tbuckley/cabot-search huggingface dataset:
Preapproval Nontrial Access and Off-Label Use: Do They Meet Criteria for Dual-Deviation Review?
Authors: Carolyn Riley Chapman, Kelly McBride Folkers, Andrew McFadyen, Lesha D. Shah, Alison Bateman-House
Journal: The American Journal of Bioethics (2019)

Preapproval nontrial access, historically called “compassionate use,” and certain off-label usage of approved medical products are two forms of innovative practice, defined by Earl as a situation “...
Phase II study of consolidation amrubicin after concurrent chemoradiotherapy for patients with limited-stage small cell lung cancer.
Authors: Hironori Yoshida, Young Hak Kim, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nishimura, Keisuke Tomii, Tadashi Mio, Toyohiro Hirai
Journal: Journal of Clinical Oncology (2019)

8555 Background: Concurrent chemoradiotherapy (CCRT) using etoposide and cisplatin has been the gold standard for limited-stage small-cell lung cancer (LS-SCLC) for decades; however, approximately three out of four cases treated by CCRT inevitably relapse. Amrubicin (AMR), a synthetic anthracycline with a structure similar to doxorubicin, has demonstrated strong antitumor activity against relapsed SCLC and has been the standard second-line treatment for SCLC in Japan. We consider consolidation AMR following CCRT to be a potential treatment for patients with LS-SCLC. Methods: In this single-arm, multicenter phase II study, all patients enrolled were treated using induction CCRT consisting of four cycles of etoposide at 100 mg/m 2 on days 1-3 and cisplatin at 60 mg/m 2 on day 1 every 3 weeks, plus concurrent thoracic radiotherapy (1.5 Gy twice daily, total 45 Gy) concomitant with the first cycle of chemotherapy. Then, eligible patients received three cycles of AMR at 40 mg/m 2 on days 1-3 every 3 weeks as consolidation treatment. The primary endpoint was the 2-year progression-free survival (PFS) rate in patients who received consolidation AMR, and the secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), and safety. This study was terminated early due to slow patient accrual. Results: Of the 36 patients who underwent induction CCRT (ITT population), 28 (78%) received AMR as consolidation therapy (consolidation population) and 24 (67%) completed all planned treatments. The 2-year PFS rate and ORR were 35.7% and 86% (8 CR and 16 PR), respectively, in the consolidation population. The median PFS and median OS were 14.3 months (95%CI, 10.8-46.6) and 60.9 months (95%CI, 29.8-NR), respectively, in the consolidation population. In the ITT population, the median PFS and the median OS were 13.4 months (95%CI, 7.5-19.0) and 60.9 months (95%CI, 29.8-NR), respectively. Grade 3/4 toxicities during the consolidation phase included neutropenia (39%), thrombocytopenia (14%), and febrile neutropenia (7%). There were no treatment-related deaths in the ITT population. Conclusions: Consolidation AMR following standard CCRT consisting of etoposide and cisplatin plus concurrent thoracic radiotherapy was feasible, and demonstrated promising efficacy for LS-SCLC. Clinical trial information: 000002352.
Molecular characterization and monitoring of patient ctDNA in phase I study of H3B-6545 in ER+ MBC.
Authors: Vicki Rimkunas, Zhaojie Zhang, Erika Paige Hamilton, Dejan Juric, Judy Sing-Zan Wang, Elizabeth Claire Dees, Lihua Yu, Ping Zhu, Huilan Yao, Laura Ankstitus, Subhasree Das, Manav Korpal, Peter Smith, Joanne Schindler, Pavan Kumar
Journal: Journal of Clinical Oncology (2019)

1052 Background: Because of lack of effective treatment in endocrine resistant metastatic breast cancer (MBC), we developed H3B-6545, a novel selective ERa covalent antagonist, capable of irreversibly inactivating both wild-type and mutant ERa. The aims of this study are to 1) characterize hotspot mutation profiles in heavily pretreated MBC and correlate ESR1, PIK3CA and AKT1 mutations in plasma vs tumor tissue 2) determine if mutations in ESR1 or PIK3CA predict response to H3B-6545 and 3) evaluate if longitudinal tracking of ctDNA correlates with response to H3B-6545. Methods: Fresh plasma samples were collected at baseline (predose), cycle 1 day 15 (C1D15), C2D1, C3D1 and every 8 weeks thereafter with a final sample collection at disease progression. At baseline, BEAMing digital PCR was used to evaluate hotspot mutations in ESR1, PIK3CA and AKT1. Patient specific ctDNA mutations were subsequently monitored by ddPCR. Baseline tumor biopsies were subjected to a targeted Next Generation Sequencing (NGS) panel to identify hotspot mutations. Results: In 77% of patients (30/39), mutations were detected at baseline by the BEAMing assay and of those, 21/39, 16/39 and 3/39 had mutations in ESR1, PIK3CA and AKT1, respectively. 20% (9/39) of patients exhibited co-mutations in ESR1 and PIK3CA. In 60% (9/15) of patients, DNA mutations identified by the plasma BEAMing assay were also detected in the tumor biopsy whereas; DNA mutations found in tissue were also detected in plasma in 86% (12/14) of cases. Serial ctDNA monitoring revealed that in patients with confirmed partial responses (3/3), ctDNA levels were undetectable by C2D1. In contrast, ctDNA levels increased from baseline in 3/4 patients with progressive disease. Exploration of ctDNA ratios (day 15/baseline and day 30/baseline) and correlations of PIK3CA and ESR1 mutations with response to H3B-6545 will be presented. Conclusions: ctDNA is a reliable sample type for assessing ESR1, PIK3CA, and AKT1 mutations in MBC, overcoming the challenges of obtaining biopsies in the metastatic setting. In addition, ctDNA dynamics may be a useful tool to monitor the efficacy of H3B-6545. Clinical trial information: NCT03250676.
Impact of solid tumor brain metastases on end-of-life healthcare utilization.
Authors: Emily Miller Ray, Lisette Dunham, Katherine Elizabeth Reeder-Hayes, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2019)

e18373 Background: Patients with brain metastases (BMets) represent a subset of cancer patients who may experience high costs and frequent healthcare utilization. This study aims to assess whether patients with BMets have higher likelihood of low-value healthcare utilization at the end of life compared to other patients with metastatic cancer. Methods: Using the Cancer Information and Population Health Resource, linking North Carolina Medicare and Medicaid and cancer registry data, we conducted an observational cohort study of decedents with metastatic cancer with or without BMets. The cohorts included adults with melanoma, renal cell carcinoma, breast cancer, or lung cancer, diagnosed 2003 to 2014. Multivariate logistic regression, adjusting for demographics, cancer type, systemic treatment, comorbidity, frailty, and hospice use, was used to examine the impact of BMets on emergency department (ED) use, hospitalization, and intensive care (ICU) in the 30 days prior to death. Results: Relative to patients without BMets, patients with BMets were more likely to experience a hospitalization (12.9% vs 9%, p &lt; 0.001), but experience no difference in ED or ICU use. In adjusted analyses, BMets patients receiving systemic treatment were particularly high risk for hospitalization (OR 1.823, CI 1.504, 2.209). Black race; receipt of systemic therapy near the end of life; and Charlson comorbidity score of 3+ confers increased risk of ED use, hospitalization, and ICU use (Table). Utilization did not vary by cancer type. Conclusions: Patients with BMets are high risk for hospitalization at the end of life. Further study is needed to determine if targeted health system interventions can decrease hospitalizations in this patient group. [Table: see text]
Avascular necrosis of the hip
Authors: Jonathan N Lamb, Colin Holton, Philip O’Connor, Peter V Giannoudis
Journal: BMJ (2019)

### What you need to know

A 36 year old woman presents to her GP with a history of left groin pain radiating to the knee. The pain is severe, worse on walking, and associated with a limp. The patient revisits the GP a year later with persistent pain despite analgesia. Plain radiographs of the hip and knee show slight narrowing of the hip joint space with no other features and she is referred to a secondary care orthopaedic clinic. A magnetic resonance imaging (MRI) scan of the hip shows classic features of avascular necrosis of the femoral head (AVNFH) with collapse. 

Osteonecrosis of the femoral head (AVNFH) causes loss of integrity of subchondral bone structure due to abnormal microcirculation. The underlying pathogenesis is unclear1; risk factors are likely to affect microcirculation in some way but this has not been confirmed by research. The common end point is abnormal microcirculation and necrosis. Subchondral bone subsequently collapses, which leads to progressive secondary arthritis.

Mean age of presentation in the UK is 58.3 years, with a prevalence of two per 100 000 patients.2 On average, AVNFH occurs earlier in life than typical osteoarthritis. It is more common in men and the highest prevalence is in men aged 25 to 44 and women aged 55 to 75.3 In the UK it is the third most common indication for total hip replacement in people under 50.4

The following factors are associated with an increased risk of …
Evaluating the challenges of cancer care in Botswana: Chemotherapy utilization and stock outs.
Authors: Sukhdeep Kaur, Ashwin Chandar, Tina M. Mayer, Deborah Toppmeyer, Roger Strair, Richard Marlink, Reena Antony, Marilyn DiGiacobbe, Refeletswe Lebelonyane, Tendani Gaolathe, Tlotlo Bathethi Ralefala
Journal: Journal of Clinical Oncology (2019)

e18309 Background: As a significant percentage of cancer deaths are occurring in low- and middle-income countries, there is an unmet need in facilitating cancer care delivery in these countries. Data on stock-outs and shortages of cancer medicines in Botswana have been reported as one of the roots hindering treatment and potentially increasing mortality, with at least 40% of essential drugs being out of stock for at least 30 days in 2015. A methodologic approach was published in 2018 to forecast chemotherapy (CT) volume, however, this was based on incidence and prevalence data, using multiple estimated assumptions. To obtain objective data, we examined trends in CT utilization at Princess Marina Hospital (PMH), largest referral hospital in Botswana, over a 12-month period evaluating indications for CT, dosages, and potential issues with stock outs of essential medications. Here we present the 21 injectable essential CT utilized during this period. Methods: This is a retrospective analysis, with data collected from October 2017 to September 2018 from the log book which is used daily by the pharmacy at PMH to record CT preparations. Data was organized to reflect dosage of CT, regimen used, and its indication. Results: Over 1 year period, 21 injectable CT agents were utilized for cancer therapy, with common treated diseases being Kaposi Sarcoma, Gyn cancer, Breast cancer, and Lymphomas. The 10 most utilized agents are listed with the monthly dosage used. Conclusions: We hope to analyze trends in CT utilization based on the available stocks of drugs at PMH to help optimize plans for purchasing and storing medications, with goal of reducing stock outs. In addition, we will analyze treatment regimens used at PMH and compare to current standard of care CT in the US and Sub-Saharan Africa to optimize cancer pathway protocols used in Botswana. [Table: see text]
Treatment of Leprosy
Authors: James A. Doull, Rolla R. Wolcott
Journal: New England Journal of Medicine (1956)

THE terminology of leprosy has changed consider ably in recent years, making necessary some account of the present classification of the disease. Two principal types are recognized, lepromatous and tuberculoid, and two intermediate groups, indeterminate or uncharacteristic and borderline (dimorphous). The main types vary greatly in relative frequency in different parts of the world. In the Philippines, for example, lepromatous cases constitute perhaps 40 per cent of total leprosy; in India, this form accounts for only about 20 per cent. Of indigenous cases arising in the continental United States, about 85 per cent are lepromatous.1 The lepromatous type is characterized . . .
Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer.
Authors: Lawrence G. Lum, Tri Minh Le, Minsig Choi, Archana Thakur, Matthew Reilley, Paul Raymond Kunk, Abhinav Deol, Karen K. Ballen, Tamila L. Kindwall-Keller, Dana Schalk, Ewa Kubicka, Manley Huang, Philip Agop Philip, Hussein Aoun, Gregory Dyson, Qin Liu, Anthony Frank Shields
Journal: Journal of Clinical Oncology (2019)

4135 Background: Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC) has dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (BATs) makes every ATC into an EGFR-specific cytotoxic T cell that secretes cytokines, proliferates, and kills tumor. Methods: We report on 5 phase I (P1) and 15 phase II (P2) patients. In our phase I study, BATs were used to treat LAPC or MPC patients at Karmanos Cancer Institute (NCT0140874) in a dose escalation involving 3 weekly infusions of 1, 2, and 4 x 10 10 BATs/infusion, followed by a booster infusion at 3 months (mos) for a total of up to 8 x 10 10 BATs. No dose limiting toxicities were observed in the outpatient infusions. Fifteen patients treated on a phase II (NCT02620865) at KCI and (NCT03269526) at University of Virginia received biweekly infusions of 10 10 BATs/infusion over 4 weeks for a total of 8 x 10 10 EGFR BATs. Results: Four patients had stable disease (SD) for 6.1, 6.5, 5.3, and 36 mos. Two patients had complete responses (CR) when chemo was restarted after BATs. The median overall survival (OS) for 17 evaluable patients (3 of 4 infusions in the P1 and all 8 infusions in the P2) was 31 mos, and the median OS for all 20 patients (3 in the P2 who did not complete 8 infusions) is 14.5 mos (95% CI, 7.5-45.2 mos). Patient IT20104 had an apparent “pseudoprogression” after 3 BATs infusions, but achieved a CR after restarting capcitabine and is alive off therapy at 54 mos (24 mos after stopping capecitabine). Immune evaluations on the P1 patients show specific cytotoxicity to MiaPaCa-2 by peripheral blood mononuclear cells (PBMC) increased from 21% to 31% 2 weeks after the 3 rd infusion, and IFN-γ EliSpots increased from &lt; 20 to 1000 IFN-γ EliSpots/10 6 PBMC (p &lt; 0.03). Patient IT 20121 (SD for 36 mos) increased IFN-γ EliSpots from 250 to 3200/10 6 PBMC after 8 infusions. Innate cytotoxicity responses in the P1 patients increased significantly after infusions (p &lt; 0.04). Levels of IP-10 increased significantly (p &lt; 0.04), and levels of IL-8 decreased but not significantly (p &lt; 0.07). Conclusions: Infusions of BATs are safe and induce endogenous adaptive anti-tumor responses. Targeting PC with BATs may stabilize disease, leading to improved OS, as well as evidence that BATs infusions can induce anti-tumor activity and immunosensitize tumors to subsequent chemo. Clinical trial information: NCT014084,NCT03269526,NCT02620865.
Clinical course of patients with cisplatin (CDDP)-associated neuropathy compared to other neurotoxic chemotherapy.
Authors: Costantine Albany, Travis Dockter, Eric G Wolfe, Deirdre R. Pachman, Nina D. Wagner-Johnston, Kayla Marie Lazzara, Lina M Sego, Sara I Edwards, Christin I Snow, Nasser Hanna, Lawrence Einhorn, Charles L. Loprinzi, Brian Addis Costello
Journal: Journal of Clinical Oncology (2019)

e23078 Background: There are limited patient (pt) reported outcome data regarding CDDP neurotoxicity. Methods: CDDP-induced peripheral neuropathy was evaluated in pts with testicular cancer planning to receive CDDP (20 mg/m2/d for 5 days) for ≥ 3 cycles. Neurotoxicity was assessed with the EORTC QLQ-CIPN20 tool before each CDDP cycle and every 2-4 months after, out to 18 months. We compared these data to our studies evaluating pts receiving doxorubicin/cyclophosphamide (AC), paclitaxel and oxaliplatin. The total score of the EORTC QLQ-CIPN20, each of the three subscale scores and each individual item was computed following the standard scoring algorithm and converted to a 0-100 scale. Descriptive statistics and graphical plots were utilized. Results: 54 pts receiving CDDP (mean age 33 years) and 18 pts receiving AC were evaluated. Following completion of CDDP, neuropathy symptoms (sensory neuropathy score and numbness/tingling in toes/feet) worsened for about 6 months (consistent with the so-called “coasting phenomena”), similar to what had previously been seen with oxaliplatin (but different than what had been seen with paclitaxel). For CDDP pts, during therapy, numbness and tingling in fingers/hands were more prominent, than the same symptoms in the toes/feet. After therapy was completed, numbness, and tingling became more prominent in toes/feet, but improved in the fingers/hands. After stopping therapy, shooting/burning pain did not worsen in upper or lower extremities. During therapy, CDDP pts had less problems than had previously been seen with oxaliplatin or paclitaxel, maybe because of the younger ages of the CDDP pts. With AC, all of the CIPN-20 sensory neuropathy scores were better than was seen in the pts receiving CDDP and also in pts receiving paclitaxel and oxaliplatin in previous evaluations. Conclusions: CDDP-induced neuropathy is more similar to oxaliplatin-induced neuropathy than paclitaxel-induced neuropathy. AC chemotherapy pts do not have substantial changes in CIPN 20 scores, consistent with the CIPN 20 instrument being a measure of chemotherapy-induced neuropathy, as opposed to more general chemotherapy-induced toxicities. Clinical trial information: NCT02677727.
Impact of decision-support system and guideline treatment concordance on response rate in advanced lung cancer.
Authors: Jun Liang, Chuanhao Tang, Xiangyi Wang, Ziwei Guo, Jun Ni, Weiran Xu, Irene Dankwa-Mullan, Van Willis, Alan Chen, Gretchen Purcell Jackson, Kyu Rhee, Tianle Li
Journal: Journal of Clinical Oncology (2019)

e20006 Background: Clinical decision-support systems (CDSS) provide up-to-date evidence to practitioners overwhelmed by the deluge of clinical findings. Few studies, however, have evaluated their impact on patient outcomes. This cross-sectional retrospective study was conducted to: 1) measure concordance of real-world clinical decisions with therapeutic options from the IBM Watson for Oncology (WfO) CDSS and the Chinese Society of Clinical Oncology (CSCO) guidelines, 2) the effect of concordance on objective response rate (ORR). Methods: Health records from patients receiving 1 st line treatment at Peking University International Hospital Oncology Center in China between January 2016 and December 2018 (69 stage IV NSCLC, 30 with SCLC) with documented tumor progression after 2+ cycles of treatment, were reviewed to determine concordance of actual treatment with WfO therapeutic options and CSCO guidelines. Patients’ treatments were grouped as concordant with: WfO+CSCO, WFO only, CSCO only, or neither. ORR, defined as partial or complete response after 2+ treatment cycles (RECIST criteria)was determined for each group. Results: For NSCLC, ORR ranged from 21.4% for discordance with both WfO and CSCO to 100.0% for WfO only concordance. For SCLC, ORR ranged from 37.5% for CSCO only concordance to 73.3% for WfO+CSCO concordance (Table). The main reasons for discordance were: 1 st generation TKIs like Gefitinib and Erlotinib (vs. Osimertinib) are standard of care for EGFR mutant patients in China, (2) Local CSCO guideline drugs like Lobaplatin and Icotinib are not included in WfO. Conclusions: This study provides preliminary evidence to suggest that treatment concordance with WfO may be associated with improved ORR in some cases of NSCLC (WfO only) and SCLC (WfO + CSCO). ORR in NSCLC patients who were discordant with both WFO and CSCO guidelines was the lowest at 21.4%. Larger studies are needed to understand the effect of guideline and WfO concordance on ORR. [Table: see text]
Does the extent of brain metastasis affect outcome of non-small cell lung cancer patients treated with chemotherapy?
Authors: Yong Won Choi, Mi Sun Ahn, Hyun Woo Lee, Seok Yun Kang, Jin-Hyuk Choi
Journal: Journal of Clinical Oncology (2019)

e20616 Background: More than one third of advanced non-small cell lung cancer (NSCLC) patients (pts) experience brain metastases in the course of their disease. Although the outcome of NSCLC pts with brain metastasis is generally poor, identifying subgroups of pts that could benefit from appropriate therapeutic approach is clinically important, particularly in EGFR tyrosine kinase inhibitor (TKI) era. Methods: A retrospective review was conducted on 85 NSCLC pts with synchronous brain metastasis who underwent at least first-line chemotherapy, after treatment (Tx) for brain metastasis (gamma knife surgery or fractionated stereotactic radiotherapy : 42, whole brain radiation therapy : 38, surgical resection : 1, and no Tx : 4) from Jan 2002 to Dec 2013. Overall survival (OS) of all pts was analyzed according to the clinicopathological characteristics, Tx modality for brain metastasis, and chemotherapy. Results: The median OS for all pts after the initiation of first-line chemotherapy was 9 months. In univariate analysis, pts who received TKI (13 months versus 6 months, p= 0.001) and third- or further-line chemotherapy (15 months versus 6 months, p&lt; 0.001) had significantly longer median OS. The presence of extracranial extrathoracic metastasis, number of brain metastasis, and Tx modality for brain metastasis showed no significant association with OS. In multivariate analysis, third- or further-line chemotherapy (24 pts) was the only independent prognostic factor for favorable OS ( p&lt; 0.001). Pts who underwent third- or further-line chemotherapy were characterized by high proportion of non-squamous histology ( p= 0.016), extracranial extrathoracic metastasis ( p= 0.015), and TKI Tx ( p&lt; 0.001). Conclusions: The present study suggests that judicious but active use of chemotherapy after appropriate Tx for brain metastasis may result in favorable outcome in NSCLC pts with synchronous brain metastasis, regardless of the number of brain metastatic lesions or local Tx modalities.