in the 8-item sensory subscale (ΔCIPN8) of the EORTC CIPN20, a validated patient-reported PN assessment tool, was compared in nutrient insufficient and sufficient patients. The effect of vitamin insufficiencies on PN-induced treatment disruptions (dose decrease, delay, or discontinuation) was conducted as a secondary analysis. Results: Only vitamin D insufficiency was identified in enough patients for analysis (15/37 = 41%). Vitamin D insufficient patients reported a greater mean (+/- SD) ΔCIPN8 (36.39 ±22.8) than vitamin D sufficient patients (16.29 ±16.3) (p = 0.003). However, the increase in treatment disruption for vitamin D insufficient patients was not significant (OR = 2.98, 95% CI [0.72, 12.34], p = 0.16). Conclusions: Paclitaxel-treated patients who were vitamin D insufficient at baseline had greater increases in patient-reported PN. If validated in larger studies, vitamin D insufficiency may be a clinically translatable, modifiable risk factor that can be used to prevent paclitaxel-induced PN in patients with non-metastatic breast cancer.
Case 10-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Carlos S. Kase, Jean-Paul Vonsattel
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 73-year-old man was admitted to the hospital because of right hemiparesis.He was well until 15 months earlier, when he awoke from a nap with nausea and a severe supraorbital headache that was more marked on the left side; he experienced great difficulty with vision and with ambulation. Examination showed that eye movements were normal and the pupils were equal and reactive. A dense homonymous right hemianopia was present, and the patient had difficulty seeing objects in the left visual field, especially in its inferior portion; the visual acuity on the left side was 20/100. Initially, . . .
A randomized phase II study of atezolizumab plus recombinant human IL-7 (CYT107) or atezolizumab alone in patients with locally advanced or metastatic urothelial carcinoma (mUC): A Cancer Immunotherapy Trials Network Trial (CITN-14).
Authors: Evan Y. Yu, Steven Fling, Bob Salim, Randy F. Sweis, Gurkamal S. Chatta, Rohit K. Jain, Scott Edward Delacroix, Helen Moon, Andreanne Lacroix, Judith C Kaiser, Elad Sharon, Martin A. Cheever, Russell Pachynski
Journal: Journal of Clinical Oncology (2019)

TPS4586 Background: Atezolizumab is a regulatory-approved PD-L1 antagonistic antibody for the post-platinum mUC setting. Responses to atezolizumab are highly efficacious in a subset of patients, but suboptimal or absent in most patients. IL-7 (CYT107) is a homeostatic growth factor that promotes proliferation, differentiation, and survival of T lymphocytes. We recently demonstrated CYT107 significantly increases peripheral absolute lymphocyte and T cell numbers in metastatic castration-resistant prostate cancer patients when administered after sipuleucel-T. We hypothesize expansion of T cells by CYT107 may improve responses to PD-L1 inhibition. To test this hypothesis, we designed a randomized trial (NCT03513952) in mUC comparing the combination of CYT107 and atezolizumab to atezolizumab alone. Methods: Patients with ECOG PS ≤2 and RECIST v1.1 measurable mUC with disease recurrence after platinum-based chemotherapy are eligible. A safety run-in of 6 patients with staggered enrollment to atezolizumab plus CYT107 will be followed by randomization if &lt;2 patients experience a DLT. An additional 48 patients will then be randomized 1:1 to atezolizumab 1200 mg IV q3wks with or without CYT107 10 ug/kg IM qwk X 4, started 1 wk before atezolizumab. The primary endpoint is RECIST v1.1 ORR, with H 0 14.8% and H A 45%, one-sided α 0.10; power 88%. An interim futility analysis will be performed after 24 randomized patients have their first disease assessment; cessation of the trial will occur if an O’Brien-Fleming futility boundary of &lt;-0.0063 in the ORR scale is observed between the experimental and control arm. Secondary endpoints include clinical benefit rate, PFS, DOR, OS, results by PD-L1 expression stratification, and safety. Exploratory correlative evaluations of tumor-infiltrating immune cells, interferon γ expression, inflammatory gene expression, ELISPOT, T cell receptor sequencing, serum metabolite levels, gut microbiome, and PK analyses will be performed. Current state: Trial accrual has begun and is anticipated to complete around mid-2020. Clinical trial information: NCT03513952.
A neutrophil to lymphocyte ratio is predictive of response to neoadjuvant HER2-targeted therapies in the patients with HER2-positive breast cancer.
Authors: Soong June Bae, Chang-Ik Yoon, So Eun Park, Chi Hwan Cha, Dooreh Kim, Janghee Lee, Sung Gwe Ahn, Hyung Seok Park, Youngup Cho, Joon Jeong
Journal: Journal of Clinical Oncology (2019)

587 Background: The neutrophil to lymphocyte ratio (NLR) has been reported that is associated with response to treatment and prognosis in breast cancer, but its role is unclear in HER2 positive breast cancer. In this study, the relevance of NLR for treatment efficacy was analyzed in HER2 positive breast cancer patients underwent neoadjuvant therapy. Methods: Pre-treatment NLR was assessed in 546 HER2 positive breast cancer patients divided into three groups according to neoadjuvant treatment regimens: i) chemotherapy alone, ii) chemotherapy plus trastuzumab, and iii) chemotherapy plus trastuzumab and pertuzumab. The cutoff value of NLR was defined as 2.75. We evaluated the correlation of NLR with pathologic complete response (pCR) rate to neoadjuvant treatment regimen. Results: Of all patients, 422 (77.3%) patients were classified as low NLR group (NLR &lt; 2.75) and 124 (22.7%) patients as high NLR group (NLR≥2.75). In the low NLR group, a pCR was achieved in 59 (25.7%) of 230 patients with chemotherapy alone, 69 (57.5%) of 120 patients with chemotherapy plus trastuzumab, and 47 (65.3%) of 72 patients with chemotherapy plus trastuzumab and pertuzumab ( P&lt; 0.001). In the high NLR group, a pCR was achieved 13 (18.8%) of 69 patients with chemotherapy alone, 5 (20.0%) of 25 patients with chemotherapy plus trastuzumab, and 18 (60.0%) of 30 patients with chemotherapy plus trastuzumab and pertuzumab in the high NLR group ( P&lt; 0.001). The pCR rate of chemotherapy plus trastuzumab and chemotherapy plus trastuzumab and pertuzumab was similar, but higher than chemotherapy alone in patients with low NLR. However, only chemotherapy plus trastuzumab and pertuzumab showed high pCR rate compared to chemotherapy alone and chemotherapy plus trastuzumab in patients with high NLR, regardless of hormone receptor status. The elevated NLR was an independent predictor of low pCR rate in patients with chemotherapy plus trastuzumab (OR 0.18, 95% CI, 0.07 to 0.52; P= 0.002), but not in those with chemotherapy alone (OR 0.67; 95% CI, 0.34 to 1.32; P= 0.248; P interaction = 0.041) and chemotherapy plus trastuzumab and pertuzumab (OR 0.80; 95% CI, 0.33 to 1.92; P= 0.614; P interaction = 0.031). Conclusions: This study identified a possibility of NLR as an easily accessible predictive marker to guide neoadjuvant HER2 target therapy in HER2 positive early breast cancer. Further study with other cohort is needed for validation.
Development of a novel dendritic cell-based immunotherapy targeting cancer stem cells.
Authors: João Calmeiro, Mylène Carrascal, Luís Mendes, Iola F. Duarte, Célia Gomes, João Serra, Amilcar Falcão, Maria Teresa Cruz, Bruno Miguel Neves
Journal: Journal of Clinical Oncology (2019)

e14009 Background: Dendritic cells (DCs) are one of the central tools in cellular anti-tumor immunotherapy, being characterized by their capacity for acquiring and processing antigens and ability to produce strong antitumor immune responses. The production of clinical grade ex-vivo monocyte-derived DCs (Mo-DCs) is the most frequent approach for antitumor vaccines production. Recently, therapeutic resistance to radio/chemotherapy and disease recurrence was shown to be in part due to a small cancer stem cell (CSCs) population present in tumors. Methods: Here, we aim to target and eradicate CSCs by developing a novel DC-based immunotherapy vaccine for pancreatic and non-small cells lung cancer (NSCLC), comparing the loading of CSCs vs. classical tumor lysates. Results: CSCs from PANC-1 (pancreatic cancer) and A549 (NSCLC) cell lines were successfully isolated and characterized, overexpressing stem-like markers: NANOG, OCT4, SOX2 and CD133. CSCs resistance to Gemcitabine was also assessed. Before comparing the 2 types of vaccine loading, we also analyzed the impact of 3 GMP free-serum culture media on the phenotype and functional abilities of Mo-DCs. DCs cultured in X-VIVO 15 and AIM-V media show enhanced production of IL-12 and are able to induce a superior stimulation of T cells, mainly CTLs and Th1 subsets. By contrast, DCs cultured in DendriMACS are more prone to induce Treg polarization. Conclusions: Overall, our data demonstrate that blood monocytic precursors present considerable plasticity allowing a tailored differentiation of DCs just by changing the nutritive support. We also highlight the need of critically defining the culture medium to be used in DC cancer immunotherapy in order to attain desired cell characteristics and by consequent robust responses. Finally, our preliminary results indicate that loading DCs with CSCs antigens may be an effective strategy to target and destroy this resilient cancer cell population.