tbuckley/cabot-search huggingface dataset:
Role of transforming growth factor-∃ in the progression of head and neck squamous cell carcinoma in a murine model.
Authors: Sunil Chatterjee, Malaya Bhattacharya-Chatterjee, Benjamin Katchman, Asim Saha, Palash Mallick, John Pancoast, Bert O'Malley
Journal: Cancer Research (2007)

2165  In an orthotopic model of head and neck squamous cell carcinoma (HNSCC) in immunocompetent mice (SCC VII/SF), we determined the vaccine efficiency of recombinant vaccinia virus expressing IL-2 (rvv-IL-2). Despite significant tumor regression, vaccine efficiency was restricted by recurrence and loco-regional metastasis. In this study we examined the mechanism of immune escape in this model. We determined the frequency and activities of CD4+/CD25+ regulatory T cells and immune suppressive myeloid CD11b+/CD31+/Gr-1+ cells in rvv-IL-2 vaccinated and control mice. These populations of suppressor cells do not appear to have any role in immune suppression in this model. Assay of expression of a number of immune modulatory molecules in tumor lesions demonstrated high expression of TGF-β, IL-10, GM-CSF and iNOS. Among these, the expression of TGF-β was most abundant. Although the cultured SCC VII/SF cells did not express TGF-β, tumor tissues express high levels of activated TGF-β and sera of tumor-bearing mice had high levels of TGF-β. Expression of TGF-β receptors, (TGFBR I and TGFBR II) in SCC VII/SF cells was significantly lower compared to normal mouse epithelial cells. Low concentrations of TGF-β stimulated the growth of cultured SCC VII/SF cells. TGF-β stimulated invasion of SCCVII/SF cells in Matrigel Invasion Chambers. TGF-β treated SCC VII/SF cells secreted VEGF in the culture media. TGF-β present in the sera of tumor-bearing mice inhibited the biological activities of T and NK cells. Tumor infiltrating lymphocytes from rvv-IL-2 vaccinated mice also showed lower biological activities compared to splenocytes and immune cells in tumor draining lymph nodes. We concluded from these data that loss of TGF-β receptors from SCC VII/SF cells resulted in the disruption of TGF-β signaling and accumulation of activated TGF-β in tumor microenvironment. Accumulated TGF-β in tumor microenvironment promoted the growth of the tumor cells and disrupted the biological activities of the immune cells in tumor microenvironment. Moreover, TGF-β stimulated the invasion of SCC VII/SF cells. Increased secretion of VEGF by TGF-β augmented the metastatic activities of SCC VII/SF cells. For successful immunotherapy in this model it would be necessary to reduce the level of TGF-β in tumor microenvironment. Supported in part by NIH grant RO1 CA 89748.
Myeloid immunosuppressive state as a predictor of rapidly progressive phenotype and poor survival in advanced non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 inhibitors.
Authors: Sally CM Lau, Lisa W Le, Sze Wah Samuel Chan, Elliot Charles Smith, Malcolm Ryan, M. Catherine Brown, Katrina Hueniken, Lawson Eng, Devalben Patel, RuiQi Chen, Alona Zer, Mike Ru Sung, Penelope Ann Bradbury, Pamela S Ohashi, Frances A. Shepherd, Ming Sound Tsao, Natasha B. Leighl, Geoffrey Liu, Adrian G. Sacher
Journal: Journal of Clinical Oncology (2019)

e20594 Background: Immune subpopulations within the tumor microenvironment (TME) play a central role in determining response to checkpoint inhibitors. Myeloid derived suppressor cells, a heterogeneous population of immature myeloid cells, have a predominantly immunosuppressive role by stimulating T regulatory cells. We hypothesize that elevated myeloid-to-lymphocyte measures in the peripheral blood predict for greater numbers of myeloid derived suppressor cells in the TME and worse outcomes. Methods: In advanced NSCLC patients who received immunotherapy between 2010-2018, baseline characteristics collected retrospectively included age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and tumor genotype. Pre-treatment neutrophil/lymphocyte (NLR) and monocyte/lymphocyte ratios (MLR) were log transformed and analyzed using cox and logistic regression models. Results: Among 219 eligible patients, a high NLR was associated with shorter time-to-treatment-failure (HR 1.38, 95%CI 1.09-1.75, p = 0.008) and poorer OS (HR 1.62, 95%CI 1.23-2.14, p &lt; 0.001), independent of PD-L1 levels. Disproportionate increases in NLR and MLR were highly correlated (Spearman’s rho = 0.78). Further, higher NLR (p = 0.09) or MLR (p = 0.06) tended to associate with best overall response (BOR) to immunotherapy, with higher rates of progressive disease (PD) and lower rates of clinical response. A high NLR (p = 0.01) and MLR (p = 0.02) were associated with a rapidly progressive phenotype defined by PD as the BOR and duration of therapy ≤2 months. This remained significant after adjusting for confounders in a multivariate model (p = 0.03 for NLR and p = 0.03 for MLR). No associations were observed between high myeloid counts and other clinical prognostic factors such as liver metastases. Conclusions: A myeloid immunosuppressive state characterized by a disproportionate increase in peripheral immune myeloid populations is significantly associated with primary refractory disease, rapidly progressive phenotype, and poorer survival. Further investigation into myeloid mediated mechanisms of resistance is warranted.
Antitumor efficacy of M3814 as a radiation sensitizer in neuroendocrine tumor (NET) preclinical models.
Authors: Aman Chauhan, Piotr Rychahou, Tadahide Izumi, Susanne M. Arnold, Lowell Brian Anthony, Mark Evers, Charles Kunos
Journal: Journal of Clinical Oncology (2019)

e15699 Background: Recent FDA approval of peptide receptor radiotherapy paved the way for radiation-based treatment for gastroenteropancreatic neuroendocrine tumors (GEPNETs). M-3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of radiation therapy in various solid tumor in vivo models. Currently there is no data evaluating anti-tumor efficacy of DNA-PK inhibitors in preclinical NET models. M-3814 inhibits DNA damage repair mechanism; antitumor efficacy of M-3814 in NETs is unknown. Methods: The efficacy of M-3814 in combination with radiation therapy (XRT) was evaluated in QGP-1 (pancreatic NET cell line) mouse model. Mice were injected with QGP-1 cells (5 mice) in 100 µL of PBS into the flank of mice with a 27-gauge needle. When tumor volumes reached average ~200 mm 3 , tumors were excised, separated into equal size tumor pieces and implanted subcutaneously into athymic nude mice. Next, mice were randomized into 4 groups for treatment with either placebo (n = 5), M-3814 (n = 5) alone (100 mg/Kg body weight (BW), XRT (n = 5) alone or in combination with M-3814 (n = 5). Treatment started when palpable tumors were established (200 mm3). Mice received M-3814 by gavage 30 minute prior to radiation therapy and irradiated with 4 daily doses of XRT at 2Gy per dose. Results: XRT and XRT+M-3814 treatment significantly decreased tumor size compared to control group. Combination treatment resulted in marked anti-tumor activity compared to both control group and XRT group. Tumors treated with XRT+M-3814 were also visibly less vascular. (Images will be provided in the poster). M-3814 alone had no effect on tumor growth as expected. Similar mouse weight changes were observed in both XRT and XRT+M-3814 treatment groups. Conclusions: M-3814 is a potent radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in QGP-1 xenograft model with marked reduction of tumor growth. Our enthusiasm for current project is driven not only by its inherent scientific importance, but also by its translational potential and the possibility to provide a more effective and less toxic radiation based treatment regimen for neuroendocrine tumors. [Table: see text]
Preventing Firearm-Related Death and Injury
Authors: Rocco Pallin, Sarabeth A. Spitzer, Megan L. Ranney, Marian E. Betz, Garen J. Wintemute
Journal: Annals of Internal Medicine (2019)

Deaths and injuries from firearms are significant public health problems, and clinicians are in a unique position to identify risk among their patients and discuss the importance of safe firearm practices. Although clinicians may be ill-prepared to engage in such discussions, an adequate body of evidence is available for support, and patients are generally receptive to this type of discussion with their physician. Here, we provide an overview of existing research and recommended strategies for counseling and intervention to reduce firearm-related death and injury.
Variation in the surgical management of locally advanced pancreatic cancer.
Authors: Bradley Norman Reames, Alex Blair, Robert Wallace Krell, James Padussis, Sarah P. Thayer, Massimo Falconi, Christopher Lee Wolfgang, Matthew J. Weiss, Chandrakanth Are, Jin He
Journal: Journal of Clinical Oncology (2019)

4122 Background: Recent reports suggest patients with locally advanced pancreatic cancer (LAPC) may become candidates for curative resection following neoadjuvant therapy, with encouraging survival outcomes. Yet the optimal management approach for LAPC remains unclear. We sought to investigate surgeon preferences for the management of patients with LAPC. Methods: An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included surgeon practice characteristics, preferences for staging and management, and 6 clinical vignettes (with detailed videos of post-neoadjuvant arterial and venous imaging) to assess attitudes regarding eligibility for surgical exploration. Results: A total of 150 eligible responses were received from 4 continents. Median duration in practice was 12 years (IQR 6-20) and 75% respondents work in a university setting. Most (84%) are considered high volume, 33% offer a minimally-invasive approach, and 48% offer arterial resection in selected patients. A majority (70%) always recommend neoadjuvant chemotherapy, and 62% prefer FOLFIRINOX. Preferences for duration of neoadjuvant therapy varied widely: 39% prefer ≥2 months, 41% prefer ≥4 months, and 11% prefer 6 months or more. Forty-one percent frequently recommend neoadjuvant radiation, and 51% prefer standard chemoradiotherapy. Age ≥80 years and CA 19-9 of ≥1000 U/mL were commonly considered contraindications to exploration. In 5 clinical vignettes of LAPC, the proportion of respondents that would offer exploration following neoadjuvant varied extensively, from 15% to 54%. In a vignette of oligometastatic pancreatic liver metastases, 32% would offer exploration if a favorable biochemical and imaging response to therapy is observed. Conclusions: In an international cohort of high volume pancreas surgeons, there is substantial variation in attitudes regarding staging preferences and surgical management of LAPC. These results underscore the importance of coordinated multi-disciplinary care, and suggest an evolving concept of “resectability.” Patients and their oncologists should have a low threshold to consider a second opinion for the surgical management of LAPC, if desired.
Risk factors associated with a second primary lung cancer (SPLC) in patients (pts) with a previous initial primary lung cancer (IPLC).
Authors: Misako Nagasaka, Dina Farhat, Kimberly Belzer, Seongho Kim, Hirva Mamdani, Ammar Sukari, Mary Ann Milczuk, Ann G. Schwartz, Antoinette J. Wozniak
Journal: Journal of Clinical Oncology (2019)

e13166 Background: The risk for development of a SPLC after treatment of an IPLC is around 1% to 2% per pt per year. The aim of this study was to characterize the risk factors associated with the development of a SPLC. Methods: Pts registered in the Karmanos Cancer Institute Tumor Registry diagnosed with an IPLC between 2000 and 2017 were included in this study. Pts with an IPLC who later developed a SPLC were matched for age, histology and stage to pts with an IPLC who did not develop a SPLC. SPLC was defined as a second lung cancer with a different pathology or if the same pathology, anatomically, molecularly, or chronologically distinct. Six variables including: stage at IPLC, histology, family history, surgery as a primary treatment for IPLC, and smoking history (determined by pack years, and continued tobacco use after first diagnosis) were reviewed. Logistic and Cox regression analyses were performed to determine the relationship of these characteristics with the development of a SPLC, and their association with overall survival (OS). Results: 121 pts with IPLC who later developed an SPLC were identified and compared to 120 pts with IPLC who did not develop a SPLC. Logistic analyses did not show that stage at first diagnosis, histology, family history, smoking history, and continued tobacco use after first diagnosis to be relevant for increased risk of SPLC. Pts who were primarily treated with surgical resection had a significantly higher probability of developing a SPLC (Odds Ratio: 0.24, 95% CI: 0.12 to 0.48, p &lt; 0.001). Pts who did not have surgical resection as their primary mode of treatment for IPLC had a significantly higher risk of death than those who received surgical resection (HR 3.02, 95% CI: 1.99 to 4.57; p &lt; 0.001). Conclusions: Based on our findings, pts who had surgical resection for an IPLC were found to have improved OS and a higher possibility of developing a SPLC. Stage at first diagnosis of IPLC, histology, family history, smoking history and continued use of tobacco after first diagnosis did not correlate with increased risk for SPLC. These results warrant further investigation and if confirmed could have an impact on surveillance recommendations post resection of initial lung cancers.
Combined oral administration of analgesia and anxiolysis for pain associated with bone marrow aspiration and biopsy.
Authors: Claudio Cerchione, Giovanni Martinelli, Lucio Catalano, Novella Pugliese, Roberta Della Pepa, Angela Gravetti, Davide Nappi, Fabrizio Pane, Vincenzo Martinelli
Journal: Journal of Clinical Oncology (2019)

e18313 Background: Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the commonly adopted local infiltration anesthesia (LIA) with lidocaine is unable to relieve the pain during the most uncomfortable phases, or the anticipatory anxiety related to pain recalling thereafter. As there are no formal guidelines for adding a sedoanalgesic premedication before beginning the BMAB, many combinations have been adopted by several authors. Our randomized and patient blinded trial aimed to evaluate, as primary end point, the efficacy and safety of opioid and benzodiazepine agent combination plus LIA in patients who underwent BMAB for hematological malignancies. Two secondary end points were: 1) to define if patients who already underwent to BMAB without LIA prefer sedoanalgesia; 2) to demonstrate if sedoanalgesia can influence the quality of the biological specimen harvested. Methods: Patients were randomly assigned into two arms for receiving either placebo plus LIA (standard group, 48,6%) or oral fentanyl citrate 200 mcg + oral midazolam 5 mg in addition to LIA (combo-group, 51,4%) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numered Rating Scale (NRS: 0-10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b, and T3) and evaluating discomfort grade during each moment of procedure in both groups. Cognitive function was measured before and 30 minutes after the procedure. Possible side effects were recorded, as well as the adequacy of tissue samples harvested. A total number 116 patients were enrolled in the study. 9 patients did not meet inclusion criteria and were excluded. 52 patients were randomized and assigned to standard group and 55 to combo group. Results: At T2b and T3 (corresponding to the biopsy time and time after the biopsy, respectively) there was a significantly lower ( p&lt; 0.05) perception of pain in the patients who received sedoanalgesia (combo-group) compared to those who did not (standard group). Moreover, 100 % of the patients in combo group who had previously undergone this procedure without premedication reported that they would prefer sedoanalgesia for the subsequent procedures. Conclusions: Administration of oral analgesia and anxiolysis is a safe and feasible option to be used in outpatient setting; sedoanalgesia is very effective in reducing pain during the biopsy and it diminishes the anticipatory anxiety related to a painful procedure. Patients should have the possibility to choose between local anesthesia alone or sedoanalgesia plus local anesthesia.
A randomized study comparing physician-directed or fixed-dose dexamethasone replacement following incomplete steroid premedication for docetaxel chemotherapy.
Authors: Tina Hsu, Carol Stober, Dean Fergusson, Kelly Daigle, Noorza Moledina, Gregory Russell Pond, Lisa Vandermeer, Christina M. Canil, Brian Hutton, John Frederick Hilton, Mark J. Clemons
Journal: Journal of Clinical Oncology (2019)

6610 Background: Prior to receiving docetaxel-based chemotherapy patients often incorrectly take all or part of their steroid-premedication. The lack of standardised steroid-replacement strategies can lead to variability in care and delays in starting chemotherapy while nursing/pharmacy/physicians establish an individualized patient plan, which can use up valuable chemotherapy chair time. A randomised controlled trial comparing a fixed-oral dose of dexamethasone and physician-directed replacement was performed. Methods: Patients who missed at least one dose of steroid-premedication were randomised to either standard replacement with dexamethasone 8mg orally or physician-directed replacement (any steroid, dose or route). The primary outcome was time from randomisation to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin rashes. Results: Sixty patients were randomized. Most patients were enrolled during cycle 1 (47.5%) and cycle 2 (22%) of docetaxel. The most frequent total doses of dexamethasone omitted were 24 mg (27%), 12 mg (20%), and 8 mg (19%). There were 7 different replacement strategies used by physicians. The most frequently used strategies were: dexamethasone 8mg IV (34.5%), 12mg IV (17.2%) and 20mg IV (13.8%). Patients in the fixed-dose arm received docetaxel earlier than patients in the physician-choice arm, at a median of 47.5 and 61 minutes after randomization (mean = 62.2 vs 83.4 minutes) (p = 0.033). No significant difference in rates of acute (0 vs 2)/delayed allergic reactions (1 vs 0), fluid retention (2 vs 1), or skin rashes (1 vs 0) was observed between the fixed-dose and physician-choice arms respectively. Conclusions: This is the first randomised trial to compare steroid-replacement strategies in this patient population. Fixed-dose replacement with dexamethasone 8 mg PO should be the preferred standard of care, as it reduces both the time to starting docetaxel and treatment variability, with no apparent increase in toxicity. Clinical trial information: NCT02815319.
A blinded evaluation of a clinical decision-support system at a regional cancer care center.
Authors: Suthida Suwanvecho, Edward H Shortliffe, Harit Suwanrusme, Surasit Issarachai, Tanawat Jirakulaporn, Nimit Taechakraichana, Palita Lungchukiet, Nittaya Thanakarn, Wimolrat Decha, Wisanu Boonpakdee, Pattanawadee Wongrattananon, Anita Preininger, Sarah Kefayati, Irene Dankwa-Mullan, Jaime Esquivel, Vimla L Patel, Gretchen Jackson, Narongsak Kiatikajornthada
Journal: Journal of Clinical Oncology (2019)

6553 Background: Clinical decision-support systems (CDSS) such as Watson for Oncology (WFO) may reduce treatment variation in oncology, provided options offered by the system are at least as acceptable as expert, evidence-based options. Deviation from expert consensus in practice is not well documented. In this blinded study, WFO therapeutic options and treatment decisions made by individual oncologists at Bumrungrad International Hospital (BIH) were evaluated by expert panel. Methods: Treatments selected by BIH that were labeled as either “for consideration” or “not recommended” by WFO were evaluated by a panel of 3 oncologists in 2018. The panel evaluated WFO options and previous BIH treatments for prospective cases from 2016-2018, blinded to the source of treatment option. Consensus of panel rated treatment pairs as: identical; both acceptable and roughly equivalent; both acceptable, but one preferred; one is acceptable and the other, unacceptable; neither is acceptable. The results of 321 treatment choices for breast, lung, colon and rectal cancers were analyzed, and McNemar’s test, a modified pairwise chi-square, was applied to identify differences between BIH and WFO. Results: 71% of both BIH and WFO treatments across all 4 cancer types were considered acceptable or identical by the panel. In 18 cases (5.6%), WFO treatments were preferred; in 14 cases (4.4%), BIH cases were preferred. Unacceptable treatments by either BIH or WFO were identified in 15% and 23% of treatments, respectively. Statistical analysis of treatment pairs revealed no significant difference between BIH and WFO treatments for breast, colon and rectal cancer. Treatment for lung cancer differed significantly ( p = 0.004); in 6% of cases, WFO was unacceptable and BIH acceptable; in 1% of cases, BIH was unacceptable and WfO was acceptable. Conclusions: This study is one of the first to compare therapeutic options from CDSS to treatment decisions made in practice, evaluated in a blinded fashion by an expert panel. 71% of treatments suggested by WFO CDSS were as acceptable as those selected by clinicians at the point of care, and some were considered superior. Decisions made in practice were unacceptable to the panel in 15% of cases, suggesting a role for CDSS.