tbuckley/cabot-search huggingface dataset:
Suvmax in 18-Fluorodeoxyglucose PET/CT Potentially Predict the Estimation of a Positive Biopsy in Cases of Lymphoma
Authors: Pooja Chandra, Olufunke Akinbobuyi, Albert Liao, Jyoti Arora, Zhengjia Chen, Mary J Lechowicz, Amelia A. Langston, Jeanne Kowalsky, Jonathon B. Cohen, Christopher R Flowers, Leon Bernal-Mizrachi
Journal: Blood (2015)
Enhanced VISTA Expression in a Subset of Patients with Acute Myeloid Leukemia
Authors: Adam Lamble, Yoko Kosaka, Fei Huang, A Kate Sasser, Homer Adams, Cristina E. Tognon, Ted Laderas, Shannon K. McWeeney, Marc M. Loriaux, Jeffrey W. Tyner, Brian J. Druker, Evan F. Lind
Journal: Blood (2016)
Continued suppression of bone turnover following a single dose of zoledronic acid: Time to re-think dosing intervals in the management of bone metastases?
Authors: Christine E. Simmons, Pamela Jean Goodwin, Sophie Hogeveen, Mark Clemons, Rashida Haq, Christine B. Brezden, Jalal Ebrahim, Dolly Han
Journal: Journal of Clinical Oncology (2012)

9111 Background: The management of patients (pts) with bone metastases has changed significantly over the past decade, with the advent of newer, more potent anti-osteoclastic agents. However, the dosing interval in which these agents are given has not changed; pts are still dosed at a frequency of monthly or q3weekly injections. It is not known if this is the optimal dosing frequency or due to convention. The purpose of this study was to determine the duration of suppression of bone turnover by Zoledronic Acid (ZA) in a population of bisphosphonate naive metastatic breast cancer (MBC) pts. Methods: This prospective single arm phase II study enrolled 26 pts with MBC to bone who had not received bisphosphonates in the metastatic setting. A single dose of ZA was given at week 0, and biomarkers of bone turnover (serum CTX) were collected every 2 weeks subsequently. Pain scores and quality of life data were collected every 4 weeks. Pts remained on study if their biomarkers remained suppressed, but came off study as soon as escape from suppression was noted, (defined as a rise &gt; 50% of baseline value). Results: At 12 weeks, 73% (95% CI 56%-90%) of pts had continued suppression of bone turnover demonstrated by serum CTX. The pts that escaped suppression did so at a median of 8 weeks after first infusion of ZA (range 8-10 weeks). The magnitude of suppression (proportion decrease from baseline) of serum CTX at week 4 was significantly greater in those who had continued suppression compared to those who escaped suppression before 12 weeks (75% vs 58%, p = 0.02). The absolute baseline value of CTX was significantly lower in pts who maintained suppression (507 vs. 745 ng/L, p = 0.04). Quality of life scores and pain medication use did not change appreciably during this period. Conclusions: This study suggests that ZA may not need to be given at conventional intervals in the majority of pts, and may safely be withheld without increased risk to morbidity or decline in quality of life over a 12 week period. Baseline CTX and the magnitude of suppression of bone turnover at 4 weeks may predict for the optimal dosing frequency. Confirmation in a randomized trial is needed.
Phase II study of conversion therapy using S1/paclitaxel chemotherapy plus apatinib in unresectable gastric cancer (Ahead-G325 trial).
Authors: Xiangdong Cheng, Zhiyuan Xu, Yian Du, Ping Hu, Guofa Yu, Conggang Hu
Journal: Journal of Clinical Oncology (2017)

53 Background: Occasionally, an initially unresectable gastric cancer (GC) can be converted to a resectable one by chemotherapy. Combination with inhibitors against VEGFR-2 can lead to a clinical improvement. We aimed to investigate the efficacy and safety of S1/paclitaxel chemotherapy plus apatinib, a novel inhibitor of VEGFR-2, in the conversion therapy of unresectable GC. Methods: This was a multicentre, single-arm, open-label, phase II design. Eligible patients (pts) were aged 20-70 years and had histologically proven unresectable, HER-2 negative, advanced GC with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2). The ECOG performance status was 0-2. No prior radiotherapy, chemotherapy, target therapy or immunotherapy was allowed. Patients received 2 cycles of S1/paclitaxel chemotherapy (S1: 60 mg, oral, bid for 2 weeks followed by a drug-free interval of 1 week; paclitaxel: 150 mg/m 2 , iv, 3h, on day 1) plus apatinib (500 mg, oral, qd) and 1 cycle of S1/paclitaxel chemotherapy prior to radical surgery. Three cycles of adjuvant chemotherapy (S1 and apatinib) were given 4-6 weeks after surgery. Primary endpoint was R0 resection rate. Thirty-three pts were enrolled. Results: Among the 28 pts eligible for preoperative efficacy evaluation, 21 achieved partial response (PR), 5 had stable disease (SD), and 2 had progressive disease (PD), resulting in an overall response rate of 75.0% and a disease control rate of 92.9%. Of the 21 pts with PR, 3 refused consents for surgery and 18 achieved R0 resection. The incidence of adverse events (AEs) was 73.9%. The common hematologic AEs were neutropenia (60.9%), leukopenia (52.2%) and hemoglobin decrease (47.8%), and nonhematologic AEs included hyperbilirubinemia (56.5%), hand-foot syndrome (34.8%), oral mucositis (30.4%), fatigue (30.4%), proteinuria (21.7%) and hypocalcemia (21.7%). There was no severe surgery-related complication. Conclusions: Combination of apatinib with S1/paclitaxel chemotherapy shows clinical benefits in unresectable GC, with acceptable safety profile. Clinical trial information: NCT02529878.
Polymer delivered, subcutaneously administered leuprolide acetate provides stable and long-term drug delivery and testosterone suppression in 4 pivotal trials.
Authors: Franklin Chu, Stuart Atkinson, John A. McLane, Vahan Kassabian
Journal: Journal of Clinical Oncology (2017)

e592 Background: Prostate cancer patients receive androgen deprivation therapy (ADT) to suppress testosterone (T) to prevent proliferation of cancer cells. T suppression levels achieved by bilateral orchiectomy remain the gold standard for the target of suppression by ADT. Although the historical threshold definition of castration is T ≤ 50 ng/dL, increasing evidence suggests T lower than 20ng/dL may improve clinical outcomes, e.g., an increased cancer specific survival and delayed disease progression. To determine the minimal threshold of serum leuprolide required to maintain castrate level T suppression in prostate cancer patients, data from 4 pivotal trials evaluating long-acting, subcutaneously (SC) administered leuprolide acetate (LA) formulated with a biodegradable polymer were pooled. Methods: 438 eugonadal prostate cancer patients (age 40-86) were treated with SC-LA at 7.5, 22.5, 30, or 45mg delivered with a single dose lasting over 1, 3, 4, or 6 months (n = 120, 117, 90, 111), respectively in 4 open-label, fixed-dose, pivotal trials. Descriptive statistics were used to summarize the median concentration of leuprolide acetate at each time point as well as to determine level of T suppression. Results: Over the dosing intervals of the 1, 3, 4 and 6-month SC-LA formulations, median serum leuprolide levels were consistent and median serum T remained below T &lt; 20 ng/dL. In the pooled analysis (n = 86), 99% of patients with LA ≥ 0.1 ng/mL after injection achieved castration after 4 Weeks. Conclusions: These data suggest that SC-LA achieves consistent and prolonged drug delivery resulting in sufficient serum LA levels to provide favorable T suppression below 20 ng/dL, which may have clinical outcomes, e.g., increased cancer specific and progression free survival.
Profiling of activated receptor tyrosine kinases in advanced gastric cancers identifies patients with poor prognosis.
Authors: Phillip Sangwook Kim, Jeeyun Lee, Sung Kim, Xinjun Liu, Joon Oh Park, Tani Ann T. Lee, Kyoung-Mee Kim, Anne Kuller, Sharat Singh, Won Ki Kang
Journal: Journal of Clinical Oncology (2012)

4011 Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge due to its poor prognosis. Trastuzumab is the only known targeted therapy that has demonstrated a survival benefit in a small subset of metastatic GCAs. Addition of molecular diagnostics for predicting prognosis and therapeutic outcomes can significantly enhance the clinical management of GCAs. Herein, we identify activated receptor tyrosine kinases (RTKs) in distinct GCA subsets that correlate with disease-free survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from 434 stage I to IV GCA patients were profiled for HER1, HER2, HER3, p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER ) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Results: p95HER2, a known trastuzumab resistance mechanism, was identified for the first time in 79% of IHC/FISH-based HER2(+) GCAs. Full-length HER2 expression was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2 protein. 232/434 GCAs expressed at least one activated RTK analyzed in our study. Of these 232 patients, 121 patients that presented with stage II or III disease at the time of surgery; demonstrated a worse progression-free survival as compared to those where none of the analyzed RTKs were activated (32.6 months vs 76.5 months, p=0.0318). HER axis members were the most commonly activated RTKs with 64% of such GCAs. Approximately 71% of activated cMET tumors demonstrated a co-activation with a HER axis member with a preference for HER1 in ~61% of cMET-activated GCAs. Patients with p-MET(+):p-HER1(+) GCAs had a worse prognosis as compared to those with p-MET(+):p-HER1(-) GCAs (46.2 months vs 82.8 months, p=0.0184). Conclusions: CEER-based RTK characterization revealed concomitantly activated signaling pathways in GCAs which could predict disease recurrence. Comprehensive molecular profiles of GCA tumors can allow for the implementation of these companion biomarkers in GCA therapeutic clinical trials.
Importance of genetic testing for patients with multiple colorectal cancer primaries.
Authors: Caroline Elsas, Holly LaDuca, Jessica Profato, Bryan Mak
Journal: Journal of Clinical Oncology (2017)

528 Background: Individuals with hereditary colorectal cancer (CRC) may be at increased risk for a second primary CRC. Therefore, a personal history of multiple CRCs may be considered an indication for genetic testing. Methods: Multi-gene panel test (MGPT) results and age at CRC diagnoses were reviewed for 7046 CRC patients who underwent testing from March 2012 to June 2016. Depending on the panel ordered, analysis of up to 49 genes associated with CRC and/or other cancers was performed. The diagnostic yield and age at CRC diagnoses were compared between patients with a history of one CRC (n=6739) and those with two or more CRCs (n=307). Results: Individuals with a history of multiple CRCs had an overall positive rate of 23.8% (n=73), as compared to 12.4% (n=836) in those with a history of one CRC (OR=2.2; p=1.1E-7; 95%CI [1.653,2.907]). In the multiple CRCs group, 77 mutations were identified as follows: MLH1 (n=29), MSH2 (n=18), MSH6 (n=5), PMS2 (n=5), biallelic MUTYH (n=5), CHEK2 (n=5), APC (n=2), BRCA2 (n=3), RAD50 (n=1), BRIP1 (n=1), BRCA1 (n=1), ATM (n=1), and PTEN(n=1). Four patients carried mutations in two different genes. Of the mutation-positive patients with multiple CRCs, 72.6% were diagnosed with their first CRC before age 50, as compared to 59.3% of mutation-positive patients with one CRC. Consequently, the mutation-positive rate increased to 36.3% in patients with multiple CRCs whose first CRC was diagnosed before age 50; whereas it was 12.4% for patients diagnosed with both CRCs at age 50 or above. Conclusions: Overall, individuals with multiple CRCs were approximately twice as likely to be mutation-positive than those with a history of one CRC. This data highlights the importance of genetic testing for those with multiple CRCs, particularly in cases where the first CRC is diagnosed before age 50. Additionally, genetic testing of patients with early onset CRC at the time of diagnosis has the potential to capture patients who may benefit from consideration of additional options to reduce their risk of developing a secondary CRC. Furthermore, mutations were identified in various genes associated with extra-colonic cancers, presenting additional opportunities for cancer risk reduction in patients and their relatives.
Relationship of loss of miRNA-296 in the circulation and clinical outcome in patients receiving systemic chemotherapy for metastatic colon cancer.
Authors: Sameh Mikhail, Narayan Shivapurkar, Wei Bai, John Marshall, Jimmy J. Hwang, Michael J. Pishvaian, Anton Wellstein, Aiwu Ruth He
Journal: Journal of Clinical Oncology (2012)

e14009 Background: Several studies highlighted the potential for serum microRNA (miRNA) as prognostic and/or predictive markers. We describe an association between miR-296 and outcomes in a phase II trial of sunitinib and capecitabine in first line treatment of patients with metastatic colorectal cancer. Methods: Serum samples were obtained from subjects at (1) Screening (2) Prior to start of study drug (3) Every four weeks while on study. We compared miRNA levels and response to treatment at baseline and at four weeks. Results: Serum from seven patients was used to run miRNA array (382 miRNAs). Among the seven patients, three patients had decrease in the level of miR-296 at 4 weeks (Table). These patients were on the study treatment for a mean duration of 2.5 months (median 1.9). They had a mean survival from the time of diagnosis of 10.5 months (median 10.4) and a mean survival from time of enrollment of 7.5 months (median 8.7). Four patients had increase in the level of miR-296 at 4 weeks. These four patients were on the study treatment for a mean duration of 5 months (median 5). They had a mean survival from the time of diagnosis of 22.8 months (median 22) and a mean survival from study entry of 17.1 months (median 18.3). The duration on study treatment and the difference in survival from diagnosis, between the two groups were statistically significant (p=0 .014 and p=0.0025, respectively). Patients with shorter survival and poor clinical outcome had decrease in the level of miR-296 at four weeks from the start of treatment (0.43 versus 28 for patients with better clinical outcome; p=0.035). Conclusions: In our study, miR-296, served as a predictive and prognostic marker for clinical outcome of patients receiving systemic treatment for advanced colorectal cancer. Further studies are needed to confirm our results in a larger population. [Table: see text]
ATM as a biomarker for DNA damage repair deficiency in pancreatic ductal adenocarcinoma.
Authors: Talia Golan, Sharon Halparin, Chani Stossel, Maria Raitses-Gurevich, Dikla Atias, Ella Buzhor, Keren Cohen, Roni Borshtein, Michael Schvimer, Raanan Berger
Journal: Journal of Clinical Oncology (2017)

308 Background: Approximately 15% of PDAC tumors display DNA damage repair (DDR) deficiency. Germline BRCA (gBRCA) mutation serves as a robust biomarker for the DDR deficiency. A subset of patients displays a similar clinical phenotype but lack the gBRCA mutation. Identification of these BRCA-like subset of patients remains a challenge and an alternative approach may include DDR functional assays. Here we suggest loss of the ATM protein as one of the biomarkers for the identification of the DDR deficiency signature in PDAC. Methods: Patients were identified from the Sheba pancreatic cancer database based on strong family/personal history of BRCA- associated cancers or a durable response to platinum containing regimens ( ≥ 6 month) or harboring germline/somatic mutations in the DNA repair pathway (excluding gBRCA mutation). Archival FFPE blocks of primary tumors/metastatic lesions were used to explore ATM protein expression by IHC. Nuclear staining was regarded as positive. Tumor infiltrating lymphocytes served as an internal positive control. ATM loss was defined as less than10% neoplastic nuclear staining at any intensity in the presence of positive lymphocytes staining. Results: We identified 53 patients with DDR deficiency phenotype between 2014-2016 from the Sheba PDAC database (n = 250). Median age at diagnosis was 65 years (46-81) and the majority were female (62%). 47% were diagnosed at stage I/II and 53% stage IV. In the subgroup of patients with DDR deficiency phenotype, 55% displayed a family history of BRCA-associated cancers, 19% had a personal history of malignancy and23% had known mutation in DNA repair pathway. 23/53 identified subjects have been analyzed to date. We identified 52% loss of ATM in the analyzed group (n = 23). Conclusions: Loss of ATM in an unselected PDAC population is 12% (H. Kim et al, 2014). Our data demonstrate that 52% of the highly selected subgroup of PDAC patients (DDR deficiency phenotype) was found to have loss of ATM protein expression, suggesting it to be one of the biomarker for DDR signature. Identification of these patients, based on ATM protein expression profile may lead to personalized treatment options.
<i>Salmonella typhimurium</i> A1-R effectively targets human-patient pancreatic tumorgrafts in nude mice.
Authors: Ming Zhao, Matthew H. G. Katz, Jason B. Fleming, Atsushi Suetsugu, Yong Zhang, Ali Maawy, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman, Yukihiko Hiroshima
Journal: Journal of Clinical Oncology (2013)

e22012 Background: Genetically-modified Salmonella typhimurium A1-R selectively targets tumors of cancer in mouse models of human cancer. The aim of this study was to determine the efficacy S. typhimurium A1-R on human-patient pancreatic tumorgrafts growing orthothopically in nude mice. Methods: Pancreatic-cancer-patient tumor specimens were initially established subcutaneously in NOD/SCID mice immediately after surgery. The patient tumors were then harvested from NOD/SCID mice and passed orthotopically in transgenic nude mice, expressing fluorescent proteins in order for the tumors to acquire fluorescent stroma for imaging. After confirmation of tumor growth by fluorescence imaging, the nude mice were treated in the following groups: (1) 5-fluorouracil (5-FU) (10 mg/kg, ip); (2) cisplatin (CDDP) (10 mg/kg, ip); (3) gemcitabine (GEM) (150 mg/kg, ip); (4) S. typhimurium A1-R (1.5x10 8 cfu/body, ip); and (5) PBS (vehicle/control) (ip). Control, 5-FU, CDDP, GEM and S. typhimurium A1-R injections were performed on a weekly basis from day-21 after tumor implantation for 4 weeks. Animals were sacrificed at 7 weeks, and tumors were harvested for analysis. Each treatment arm involved 5 tumor-bearing mice. Results: No significant effects on body weight, morbidity, or severe toxicities were observed in any treatment arm. The tumor weight of each group was as follows: (1) 5-FU, 0.044 ± 0.027g; (2) CDDP, 0.04 ± 0.032g; (3) GEM, 0.058 ± 0.051g; (4) S. typhimurium A1-R, 0.106 ± 0.038g; and (5) PBS control, 0.258 ± 0.209g. S. typhimurium A1-R treatment significantly reduced the tumor weight compared to control treatment (p = 0.011), as did the other treatments including 5-FU (p = 0.005), CDDP (p = 0.004), and GEM (p = 0.001). Conclusions: S. typhimurium A1-R treatment was effective on human pancreatic tumorgrafts and should be tested in combination with chemotherapy.
Ten-year survival data following resection of locally recurrent rectal cancer (LRRC).
Authors: David Patrick Cyr, Francis Si Wai Zih, Jossie Swett-Cosentino, Shelly Luu, Bryan J Wells, Ronald L. Burkes, Bernard Cummings, Faryal Esmail, Andrew J Smith, Carol Jane Swallow
Journal: Journal of Clinical Oncology (2017)

730 Background: The ‘Beyond TME’ Collaborative identified LRRC as a complex problem requiring multidisciplinary consultation and specialized surgical care. Aggressive en bloc resection of LRRC at specialized cancer centers is associated with 5y survival rates of 25-50%. However, skepticism persists that LRRC can be cured given the lack of published longer-term survival data. We investigated the oncologic outcomes at 10y following resection of LRRC and sought relevant clinicopathologic prognostic variables. Methods: The study cohort consists of 52 consecutive patients (31M, 21F) who underwent LRRC resection at our center between 09/1997 and 08/2005. En bloc sacrectomy was performed in 30 patients (58%) with the goal of achieving complete margin negative (R0) resection. At the time of LRRC resection, 46 of 52 patients had isolated LRRC (M0), and 6 had potentially resectable distant metastasis (M1). Patients were followed with H&amp;P, CT-CAP q4mos X2y, q6mos X3y, then annually. Results: At last follow-up (f/u), 32 patients had died of rectal cancer, 1 died of other causes, 4 were alive with rectal cancer, and 15 (30%) were alive cancer-free. For the entire cohort of 52 patients, median f/u time was 44mos (4-162) and overall survival (OS) was 42% at 5y, 37% at 10y, median 43mos. In the group who were alive at last f/u (N = 19), median f/u time was 123mos (45-162). Prognostic variables for OS in univariate analysis included: m status, resection margin status, receipt of systemic Rx, and receipt of radiotherapy. All patients who had M1 disease at the time of LRRC resection died of recurrent cancer at a median of 21mos (4-46). In the 46 M0 patients, OS was 47% at 5y, 42% at 10y, median 50mos; furthermore, disease-free survival (DFS) was 38% at 5y, 38% at 10y, median 39mos. In patients who had R0 resection (n = 41), OS was 51% at 5y, 45% at 10y, median 72mos. Preoperative chemotherapy at the time of primary presentation (n = 26) or before resection of LRRC (n = 20) was associated with significantly improved prognosis ( p= 0.004, p= 0.03, respectively). Conclusions: Complete resection of LRRC was associated with durable survival in approximately 40% of patients, with plateauing of survival curves after 5y. Preoperative therapy of LRRC may improve survival.