tbuckley/cabot-search huggingface dataset:
Cabozantinib plus androgen deprivation therapy in patients with androgen-dependent metastatic prostate cancer.
Authors: Paul Gettys Corn, Amado J. Zurita, Sumit Kumar Subudhi, Shi-Ming Tu, Ana Aparicio, John C. Araujo, Jeri Kim, Jennifer Wang, Eleni Efstathiou, Lance C. Pagliaro, Christopher Logothetis
Journal: Journal of Clinical Oncology (2017)

169 Background: Cabozantinib (Cabo), a tyrosine kinase inhibitor of c-Met and VEGFR2, modulates the tumor microenvironment in a therapeutically favorable manner. We combined Cabo with androgen deprivation therapy (ADT) in patients (pts) with androgen-dependent metastatic prostate cancer (PCa) (NCT01630590). Methods: Pts received Cabo (starting dose 60 mg PO daily) and ADT with a GnRH analogue. Pts could receive up to 3 months of ADT prior to initiating Cabo. Bone scan (BS) and CT scans were performed every 12 weeks (wks). Efficacy endpoints included response in markers, BS and RECIST, and time to castrate-resistant progression defined by radiographic progression, clinical progression, or receipt of additional anti-cancer therapy. Results: From 01/27/2014 to 01/12/2016, 62 pts were enrolled: 94% (58/62) with bone metastasis, 56% (35/62) with measurable disease, 15% (9/62) with visceral involvement and 26% (16/62) with prior treatment of their primary tumor. 79% (49/62) of pts have high volume disease defined by &gt; 4 bone lesions and/or involvement of viscera. Median time from start of ADT to start of Cabo was 3.4 wks. Improvements in BS were observed in 81% (44/54) of evaluable pts including complete responses (CR) in 15% (8/54). In evaluable pts with measurable disease, best response was stable disease in 9% (3/33), PR in 61% (20/33) and CR in 30% (10/33). Reductions in PSA &gt; 90%, bone specific alkaline phosphatase &gt; 50% and urine N-telopeptides &gt; 50% occurred in 83% (50/60), 87% (34/39), 86% (19/22) of evaluable pts, respectively. With a median follow up of 21.4 months (mo), median PFS is 15.6 mo. Median duration of Cabo treatment is 13 mo. Most common toxicities are Grade 3 hypertension (16%), pulmonary embolus (6%), diarrhea (4%), fatigue (3%), nausea (3%), and deep venous thrombosis (3%) with no Grade 4 events. Cabo dose reductions to 40 and 20 mg occurred in 68% and 18% of pts, respectively, with discontinuations due to toxicity in 10% of pts. Conclusions: Cabo plus ADT has potent clinical activity in pts with high volume androgen-dependent PCa including improvements BS and reduction in markers of bone stromal function. Studies are underway to identify biomarkers predictive of best response. Clinical trial information: NCT01630590.
Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors.
Authors: Thomas E. Hutson, Long H. Dang, Richard C. Lauer, Alexander Starodub, Ralph J. Hauke, Matt D. Galsky, Kathryn A. Bylow, Theodore Logan, Charles Lance Cowey, David C. Bibby, Gabriel Kremmidiotis, Elizabeth E. Doolin, Tina C. Lavranos, Guru Sonpavde, Noah M. Hahn, Christopher Sweeney, John Sarantopoulos
Journal: Journal of Clinical Oncology (2012)

4603 Background: BNC105P is an investigational agent that destabilizes tubulin polymers leading to selective damage of tumor vasculature, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Preclinical investigations have demonstrated that BNC105P is effective at selectively damaging the vasculature in both primary and metastatic lesions. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. It follows that the combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m 2 ; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: The phase I component has been completed. The BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia and oral mucositis were also observed. Seven phase I subjects achieved at least disease stabilization with a minimum time on therapy of 18 weeks (6 cycles). Across all subjects a median of 6 cycles (range: 1-15) was administered. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m 2 ) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.
Significance of ectopic lymph node-like structures in neuroendocrine tumors of the small bowel.
Authors: Mauro Cives, Jonathan R. Strosberg, Stacey Simons, Domenico Coppola
Journal: Journal of Clinical Oncology (2015)

e15192 Background: The formation of extranodal tertiary lymphoid follicles and lymphoid cell aggregates has been described in nonmalignant conditions including autoimmune diseases and chronic inflammation as well as in cancer. Tumor-induced lymph node-like structures (LLS) participate in the host’s antitumor immune response by driving intratumoral immune cell priming. Methods: Host immune response was evaluated by immunohistochemistry in 60 well differentiated small bowel NETs. Presence of ectopic LLS was correlated with clinical outcomes and tested for progression prediction using the Kaplan-Meier method. Results: In 13/60 samples the immune response was organized as ectopic LLS. When present, LLS were localized at the invasive edge of the tumors and contained germinal centers in different stages of maturation. CD21+ dendritic cells were present within the follicular germinal centers, while CD3+ T cells were dispersed in the parafollicular cortex zone surrounding the CD20+ B cell area of the follicles. Time to progression of metastatic tumors was compared in an exploratory cohort of 5 patients with strong evidence of LLS vs 5 patients with no evidence of LLS and was substantially longer in the former group (94 vs 28 months; p = 0.15). Conclusions: The understanding of the functional nature of LLS may provide new insights into the pathogenesis of the disease, possibly furnishing a new tool for prognostic stratification and prediction of response to immune-based treatments.
A multivariate index analyte (MIA) assay for differentiating aggressive from nonaggressive prostate cancer.
Authors: Douglas Campbell, Vicki Velonas, Julie T Soon, Sandra Wissmueller, David Gillatt, Brad Walsh
Journal: Journal of Clinical Oncology (2017)

e588 Background: Biomarkers that can assist clinicians and patients to proceed when PSA and /or DRE are equivocal. Such biomarkers should establish both sensitivity and specificity for prostate cancer detection in order to improve go-forward decisions to perform prostate biopsy. Following the successful use of a three-protein marker panel to increase the specificity of prostate cancer detection 1 we have now used the same technology to examine whether an MIA assay can assist in differentiating aggressive from non-aggressive cancer in prostate cancer patients. Methods: Samples from patients with either aggressive prostate cancer or non- aggressive prostate cancer were obtained from two sources. The cohort criteria comprised of serum samples where blood was drawn from patients with adenocarcinoma and a PSA greater than or equal to 2ng/mL. All men were Caucasian with the exception of 3 who were African American. Non-aggressive prostate cancer was defined as having a Gleason score of 6 (n = 35) and aggressive prostate cancer was characterized as Gleason score 7 and above (n = 69). Biomarker levels were determined using a plate based ELISA for GPC-1 2 and a bead-based MIA assay for the other markers. Results: By using biostatistical analysis (Simplicity Bio, Switzerland) two models were identified that were able to differentiate between aggressive and non-aggressive prostate cancer. One consisted of a combination of 5 analytes and the other used 6 analytes. Model 1 containing PSA and GPC-1 plus 4 analytes produced a combined sensitivity of 81% and specificity of 78% (AUC 0.81). The second model comprising of GPC-1 with an additional 4 analytes achieved a sensitivity of 72% with a specificity of 76% (AUC 0.76). Both models had a p value of less than 0.05. By itself PSA was a poor predictor of prostate cancer with a sensitivity of 58% and specificity of 43% (AUC 0.55). Conclusions: The analytes identified by the two statistical models demonstrate potential utility for using the combined markers as a new means of differentiating aggressive prostate cancer from non-aggressive cancer. An additional study to further validate these models is currently being constructed.
Subnormal Lymphocyte Count Predicts Inferior Survival in Myelodysplastic Syndromes: A Single Center Experience in 889 Patients
Authors: Lyla Saeed, Mrinal M Patnaik, Kebede H. Begna, Aref Al-Kali, Curtis A. Hanson, Mark R Litzow, Rhett P. Ketterling, Luis Porrata, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
Journal: Blood (2016)
Characterizing self-reported memory problems in adult-onset cancer survivors in the United States: Importance of sleep duration and insomnia.
Authors: Pascal Jean-Pierre, Michael Grandner, Ashley Jean-Pierre, Sheila N. Garland, Gloria Maciorowski, Erin Richards
Journal: Journal of Clinical Oncology (2014)

9588 Background: Memory dysfunction is a debilitating adverse effect of cancer and its treatments. We examined the relationships between self-reported memory problems (SRMP) and sleep disorders in adult-onset cancer survivors. Methods: We used data from 151 adults, 41-64 years old, cancer survivors who completed the 2007-2008 National Health and Nutrition Examination Survey. Population-weighted binary logistic regression analyses examined SRMP as outcome and included age, sex, education, race-ethnicity, income, and overall health as covariates. Sleep duration was categorized as very short (<=4hrs), short (5-6hrs), normal (7-8hrs) or long (>=9hrs). Initial insomnia was assessed as difficulty falling asleep. Middle insomnia was assessed as difficulty maintaining sleep. Late insomnia was assessed as waking too early. These insomnia subgroup were categorized as none, mild (<15 days/month) and severe (>=15 days/month). A combined insomnia variable categorized individuals as insomnia if they had severe insomnia of any type (early, middle, late). Results: Overall, presence of insomnia was associated with SRMP (p<0.0001). Severe initial insomnia was associated SRMP (p=0.006). Mild and severe middle insomnia were associated with SRMP (p=0.007 and p<0.0001, respectively). Late severe insomnia was associated with SRMP (p=0.037). Additionally, long sleep was negatively associated with SRMP (p=0.019). Among participants without a history of cancer (N=2,001), none of the sleep variables were associated with increased likelihood of memory problems (p>0.05). Conclusions: The findings seem to indicate that sleep may be a mechanistic pathway through which cancer impact memory.
Tolerability of pegylated liposomal doxorubicin 20 mg/m<sup>2</sup> every 2 weeks in the management of solid or hematologic malignancies
Authors: A. P. Staddon, S. Kilcoyne, J. N. Latham, D. H. Henry
Journal: Journal of Clinical Oncology (2006)

18500 Background: Pegylated liposomal doxorubicin (PLD, DOXIL) was developed to decrease the cardiotoxicity risk associated with conventional doxorubicin. However, hand-foot syndrome (HFS) and mucositis are more common with PLD 50 mg/m 2 every 4 weeks (q4w) than with 20 mg/m 2 q3w (all grades: HFS, 37.4% vs 3.4%; mucositis, 37.4% vs 6.8%). A lower dose intensity of PLD 10 mg/m 2 /wk (40 mg/m 2 vs 50 mg/m 2 q4w) was reported to have similar efficacy in ovarian cancer but reduced incidence of HFS and mucositis. This study evaluated the tolerability of the lower dose intensity using a 20 mg/m 2 q2w regimen in patients (pts) with Kaposi’s sarcoma (KS), hematologic tumors, and solid tumors. Methods: This retrospective chart review included pts who received PLD as a component of care at a single community oncology clinic between January 2000 and December 2004. Demographics, PLD dosing, and tolerability were recorded. Data were censored for pts with an initial PLD dose other than 20 mg/m 2 q2w. Results: Of the 157 pts given PLD, 79 received an initial dose of 20 mg/m 2 q2w. Tumors included 47 KS, 8 hematologic (3 multiple myeloma, 4 lymphoma, 1 leukemia), and 24 solid (8 breast, 5 gynecologic, 3 colorectal, 2 liver, 2 lung, 2 sarcoma, 1 prostate, 1 thyroid). Median cumulative dose was 220 mg/m 2 (range, 20–2320 mg/m 2 ); 34 pts (31 KS, 0 hematologic, 3 solid) received &gt;300 mg/m 2 and 14 pts (13 KS, 1 solid) received &gt;550 mg/m 2 . No signs (eg, decreased LVEF) or treatment-related symptoms of cardiotoxicity (eg, shortness of breath) were reported. Incidence of HFS and mucositis are reported in the Table . One HFS and 1 mucositis led to PLD discontinuation. Conclusions: Regardless of tumor type, PLD 20 mg/m 2 q2w appears well tolerated. No cardiotoxicity was observed, even at cumulative doses &gt;550 mg/m 2 . Rates of HFS and mucositis were lower than reported previously with a 50 mg/m 2 q4w schedule. Prospective studies in larger populations are warranted to further examine the efficacy of the PLD 20 mg/m 2 q2w schedule and dose intensity. [Table: see text] [Table: see text]
Effect of defective ERCC2 on cisplatin and ionizing radiation (IR) sensitivity in bladder cancer cells.
Authors: Qiang Li, Andrew Bell, Emmet Jordan, Sizhi Paul Gao, Jennifer Ma, Eugene J. Pietzak, Guido Dalbagni, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, David B. Solit, Nadeem Riaz, Gopa Iyer
Journal: Journal of Clinical Oncology (2017)

333 Background: Genetic alterations within ERCC2 correlate with extraordinary responses to neoadjuvant cisplatin-based chemotherapy and bladder-sparing ionizing radiation (IR) in muscle-invasive bladder cancer (MIBC). Two studies correlated ERCC2 mutations with pathologic response to chemotherapy and improved disease-free and bladder intact survival following trimodality therapy. We sought to characterize the biological significance of these mutations in bladder cancer cells using CRISPR/Cas9-mediated ablation of ERCC2 function. Methods: The ERCC2 T484A/M point mutation was the most common alteration (4 of 36 patients) within a prospectively collected cohort of 299 bladder cancer patients sequenced at our institution. We infected the ERCC2 wild-type KU19-19 bladder cancer cell line with a CRISPR/Cas9 lentivirus targeting residues 481-487 of ERCC2 and identified a cell clone harboring an ERCC2 in-frame deletion (M483_T484del). Following exposure to cisplatin and IR, cell viability was examined using Cell-titer Glo and clonogenic assays. Apoptosis was gauged by subG1 cell fraction measurement by flow cytometry. Results: ERCC2 mutant cells exhibited significantly increased cisplatin sensitivity compared to parental cells (IC50 0.3uM vs 2.0uM, p &lt; 0.0001). Cisplatin treatment after 48 hours resulted in increased apoptosis in ERCC2 mutant vs parental cells (sub-G1 fraction 52% vs 16%, p = 0.01). ERCC2 mutant cells were more sensitive to combined IR (2 Gy) and cisplatin (1uM) compared to parental cells (SF 2Gy (surviving fraction) 17 % vs 60%). Conclusions: ERCC2 mutations enhance cisplatin and IR sensitivity in a bladder cancer cell line model. ERCC2 alterations are likely the genetic basis for extraordinary response to cisplatin chemotherapy and IR in MIBC patients. Prospective genetic sequencing may help select ERCC2 mutant MIBC patients who are most likely to respond to chemotherapy or trimodality bladder-sparing therapy.
Prognostic effect of PgR in luminal type breast cancer.
Authors: Min Kyoon Kim, Hyeong-Gon Moon, Tae-Kyung Yoo, Eunshin Lee, Jongjin Kim, Han-Byoel Lee, Yun Kyeong Kim, Young Joon Kang, Dong Young Noh, Wonshik Han
Journal: Journal of Clinical Oncology (2015)

e11566 Background: PgR is synthesized by tumor cells that are stimulated by estrogens through an interaction with ER. In theory, the presence of PgR might be a better indicator of hormonal dependence than ER because ER may be present but not functional in some patients. Positive PgR assay identifies a more tamoxifen-responsive subgroup of patients even when patients have ER-negative tumors. The aim of the present study was to evaluate the prognostic significance of semiquantitative measurement of PgR expression in the IHC-based luminal subtype of breast cancer. Methods: 1327 consecutive patients with ER and/or PgR+ HER2- invasive breast cancer treated with surgery and adjuvant treatment at the Seoul National University Hospital from July 2009 to December 2011 were reviewed. ER, PgR, HER2, and Ki-67 were determined from surgically resected tumor tissue. The RFS and OS in Kaplan-Meier plots for the PgR high and low expression groups were compared using the log-rank test. Multivariate analyses of survival in relation to various factors were performed with a Cox proportional hazards model, which yielded the HR and 95% of CI. Results: Based on pathology data of semiquantitative measurement of the percentage of PgR-positive cells, patients were separated into two groups with PgR percentage cutoff 20%. Among 1372 patients, 665(48.5%) showed high PgR expression, 707(51.5%) showed low PgR expression. PgR expression was relatively high in younger age ( < 50 years, p < 0.001). Higher PgR expression was related to low Ki-67 expression ( < 10%, p = 0.003), and low cancer stage(p < 0.001). The DFS and OS of patients in the high PgR subset were significantly better than the low PgR subset only in patients under 50years old.(p = 0.005 and 0.037) Cox analysis showed that low PgR expression(HR, 3.06; 95% CI, 1.44-6.47) and negative ER expression(HR, 19.68; 95% CI, 5.89-65.80) were significant independent risk factors for patients' survival. Conclusions: We were able to demonstrate that high PgR expression is associated with a better prognosis for luminal type breast cancer. The semiquantitative determination of PgR expression might thus improve the accuracy of the IHC-based classification of luminal A and luminal B breast cancer, especially for premenopausal patients.
Factors associated with local-regional failure after definitive chemoradiation for locally advanced esophageal cancer.
Authors: Arya Amini, James Welsh, Pamela Allen, Lianchun Xiao, Akihiro Suzuki, Mariela A. Blum, Wayne Lewis Hofstetter, Zhongxing X. Liao, Jeffrey H Lee, Manoop S. Bhutani, Ritsuko Komaki
Journal: Journal of Clinical Oncology (2012)

e14669 Background: Esophageal cancer is often treated with a trimodality approach (chemotherapy and radiation followed by surgery). However a significant proportion of such patients achieve a clinical complete response (cCR) following chemoradiation alone. We retrospectively analyzed patients who reached cCR after definitive chemoradiation for locally advanced esophageal cancer to identify clinical predictors of local disease recurrence. Methods: We identified 141 patients who obtained initial cCR after definitive chemoradiation for esophageal cancer from January 2002 through January 2009. The initial response to treatment was assessed by endoscopic evaluation and biopsy results, with cCR defined as having no evidence of disease present. Patterns of failure were categorized as in-field (within the planned treatment volume [PTV]), outside the radiation treatment field, or both. Results: At a median follow-up of 22 months (range 6-87 months), 77 patients (55%) had experienced disease recurrence. Most first failures (32, or 23%) were outside the radiation field, followed by 30 (21%) within the field and 15 (11%) were both. In multivariate analysis, in-field failure after cCR was associated with a post-treatment standardized uptake value (SUV) on positron emission tomography of &gt;3.5 (odds ratio [OR] 4.93, p=0.022), squamous histology (OR 0.07, p=0.010), and borderline for T3/T4 disease (OR 10.25, p=0.055). All failures, in-field and out-of-field, correlated with T3/T4 disease (OR 11.61, p=0.015), N1 disease (OR 5.07, p=0.010), pretreatment SUV &gt;10 (OR 4.00, p=0.048), and post-treatment SUV &gt;3.5 (OR 3.59, p=0.052). Conclusions: Clinical characteristics can be used to predict failure patterns after definitive chemoradiation. Such risk-assessment strategies can help individualize therapy.
The survival benefit offered by the surgical management of low-grade ductal carcinoma in situ of the breast.
Authors: Yasuaki Sagara, William Thomas Barry, Melissa Anne Mallory, Stephanie M. Wong, Fatih Aydogan, Stephen DeSantis, Mehra Golshan
Journal: Journal of Clinical Oncology (2015)

1006 Background: The current management of ductal carcinoma in situ (DCIS) of the breast includes lumpectomy with/without whole breast radiation or mastectomy, however the magnitude of benefit for surgery has not been well established. We sought to identify the survival benefit conferred by surgical resection over non-operative management in patients with low-grade DCIS. Methods: We performed a retrospective longitudinal cohort study using the Surveillance Epidemiology and End Results database. Between 1988 and 2011, 57,222 eligible cases of DCIS were identified. Patients (pts) were divided into a surgery and a non-surgery group; propensity score weighting was used to balance clinico-pathologic factors between groups. Breast cancer specific and overall survival (BCSS/OS) were assessed using a log-rank test and Cox proportional hazards model. Results: Of 57,222 cases of DCIS, 56,053 cases (98.0%) received definitive surgery (lumpectomy: 34,439 pts, mastectomy: 16,334 pts) and 1,169 cases (2.0%) were managed non-operatively. The proportion of the following clinico-pathologic factors was higher in the non-surgery group compared to the surgery group: age > 60, diagnosis after year 2000, black race, low-grade DCIS and absence of radiation therapy. There were 576 breast cancer-specific deaths over the 72-month median follow-up period. The weighted ten-year BCSS for the surgery group was 98.5%, compared to 93.5% (p < 0.001) for the non-surgery group. Survival benefit for the surgery group differed by nuclear grade (p = 0.003). The weighted ten-year BCSS of low-grade DCIS was similar between patients managed with and without surgery (98.8% and 98.6%, respectively; p = 0.93). Conclusions: The survival benefit offered by surgery for DCIS varies by nuclear grade. In contrast to high/intermediate grade DCIS, definitive local therapy of low-grade DCIS does not offer a significant survival advantage over non-operative management. Hazard ratio (HR) comparison between DCIS patients managed surgically versus non-operatively as adjusted by clinico-pathologic factors. Grade BCSS Weighted HR 95% CI OS Weighted HR 95% CI I 0.88 0.21 - 3.71 0.86 0.53 - 1.40 II 0.25 0.15 - 0.42 0.70 0.52 - 0.94 III 0.16 0.11 - 0.23 0.40 0.32 - 0.51