tbuckley/cabot-search huggingface dataset:
Magnitude and quality of tumor-infiltrating T-cell response upon poxvirus-based active immunotherapy alone and in combination with CTLA-4 immune checkpoint inhibition.
Authors: Susan P Foy, Stefanie J Mandl, Tracy dela Cruz, Joseph Cote, Evan Gordon, Erica Trent, Alexis J. Franzusoff, Ryan B Rountree
Journal: Journal of Clinical Oncology (2014)

3013 Background: PROSTVAC PSA-targeted immunotherapy for metastatic castration-resistant prostate cancer is being tested in the PROSPECT Phase 3 trial. Another poxvirus-based immunotherapy product, MVA-BN-HER2, has been tested in early-phase clinical trials for breast cancer. The potential for synergistic benefit from combination active immunotherapy plus immune checkpoint inhibition is hypothesized. Survival benefit plus magnitude and quality of immune responses were evaluated in non-clinical studies following MVA-BN-HER2 dosing alone and in combination with CTLA-4 immune checkpoint inhibition. Methods: In a therapeutic CT26-HER2 lung metastasis model, mice were treated with MVA-BN-HER2 without and with anti-CTLA-4 antibody. Tumor infiltrating and peripheral antigen-specific CD4 and CD8 T cells were evaluated by FACS. Results: Combining MVA-BN-HER2 immunotherapy with CTLA-4 inhibition in therapeutic mouse tumor models demonstrated synergistic efficacy for median overall survival (p<0.001). Improved survival following MVA-BN-HER2 administration was accompanied by a 30 fold increase in tumor infiltrating antigen-specific CD8 T cells (CD8 TILs) compared to no treatment, which was augmented to 90 fold in combination with anti-CTLA-4. By contrast, single agent CTLA-4 inhibition provided a 10 fold increase in antigen-specific CD8 TILs over no treatment. The CD8 T cell response was characterized by an activated IFNγ+TNFα+ signature following poxvirus active immunotherapy compared to an IFNγ+TNFα- response with CTLA-4 inhibition alone. Infiltrating ICOS+ CD4 T cells were primarily FoxP3+ regulatory T cells in untreated and anti-CTLA-4 treated mice, but were FoxP3- effector T cells in mice treated with MVA-BN-HER2 alone or in combination with anti-CTLA-4. Conclusions: In non-clinical studies, poxvirus-based immunotherapy induces a robust, functional tumor-infiltrating T cell response for improved survival that is augmented significantly in combination with CTLA-4 immune checkpoint inhibition. Therapy Median survival (days) Untreated 30 α-CTLA-4 35 MVA-BN-HER2 49.5 MVA-BN-HER2 + α-CTLA-4 not reached by day 100
Gene expression analysis of B-cell receptors (BCR) pathway for identification of PDE4B gene as potential therapeutic target to overcome glucocorticoid resistance in primary CNS lymphoma.
Authors: Ariz Akhter, Noraidah Masir, Etienne Mahe, Ghaleb Elyamany, Meer-Taher Shabani-Rad, Douglas Allan Stewart, Donald Morris, Adnan Mansoor
Journal: Journal of Clinical Oncology (2014)

2088 Background: Gene expression profile (GEP) and supervised learning has identified effective targeted therapies and B-cell receptors (BCR) pathway inhibitors have improved outcomes in refractory Diffuse Large B-cell lymphoma (DLBCL) patients (pts). Primary lymphoma of the central nervous system (PCNSL) is a specific DLBCL entity arising in and confined to the CNS. BCR pathway is frequently dysregulated in PCNSL due to mutations affecting CD79B, CARD11, and MYD88 genes. Studies focusing on GEP in PCNSL; thus providing clinical tool for selection of novel targeted therapies is lacking. Methods: Here, we report GEP data on BCR related genes and associated downstream pathways (154 gene-probeset) in a cohort (n=21) of PCNSL pts, utilizing mRNA from diagnostic tissue, assessed by Nano string technology. Results: Hierarchical clustering (based on BCR genes) revealed two distinct clusters (A, n=15 and B, n=6) with differential expression of CD79a, CD79b, Bcl10 and CARD-11 (p<0.002). Cell of origin signatures were not distinct between two clusters (p=0.825). However, MAP kinase pathway (MEK1/ERK2) (p<0.018); TAB2/TAB3 (p<0.05); CCDN1 (p<0.05); TLRs (p<0.02) genes were differentially expressed. PDE4B gene, that regulates responses to BCR signaling and apoptosis, exhibited higher (1.5 x) expression in cluster A vs. cluster B (0.004). PDE4B expression correlated well with mTOR expression (p=0.018). Conclusions: BCR activity defines two distinct sub-groups within PCNSL with distinct signatures including expression of PDE4B. PCNSL pts may benefit from PDE4B inhibitors, through improving glucocorticoid sensitivity. It also demonstrates that insights into disease pathogenesis can be exploited to rationally overcome drug resistance.
Clinical outcome of patients with metastatic seminomatous germ cell tumor: Results of a single high-volume cancer center in Japan.
Authors: Ken-Ichi Kakimoto, Yujiro Hayashi, Yu Ishizuya, Ken Takeda, Yuichiro Yamaguchi, Yasuyuki Arai, Masashi Nakayama, Kazuo Nishimura
Journal: Journal of Clinical Oncology (2014)

e15539 Background: Metastatic seminomatous germ cell tumor (GCT) is a rare clinicopathologic entity. Here, we report the results of a retrospective analysis of patients with metastatic seminomatous GCT. Methods: We performed a retrospective review of the medical records of 44 men aged 21–62 years (median age, 35 years) who were treated at our institution between December 1978 and August 2013. Median follow-up was 6.5 years (range, 0.4–27.7 years). The primary site of disease was gonadal in 38 patients and extragonadal in 6. Extranodal metastases were present in 6 patients at lung, in 2 patients at bone and in 1 patient at brain. At the time of diagnosis, 25 patients had elevated serum levels of human chorionic gonadotropin (hCG), and 20 patients had elevated serum levels of lactate dehydrogenase (LDH). Survival curve was calculated by the Kaplan- Meier method. Results: Among 44 patients, 37 (84%) had received cisplatin-based chemotherapy as initial therapy, 5 (11%) had received radiation therapy for metastatic lymph nodes after high orchiectomy. Two patients underwent surgical procedures as an initial treatment under the diagnosis of a mediastinal tumor and a late relapse at retroperitoneal lymph node. After cisplatin-based chemotherapy, 9 of 37 patients achieved a complete response (CR), 27 achieved a marker-negative partial response (PR), and 1 presented progressive disease (PD). Nineteen retroperitoneal lymphnodes dissections and 5 lung metastasectomies were performed as post-chemotherapy surgery. In only 1 case, residual viable malignant cells were shown at retroperitoneal lymph node. The patient who had residual viable cancer cells had no relapse without adjuvant chemotherapy. Among the patients who achieved PR after chemotherapy, 14 were followed-up without excision of the residual masses and no relapse was observed. In total, 38 patients (86%) showed no evidence of disease, 5 patients (11%) died of disease progression, and 1 patient committed suicide without disease progression. The 5-year disease specific survival rate for all the patients was 92%. Conclusions: Patients with advanced seminomatous GCT undergoing cisplatin-based chemotherapy have an excellent prognosis.
The impact of 5-fluorouracil (5FU) dose intensity (DI) on survival outcomes in patients (pts) receiving multimodality therapy for locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).
Authors: Michael J. McNamara, David J. Adelstein, Gregory M.M. Videtic, Davendra Sohal, Thomas W. Rice, Cristina P. Rodriguez, Jerrold P. Saxton, Kevin L. Stephans, John Greskovich, David P. Mason, Sudish C. Murthy, Denise I. Ives, Joanna Bodmann, Lisa A. Rybicki
Journal: Journal of Clinical Oncology (2014)

e15031 Background: Perioperative chemotherapy improves outcomes for pts with LRA ACA of the E/GEJ compared to surgery alone. Combination chemotherapy regimens are frequently employed, and toxicity requiring dose modification is common. We investigated whether induction chemotherapy DI was prognostic for survival in pts receiving a tri-modality treatment regimen. Methods: From 2/08 to 1/12, 60 pts with ≥ cT3 or N1 or M1a (AJCC 6th) ACA of the E/GEJ enrolled in a phase II trial of induction chemotherapy, surgery, and adjuvant chemoradiotherapy (CRT) at the Cleveland Clinic. Pts received 3 cycles of induction chemotherapy with EOF [epirubicin 50mg/m2 day(d) 1, oxaliplatin 130mg/m2 d 1, 5FU 200 mg/m2/d CIVI for 3 weeks] q 21 days, followed by surgery and adjuvant CRT. The CRT consisted of 50-55 Gy in 1.8-2.0 Gy daily fractions concurrent with 2 cycles of cisplatin 20mg/m2/d and 5FU 1000 mg/m2/d, both administered as CIVI over 96 hours q21 days. Stepwise Cox proportional hazards analysis was used to examine the impact of induction chemotherapy DI on overall survival (OS) and recurrence free survival (RFS). Results: Of the 60 pts enrolled, 58 completed induction therapy and 54 underwent curative intent surgery. Dose reductions for oxaliplatin and epirubicin were infrequently required, with 10% of patients receiving less than 90% scheduled dose of either agent. 5FU dose modifications, however, were commonly required due to diarrhea, mucositis and hand-foot syndrome, with 22 pts (37%) receiving <70% and 43 pts (72%) receiving less than 90% scheduled dose. Multivariable (MV) analysis was performed on the 54 pts who completed induction therapy and underwent curative intent resection. Induction chemotherapy DI (<full dose vs. full dose) of 5FU (but not oxaliplatin or epirubicin) proved prognostic for OS [HR 4.5 (95% CI 1.8-11.8), p=0.002] and RFS [HR 4.6 (95% CI 1.9-11.3), p<0.001]. Conclusions: In our study of induction EOF, surgery and adjuvant CRT, 5FU dose reductions during induction therapy were frequently required. In MV analysis, compromised 5FU DI was associated with inferior RFS and OS.
Effect of pre-existing mental health comorbidities (MHC) on stage and timeliness of care of solid tumors in Veterans Affairs Connecticut Healthcare System (VACHS).
Authors: Roxanne Jimmy Wadia, Xiaopan Yao, Yanhong Deng, Jia Li, Steve Maron, Donna Connery, Handan Gunduz-Bruce, Michal G. Rose
Journal: Journal of Clinical Oncology (2014)

6542 Background: Axis I MHC affects approximately 18% and 30% of the adult US and VA population, respectively. There are limited and conflicting data on the impact of MHC on stage and timeliness of cancer care. The purpose of this study was to compare stage and timeliness of care in colorectal (CR), urothelial (UR) and head/neck (HN) cancers among Veterans with and without MHC. Methods: After IRB approval, we reviewed charts of Veterans with CR, UR and HN cancers diagnosed at VACHS between 2008 and 2011. Pts were identified via the cancer registry. NCCN guidelines were used to define standard of care. MHC was defined as an Axis I diagnosis treated in the year prior to the cancer diagnosis. Three time intervals were calculated: initial cancer symptom to presentation to a provider (TSP); provider to tissue diagnosis (TPD); and diagnosis to initiation of treatment (TDT). Data was analyzed using Chi-square, Fisher’s Exact and non-parametric Wilcoxon rank sum tests as appropriate, using SAS. Results: We reviewed 412 charts including 174 pts with UR, 155 with CR and 83 with HN cancers. Of our pts, 36.6% (151) had Axis I MHC, 18.7% (77) had alcohol abuse/dependence, and 5% (21) had illicit drug abuse/dependence. In regard to staging, 221 (45%), 171 (41.5%) and 96 (23.3%) had Stage 0-1, stage II-III, and stage IV cancer. Diagnosis and treatment delays of at least 2 weeks were found in 73 pts (17.7%) and 63 (15.3%), respectively. In addition, 61 pts (14.8%) chose not to accept the standard of care. We found no difference between pts with or without MHC in stage distribution, symptomatic disease at presentation, diagnostic or treatment delays, or deviation from standard of care. Furthermore, there were no significant difference in the three measures of timeliness of care (TSP, TPD and TDT) between pts with and without MHC. Conclusions: Stage at diagnosis of CR, UR and HN cancers in VACHS did not differ between pts with and without Axis I MHC. The presence of MHC did not result in delays in care. Our data provides reassurance that within a healthcare system that provides integrated, comprehensive medical and psychiatric care, pts with Axis I MHC do not experience significant delays in cancer care.
Impact of 25-gene panel testing and integrated risk management tool on medical management in hereditary cancer syndrome evaluation.
Authors: Lucy R. Langer, Laurie Korst, Larry J. Geier, Jennifer Saam, Kelsey Moyes, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2014)

1553 Background: The identification of patients (pts) with hereditary cancer syndromes such as Hereditary Breast and Ovarian Cancer (HBOC) or Lynch syndrome (LS) leads to profound clinical management changes. Using next generation sequencing, more comprehensive gene panels with greater sensitivity have been developed. However, most pts still receive a negative genetic test result. Integrating personal and family cancer history identified during the screening process with genetic test results can offer refined management recommendations. Methods: Patients identified using criteria for HBOC or LS were tested using a 25-gene hereditary cancer panel. Recommendations from testing incorporated the genetic test result and a personalized cancer risk and management tool (CRMT) based on a patient’s personal and family history and professional guidelines. Health care providers (HCPs) were surveyed for their management advice to the patient for four cancers (breast, ovarian, endometrial and colon) before and after testing. Pre-test surveys were received from 1414 patients at the time of the data analysis. We report data from matched pre and post-test survey pairs for a preliminary 100 pts to be updated upon presentation. Interventions were ranked from least aggressive (surveillance) to most aggressive (surgery). Results: In this sample set, 48% of pts had a diagnosis of breast, ovarian, colorectal, endometrial, pancreas, melanoma, stomach and/or prostate cancer, 3% had a history of other cancers and 49% had no personal history of cancer. 65% of pts met NCCN guidelines for HBOC, 10% for LS and 18% met guidelines for both syndromes. Overall, HCPs used the genetic test result with the CRMT to guide their management decisions in 91% of cases. After testing, 25% of pts received a change in management recommendations, 60% of pts with a positive result and 23% of pts with a negative result. Of the management changes, 72% were in surveillance, 16% in chemoprevention, 20% in surgery and 28% other. Conclusions: Integrating expanded genetic panel test results with a personalized cancer risk and management tool aids HCPs in providing tailored cancer risk management in both gene positive and negative populations.
Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.
Authors: Holly Jane Meany, Jeffrey Dome, Pamela S. Hinds, Rochelle Bagatell, Suzanne Shusterman, Brigitte C. Widemann, Emily Stern, Wendy B. London, AeRang Kim, Elizabeth Fox, Carlos Rodriguez-Galindo, Jane E. Minturn
Journal: Journal of Clinical Oncology (2014)

10052 Background: Sorafenib, an orally bioavailable, multi-target tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated single agent activity in various malignancies. This study was designed to determine the maximum tolerated dose of sorafenib in combination with irinotecan and assess the feasibility of incorporating patient reported outcome (PRO) measures into a phase I trial in children with relapsed or refractory solid tumors. Methods: Sorafenib was administered orally twice daily, continuously, beginning at 150 mg/m2/dose with irinotecan, 70 mg/m2/dose orally, once daily for 5 days to complete a 21-day cycle (dose level 1). Sorafenib was escalated to 200 mg/m2/dose (dose level 2) followed by escalation of irinotecan to 90 mg/m2/dose (dose level 3). Three patients enrolled initially at each dose level. Secondary aims included evaluating PRO measures as an adjunct to traditional phase 1 endpoints and determining the pharmacokinetic profile of sorafenib and irinotecan in children. Results: Twelve evaluable patients [6 male, 6 female; median age 13 years (range 4.6-19.8)] with Wilms tumor (n= 4), osteosarcoma (n=3), neuroblastoma (n=1), CNS tumor (n=1), desmoplastic small round cell tumor (n=1), soft tissue sarcoma (n=1) and germ cell tumor (n=1) have enrolled to date. No dose limiting toxicities (DLT) were seen at dose level 1 (n=3). Two of 3 patients at dose level 2 experienced DLT (grade 3 diarrhea with dehydration, grade 3 hyponatremia). Dose level 1 was expanded to evaluate up to 12 patients. Of 9 patients who have completed therapy at this dose level, one patient had DLT, grade 4 thrombocytopenia. Three patients received ≥6 cycles with stable disease prior to disease progression. Two additional patients were removed from protocol therapy after experiencing responses that rendered them eligible for surgical resection. All eligible patients (n=4) completed PRO measures. Conclusions: The recommended dose for children is anticipated to be sorafenib 150 mg/m2/dose, twice daily, continuously with irinotecan 70 mg/m2/dose, once daily for 5 days, repeated every 21 days. This convenient, oral outpatient regimen is well tolerated in pediatric patients. Clinical trial information: NCT01518413.
Long-term results and prognostic factors for survival following adjuvant chemotherapy (AC) for muscle-invasive urothelial bladder cancer (UC): A French retrospective multicenter cohort.
Authors: Damien Pouessel, Aurelie Le Thuaut, Dimitri Vordos, Nadine Houede, Yohann Loriot, Christine Chevreau, Florence Joly, Philippe Beuzeboc, Alexandre de la Taille, Sylvie Bastuji-Garin, Yves Allory, Stephane Culine
Journal: Journal of Clinical Oncology (2014)

4549 Background: Role of AC in patients (pts) with UC undergoing radical cystectomy (RC) is debated. Methods: We retrospectively analyzed survival of 226 consecutive pts treated with RC and AC for UC with muscle-invasion or lymph node (LN) involvement in 6 French academic hospitals between 2000 and 2009. Non-urothelial cases were excluded. Multivariate Cox proportional hazards regression adjusted for center was used to estimate adjusted hazard ratios with 95% confidence interval. Results: Median age was 62.4 [range: 35-82], 189 (84%) were male. ECOG performance status was 0-1 in 211 pts (93.3%). Stage were p<T2 (n=15), pT2 (n=31), or pT≥3 (n=180), pN0 (n=37), pN1 (n=54), pN≥2 (n=114) or pNx (n=21), M0. Mixed UC were 43 (19%). Median number of resected LN was 11.5 [1-36]; density (LND) 25% [3.1-100]. Median time between RC and AC was 61.5 days [18-162]. Gemcitabine-cisplatin (GC), gemcitabine-carboplatin (GCb), and methotrexate-vinblastine-doxorubicine-cisplatin (MVAC) regimen were delivered in 71.2%, 21.7% and 5.3% of pts. Median number of cycles was 4 [1-6]. Thirteen pts (5.7%) with LN metastases (LN+) received adjuvant pelvic radiotherapy (ART) after AC. Median follow-up was 4.2 years [0.38-11.0], 135 (59.7%) pts have relapsed, 99 (73.3%) received at least one chemotherapy regimen for metastasis. Also 133 pts (59.2%) died, most death (90.1%) were related to recurrence. Median overall survival (OS) and disease-free survival were 3.4 and 1.03 years. Five-year OS and cancer-related survival (CRS) rates were 40.7% and 42.6% respectively. In multivariate analysis, pT≥3 stage (HR: 2.31, 95%CI 1.27-4.19, p=0.006), < 4 cycles (1.99, 1.15-3.45, p=0.01), and LND > 50% (2.34, 1.23-4.46, p=0.01) were adverse prognostic factors for CRS. ART (0.33, 0.10-1.11, p=0.07) tend to provide survival benefit. Conclusions: In this large contemporary retrospective study reporting real-life survivals in pts receiving AC after RC with survival results consistent with published data, LND < 50% and ART in LN+ pts predict a more favorable prognosis after AC. Further studies are warranted to reveal the exact impact of ART in this subset of pts.
The Prognostic Roles of the Ki-67 Proliferation Index, P53 Expression, Mitotic Index, and Radiological Tumor Invasion in Pituitary Adenomas
Authors: Rovshan Hasanov, Berna İmge Aydoğan, Saba Kiremitçi, Esra Erden, Sevim Güllü
Journal: Endocrine Pathology (2019)
Policies of Exclusion: Implications for the Health of Immigrants and Their Children
Authors: Krista M. Perreira, Juan M. Pedroza
Journal: Annual Review of Public Health (2019)

Public policies play a crucial role in shaping how immigrants adapt to life in the United States. Federal, state, and local laws and administrative practices impact immigrants’ access to education, health insurance and medical care, cash assistance, food assistance, and other vital services. Additionally, immigration enforcement activities have substantial effects on immigrants’ health and participation in public programs, as well as effects on immigrants’ families. This review summarizes the growing literature on the consequences of public policies for immigrants’ health. Some policies are inclusive and promote immigrants’ adaptation to the United States, whereas other policies are exclusionary and restrict immigrants’ access to public programs as well as educational and economic opportunities. We explore the strategies that researchers have employed to tease out these effects, the methodological challenges of undertaking such studies, their varying impacts on immigrant health, and steps that can be undertaken to improve the health of immigrants and their families.
Trends in critical chemotherapy drug manufacturing: Implications for future drug shortages and treatment.
Authors: Helen M. Parsons, Susanne Schmidt, Mary Jo Pugh, Anand B. Karnad
Journal: Journal of Clinical Oncology (2014)

e17522 Background: In 2010, the US Food and Drug Administration identified 178 reported drug shortages, 132 of which involved sterile injectable drugs, such as cancer drugs. These shortages may lead physicians to prioritize patients, improvise standard treatment regimens and possibly choose unproven treatment options. Our aim was to evaluate trends in the number of manufacturers of critical chemotherapy drugs. Methods: We conducted our study using information from the 2003-2009 Redbook, which publishes manufacturing information for all FDA-approved drugs in the US each year. We abstracted complete information on the number of distinct manufacturers for each approved cancer drug for first-line treatment of colon, lung and breast cancer by year. Exploratory analysis was used to quantify trends in manufacturing by cancer site and drug over time. Results: Seventeen drugs were approved for first-line treatment of colon, breast or lung cancer in 2003, increasing to 32 in 2009. While there were 3 approved colon cancer drugs in 2003, one had only one manufacturer. By 2009, 5 out of 8 approved colon cancer drugs had one manufacturer—but the 2 mainstay therapies, fluorouracil and leucovorin, had 3-10 manufacturers all years. Of 8 approved drugs for breast cancer in 2003, 2 had one manufacturer. By 2009, 7 out of 14 had one manufacturer, but many components of common therapeutic regimens (cyclophosphamide, doxorubicin, fluorouracil, and methotrexate) had 3-15 manufacturers all years. Finally, there were 6 approved lung cancer drugs in 2003, 2 of which had one manufacturer. In 2009, 5 out of 10 drugs had only one manufacturer, but common therapeutic regimens (carboplatin, cisplatin, and etoposide) all had 1-11 manufacturers. Conclusions: Our data indicate that the majority of mainstay chemotherapy regimens for colon, lung and breast cancer have multiple registered manufacturers each year, which can fluctuate greatly. However, the number of manufacturers does not necessarily correlate with the available supply for a given drug considering the large number of reported drug shortages for chemotherapy drugs that continue throughout the US.