tbuckley/cabot-search huggingface dataset:
Safety analysis of regorafenib prior to selective internal radiation therapy (SIRT) using <sup>90</sup>Y resin microspheres for the treatment (tx) of patients (pts) with refractory metastatic colorectal cancer (mCRC) with liver metastases (mets).
Authors: Andrew S. Kennedy, Dianna Shipley, L. Johnetta Blakely, Michael Brian Hemphill, Kent C. Shih, Mark G. Mainwaring, James D. Peyton, John D. Zubkus, David Donald Wright, Johanna C. Bendell, Jaswinder Singh
Journal: Journal of Clinical Oncology (2017)

e15040 Background: SIRT (or radioembolization) has been successfully used in the tx of mCRC patients with liver mets who are not surgical candidates. The addition of the multi-kinase inhibitor, regorafenib to SIRT is an attractive option as anti-tumor and maintenance tx for refractory CRC. Here we present the safety analysis of the 1 st of 2 cohorts of our Phase II, open-label study comparing the safety of the combination of SIRT and regorafenib where chemotherapy occurs either before or after SIRT. Methods: mCRC pts with evidence of liver mets not treatable by surgical resection or local ablation were tx with 160 mg regorafenib QD PO on days 1-21 of a 28-day cycle followed by a 1 week (wk) washout then SIRT infusion (SIR-Spheres; Sirtex, North Sydney, Australia). Liver function was evaluated 2 wks and 4 wks after SIRT, and regorafenib was re-initiated if liver function was normal. Pts were evaluated for safety, and restaged on wk 6 and 12 following SIRT. The primary objective was to evaluate the safety of this tx schema. Results: 25 pts were enrolled from 7/15 to 8/16: median age 56 yrs, 48% male; 88% colon cancer, 12%, rectal cancer; 48% KRASmt, 4% BRAFmt. 68% of pts had prior systemic therapy for metastatic disease and 80% of pts had prior CRC surgeries. Pts received a median 11 wks regorafenib. 3 pts received regorafenib, but not SIRT due to disease progression. The median activity of SIRT delivered to the liver was 38 mCi and the median lung shunt fraction was 4%. The median tumor volume treated was 76 mL. The most common tx-related adverse events (AEs) were fatigue (60% all grades [G]; 8% G3/4), decreased appetite (32% all G; 0 G 3/4), and nausea (32%, all G; G 3/4). There were 4 tx-related serious AEs (bowel perforation, intractable abdominal pain, portal hypertension, and diarrhea) and no tx-related deaths. The overall response rate was 4%. The median PFS was 4 months and the median OS was 12 months. Conclusions: The treatment of mCRC pts with liver mets with regorafenib followed by SIRT infusion was found to be tolerable in this pt population. Further efficacy analysis of this treatment schema is merited. Clinical trial information: NCT02195011.
Evaluating the use of prophylactic cranial irradiation in small cell lung cancer.
Authors: Asaad Trabolsi, Jorge Martinez Bencosme, Estelamari Rodriguez
Journal: Journal of Clinical Oncology (2018)

e18838 Background: Intracranial metastases occur in more than 50% of patients with small cell lung cancer (SCLC). Cranial irradiation (PCI) is effective in decreasing the incidence of cerebral metastases and improving survival. NCCN recommend PCI for all patients with limited disease (LD-SCLC) with complete response (CR) or partial response (PR) to chemotherapy and to consider PCI for patients with extensive disease (ED-SCLC). The aims of this study were to evaluate overall survival (OS) in patients undergoing PCI and to assess if patients received PCI per national guidelines Methods: A retrospective chart review was conducted of patients with LD-SCLC and ED-SCLC diagnosed at the Mount Sinai Comprehensive Cancer Center between January 2010 and December 2014. Overall survival was assessed using means and standard deviation Results: From 2010 to 2014 a total of 76 patients were diagnosed with SCLC. At diagnosis, 28 patients (37%) had LD-SCLC and 48 (63%) had ED-SCLC. The median age was 65 years. The median overall survival from the time of diagnosis was 13 months (range: 1-86 months) for LD-SCLC patients, and 6.0 months (range: 0-24 months) for ED-SCLC patients. Only seven patients (25%) of those with LD-SCLC completed PCI (25 Gray in 10 fractions) after achieving CR/PR. One patient with ED-SCLC completed PCI after PR. Median OS in LD-SCLC patient receiving PCI was 18.0 months (range: 9-86 months), compared with 12.5 months (0.1-66) in patients who did not (P < 0.001). Twenty-one LD-SCLC patients (75%) did not receive PCI due to patient suitability reasons, including poor performance status, neurocognitive dysfunction and patient refusal Conclusions: PCI use at our institution was lower than national utilization rates and not concordant with NCCN recommendations. In our LD-SCLC cohort who received PCI, median OS was comparable to published data and significantly improved compared to those who did not. This was predominantly due to poor chemotherapy tolerance, advanced age or neurocognitive dysfunction. Hence, PCI should be offered to all patients who responded to treatment and withheld only if contraindications exist. Finally, standard neurocognitive testing use can identify patients at high risk of neurocognitive toxicity after PCI.
Time’s Up for Medicine? Only Time Will Tell
Authors: Esther K. Choo, Jane van Dis, Dara Kass
Journal: New England Journal of Medicine (2018)

Interview with Dr. Esther Choo on steps that medical institutions can take to support and empower women. (08:14)Download Putting an end to the culture of gender-based harassment is key to recruiting, retaining, and realizing the full potential of nearly half the medical workforce. Doing so will depend on our willingness to undergo a complete transformation in how we approach this problem.
Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness
Authors: Bernhard W. Renz, Takayuki Tanaka, Masaki Sunagawa, Ryota Takahashi, Zhengyu Jiang, Marina Macchini, Zahra Dantes, Giovanni Valenti, Ruth A. White, Moritz A. Middelhoff, Matthias Ilmer, Paul E. Oberstein, Martin K. Angele, Huan Deng, Yoku Hayakawa, C. Benedikt Westphalen, Jens Werner, Helen Remotti, Maximilian Reichert, Yagnesh H. Tailor, Karan Nagar, Richard A. Friedman, Alina C. Iuga, Kenneth P. Olive, Timothy C. Wang
Journal: Cancer Discovery (2018)

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras +/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras +/G12D;LSL-Trp53 +/R172H;Pdx1-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC.Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458-73. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.
Abstract 14072: Novel Atheroprotection Therapy: Reduction in Serum Lipid Levels by HSP27 Via Down-regulation of HNF1a and PCSK9 Expression
Authors: Chunhua Shi, Yong-Xiang Chen, Catherine Diao, Zarah Batulan, Edward R OBrien
Journal: Circulation (2016)

Background: Heat Shock Protein 27 (HSP27) levels are reduced in patients with CAD and are predictive of future cardiovascular risk. Experimental atherogenesis is attenuated when HSP27 levels are au...
A new combination therapy using recombinant human adenovirus p53 injection (rAd-p53) to manage advanced thyroid cancer.
Authors: Jingqiang Zhu
Journal: Journal of Clinical Oncology (2017)

e17585 Background: Although most thyroid cancers have good clinical outcomes, there still have some advanced and radioiodine-resistant thyroid cancers being lack of effective treatment. In this study, we reported a new combination therapy including recombinant adenovirus-p53 (rAd-p53) to treat advanced thyroid cancers. Methods: Two types of unresectable cancers (one advanced PTC and one ATC) received preoperative intratumoral injection of rAd-p53 combined with radiotherapy to shrink the tumor and surgery to remove the tumor. In the matched controlled clinical trial, 82 advanced PTC patients accorded with the inclusive criteria and exclusion criteria were included and matched into experimental group (EG, n = 41) and control group (CG, n = 41). Compared CG received surgery only, EG received preoperative intratumoral injection of 2×10 12 rAd-p53 viral particles (VP) per 3 days for 5 times and surgery. Results: In the advanced PTC case, the combination treatments including rAd-p53 gene therapy combined with radiotherapy evidently shrunk the tumor and improved the operative condition. Finally, the patient received a successful surgery to remove the tumor totally. In the ATC case, rAd-p53combined radiotherapy obvious relieved enlargement of the lump in the neck and shrunk the tumor. More importantly, the program of surgery to excise the tumor was deemed suitable for this ATC patient through a series of treatments and severity evaluation. In the matched controlled clinical study, compared the control group (CG), rAd-p53 significantly increased the radically operative rate in experiment group (EG) (92.7% vs73.2 %, P= 0.021, n = 41). The 7 years follow-up data showed rAd-p53 decreased locoregional recurrence rate (19.51% vs 36.59%) and new metastasis rate (7.32% vs 17.07%) and increased the median time to locoregional recurrence (24.5 M vs 23.27 M) and new metastasis (19.0 M vs 9.2 M) and the disease-free survival rate (75.61% vs 46.34%) for patients in EG. Conclusions: The combination therapy improved the prognosis to patients with advanced thyroid cancer, indicating this combination therapy including rAd-p53 has an important implication for managing advanced thyroid cancer.
Randomized phase 2 trial of polatuzumab vedotin (pola) with bendamustine and rituximab (BR) in relapsed/refractory (r/r) FL and DLBCL.
Authors: Laurie Helen Sehn, Manali Kamdar, Alex Francisco Herrera, Andrew McMillan, Christopher Flowers, Won Seog Kim, Tae Min Kim, Muhit Özcan, Judit Demeter, Mark Hertzberg, Marek Trněný, Gilles A. Salles, Andrew Davies, Jamie H. Hirata, Ji Cheng, Grace Ku, Matthew J. Matasar
Journal: Journal of Clinical Oncology (2018)

7507 Background: Pola is an antibody-drug conjugate targeting CD79b+ cells in B-NHL. Early results led to FDA breakthrough therapy status and EMA PRIME designation. We now report combined results for safety and efficacy from the randomized r/r FL and DLBCL cohorts of a phase 1b/2 study (ClinicalTrials.gov NCT02257567). Methods: 80 FL and 80 DLBCL transplant-ineligible patients (pts) were randomized 1:1 to pola 1.8 mg/kg + BR (B: 90mg/m2 x 2 days; R: 375mg/m2) or BR for 6 cycles (q28 days FL, q21 days DLBCL). Primary endpoint: PET-CR, 6–8 weeks after treatment end, by independent review committee (IRC) using modified Lugano criteria. Results: For FL pts (pola+BR v BR), median age was 65 v 63 years, both arms had median 2 prior therapies, 41% v 42% were refractory to last therapy, and 64% v 37% had FLIPI 3–5. At 24 Oct 17, median follow up was 15 months. DLBCL characteristics and follow up were previously described (Sehn, ASH 2017). The most common grade 3–5 AEs higher in pola+BR v BR were cytopenias, febrile neutropenia, and infections. SAEs higher in pola+BR v BR were febrile neutropenia (FL, DLBCL) and infection (FL). Grade 5 AE rates were similar between treatment arms: 5% (FL) and 18% (DLBCL). PET-CR and PFS were similar between FL arms. In DLBCL, pola+BR showed significantly higher PET-CR rates (p = 0.012) and longer median (m) PFS (p < 0.0001) and mOS (p = 0.0008) (Table). In DLBCL, longer PFS and OS were seen for pola+BR in 2nd-line (2L), 3rd-line plus (3L+), relapsed, and refractory pts. mPFS (pola+BR v BR [months]): 2L (11.1 v 3.7), 3L+ (6.0 v 2.0), relapsed (11.1 v 5.1), refractory (6.0 v 1.9). mOS: 2L (not reached [NR] v 5.9), 3L+ (11.5 v 3.8), relapsed (NR, NR), refractory (11.5 v 3.8). Conclusions: The toxicity of pola+BR was manageable. In FL, pola+BR did not improve PET-CR rate; longer follow up is necessary to assess survival. In contrast, in DLBCL, pola+BR led to significantly higher PET-CR rates and notably longer PFS and OS v BR regardless of prior treatment status. Clinical trial information: NCT02257567.Efficacy (ITT). FL DLBCL Pola+BR (N = 39) BR (N = 41) Pola+BR (N = 40) BR (N = 40) IRC PET-CR, % 69 63 40 15 Median PFS, months (95% CI) 17 (13.4, NR) 17.3 (12.5, NR) 6.7 (4.9, 11.1) 2 (1.5, 3.7) Median OS, months (95%CI) NR NR 11.8 (9.5, NR) 4.7 (3.7, 8.3)
Everolimus/sorafenib combination in the treatment of refractory pediatric osteosarcomas: Single center experience.
Authors: Alexander A. Fedenko, Elmira Senzhapova, Mamed Aliev, Aslan Dzampaev, Beniamin Bokhyan
Journal: Journal of Clinical Oncology (2016)

e22501 Background: Treatment results of heavily pretreated refractory childhood osteosarcoma are not satisfactory. According to the data of different pilot trials progression-free survival (PFS) curves dramatically tend to zero with a median follow-up in 6-8 months. Possibility of using these drugs combination in children is unknown. Methods: From May 2013 to January 2016 fourteen children and adolescents with refractory osteosarcoma were included in this pilot trial. Male/female ratio was 8/6. Median age – 14.3 years (range from 7 till 17). All patients had advanced disease, underwent chemotherapy including doxorubicin, cisplatin, high-dose methotrexate, high-dose ifosfamide, gemcitabine and docetaxel, had progression on this chemotherapy before they were enrolled in this trial. Sorafenib was administered orally at the starting dose 150 mg/m2 (with following possible escalation up to 200 mg/m2) every 12 hours, everolimus - orally at the starting dose 2.5 mg/m2 (with following possible escalation to 5 mg/m2) once a day for consecutive 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was median PFS and OS. Results: The most common toxicity was skin erythema (100%), hand and foot skin syndrome (14.2%) and oral mucositis (21.4%). Hematological toxicity was not more than grade I-II (100%) and mainly due to thrombopenia and leukopenia. Responses included mostly stable disease and rarely minor responses. Median PFS was 4.4 months and median OS was 6 months. Conclusions: The combination of sorafenib and everolimus showed activity as a further-line treatment of heavily pretreated children and adolescents with refractory osteosarcoma with tolerable toxicity profile and further trials are needed.
Themes and costs underlying avoidable terminal oncology ICU hospitalizations.
Authors: Robert Michael Daly, Andrew Hantel, Blase N. Polite, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2017)

6548 Background: ICU admissions in the last 30 days of life are an indicator of poor care. Our prior research found nearly half of terminal oncology ICU hospitalizations are potentially avoidable. Methods: Data were derived from 72 patients consecutively cared for in an academic medical center’s oncology practice who died in an ICU between July 1, 2012 and June 30, 2013. Oncologists, intensivists, and hospitalists used a standardized assessment tool to review each patient’s electronic health record from 3 months prior to hospitalization until death; they made a clinical determination of avoidability. Two investigators, blinded to the specialty, used a grounded theory approach to extract clinical themes associated with the reviewer’s determination of avoidability. Total, direct, and indirect costs were abstracted for each avoidable hospitalization. Results: Thirty-four (47%) of the examined hospitalizations were deemed avoidable. The primary themes associated with avoidability, and the percentage by specialty, were as follows: 1) failure to initiate appropriate advance care planning in the outpatient setting (68% oncologists, 55% intensivists, 65% hospitalists), 2) failure to integrate understanding of limited prognosis (23% oncologists, 24% intensivists, 26% hospitalists), and 3) failure of clinical management (6% oncologists, 21% intensivists, 6% hospitalists). A failure to educate and integrate surrogates into timely medical decision-making was a prominent secondary theme for oncologists (22%), intensivists (18%), and hospitalists (29%). The total cost per patient averaged $44,532 with direct and indirect costs averaging $25,215 and $19,317, respectively. High cost areas were ICU level care (35%) and pharmaceuticals (16%). Conclusions: The themes identified suggest potential preventative interventions, including higher rates of outpatient advance care planning, oncology inpatient communication to promote patient’s prognostic understanding, prevention of failures in clinical management, and better education and integration of surrogates. Given 8% of oncology patients expire in the ICU and 47% were identified as avoidable, the potential national annual cost of these avoidable hospitalizations is $997MM.
Survival and predictive factors related to comprehensive geriatric assessment for the occurrence of healthcare-associated infections (HAI): A cohort study with elderly cancer patients.
Authors: Guacyra Magalhaes Pires, Jurema Telles O Lima, Letícia telles Sales, Maria Julia Gonçalves Mello, Anke Bergmann, Mirella Rebello Bezerra, José Natal Figueiroa, Luiz Claudio Santos Thuler, Vera da silveira Magalhães
Journal: Journal of Clinical Oncology (2018)

e22053 Background: Elderly oncology population(EOP) corresponds to an increasing and heterogeneous group with high risk to infectious complications. Advances in antimicrobial therapy have not accompanied progress in cancer therapy. Identifying at admission the predictive factors for infection and death in the elderly population oncology is highly desirable for offering personalized care. Methods: Prospective cohort involving elderly people with cancer, followed by six months. At admission, evaluation of sociodemographic, clinical-laboratory and CGA variables. The outcomes studied were the first HAI and death. Multivariate Cox proportional hazards analysis identified risk factors for HAI and survival of patients with and without HAI by Kaplan-Meier was compared by the log rank test. Results: 605 patients were eligible, mean age 71.3 (SD ± 7.4). 29.1% developed HAI and 33.0% died during the study follow-up, 14.2% died within three weeks after the diagnosis of HAI. The risk factors for HAI were: risk of malnutrition / malnutrition by global nutritional assessment (MAN-global ≤ 23.5) (HR 2.18 95% CI 1.53-3.11); functional performance ≤ 50 by Karnofsky (HR 1.69 95% CI 1.14-2.50); severe renal dysfunction / final stage (HR 2.51 95% CI 1.37- 4.60).The topographies of the most frequent IRAS were urinary tract infection (UTI) (39.2%), pneumonia (22.7%) and bloodstream infection (14.8%). Minor survival among patients with HAI (log rank < 0.001). About half of those with pneumonia (50.0%) or ICS (46.2%) died within six months, with 30% and 23.1% of these deaths occurring within 21 days of the diagnosis of pneumonia or ICS, respectively. Conclusions: HAI represents a problem of high morbidity and mortality for EOP. Reduced renal function, risk of malnutrition and low functional performance were independent factors for HAI, significantly reducing the survival of elderly cancer patients. These aspects should be evaluated systematically in the admission of the elderly cancer patient and taken into account in the planning of the care to be offered.
Phase II study of chemoselection with docetaxel plus 5-fluorouracil and cisplatin induction chemotherapy and subsequent conversion surgery for locally advanced unresectable esophageal cancer.
Authors: Tomoya Yokota, Ken Kato, Yasuo Hamamoto, Yasuhiro Tsubosa, Hirofumi Ogawa, Yoshinori Ito, Hiroki Hara, Takashi Ura, Takashi Kojima, Keisho Chin, Shuichi Hironaka, Takayuki Kii, Yasushi Kojima, Yasunori Akutsu, Hisayuki Matsushita, Kentaro Kawakami, Keita Mori, Yushi Nagai, Chika Asami, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2016)

4021 Background: This multicenter phase II trial assessed the safety and efficacy of docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (IC) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer (LAUEC). Methods: Esophageal cancer patients (pts) with clinical T4 disease and/or unresectable supraclavicular lymph node metastasis were eligible. The treatment starts with 3 cycles of DCF-IC, followed by CS if resectable, or by concurrent radiation plus chemotherapy with 5-fluorouracil and cisplatin (CF-RT) if not resectable. In case of CF-RT, the resectability is re-evaluated at 30 Gy-40Gy, followed by CS if resectable, or by additional CF-RT with total irradiation dose of 60Gy. If resectable after completion of CF-RT, CS is performed. The primary endpoint is 1-year overall survival (OS). We assumed a null hypothesis with 50% and expected 65% of 1-year OS. Results: Characteristics of 48 pts enrolled were as follows: median age, 66 years; PS0/1, 28/20; primary tumor sites, Ut/Mt/Lt, 13/33/2; T3/T4a/T4b, 5/1/42; N0/N1/N2/N3, 4/12/22/10; M0/M1, 39/9. Eleven pts (22.9%) developed febrile neutropenia related to DCF-IC. CS was performed in 20 pts (41.7%), including DCF-CS (n = 18), DCF-CF-RT40Gy-CS (n = 1), and DCF-CF-RT60Gy-CS (n = 1). R0 resection was confirmed in 19 pts (39.6%). Grade ≥ 3 postoperative complications includes 1 recurrent laryngeal nerve palsy, 1 lung infection, 1 wound infection, 1 pulmonary fistula, and 1 dysphagia; but no remarkable postoperative complications were observed in pts who underwent CS. The overall cure rate including R0 resection or the clinical complete response after CF-RT was 47.9%. The estimated 1-year OS was 67.7% and lower limit of 80% confidence interval was 59.5%. The OS for pts who underwent R0 resection was significantly longer than those who did not undergo R0 resection (median survival time: not reached vs. 326 days, p < 0.01). There was 1 treatment-related death in patient who received DCF-CF-RT60Gy. Conclusions: DCF-IC followed by CS showed promising signs of tolerability and efficacy in pts with LAUEC. Clinical trial information: 000011089.