tbuckley/cabot-search huggingface dataset:
Abstract 13324: Mouse Model of Human Congenital Heart Disease: High Incidence of Diverse Cardiac Anomalies and Ventricular Noncompaction by Heterozygous Nkx2-5 Homeodomain Missense Mutation
Authors: Hideko Kasahara, Hassan Ashraf, Lagnajeet Pradhan, Eileen Chang, Ryota Terada, Nichole Ryan, Laura Briggs, Hyun-Joo Nam, D.Woodrow Benson, Robert Anderson
Journal: Circulation (2013)

Background: The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy in human and mouse genetics. Since missense mutations in the NKX2-5 homeodomain (DNA binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine model.

Methods and Results: To address mechanistically whether a missense mutation in the homeodomain of NKX2-5 underlies a high disease penetrance, we generated a novel murine model in a 129/Sv genetic background by knocking-in a homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). To directly compare missense and nonsense mutations, we generated a second murine model, heterozygous Nkx2-5 knockout in a 129/Sv genetic background.

Periodically, newborn heterozygous Nkx2-5+/R52G mice were found cyanotic or dead. The ratio between P1 Nkx2-5+/+ (48%) vs. Nkx2-5+/R52G (52%) mice (n=65) and P10 Nkx2-5+/+ (58%) vs. Nkx2-5+/R52G (42%) mice (n=61) suggested that approximately one-quarter of the Nkx2-5+/R52G mice die perinatally. Detailed analyses using serial tissue-sectioning and 3-dimensional reconstruction of 15 P1 Nkx2-5+/R52G mice displayed complete penetrance of ventricular noncompaction, and a high incidence (~80%) of ventricular septal defects, as well as perinatal lethal complex cardiac anomalies, such as common atrioventricular junction, tricuspid atresia, or Ebstein’s malformation of the tricuspid valve. Furthermore, quantitative analyses from a total of 27 P10 hearts showed a significant increase in the size of the interatrial communication and the foramen ovalis, with the maximum length of the septum primum being decreased in Nkx2-5+/R52G compared to age-matched Nkx2-5+/+ or Nkx2-5+/- mice.

Conclusion: The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) are highly penetrant, and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knock-in mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain.
Association between race and BMI with response to neoadjuvant endocrine therapy in postmenopausal women with large estrogen receptor-positive breast cancers.
Authors: T. Ambros, V. Sujoy, C. G. Fernandez, I. Reis, J. L. Wright, M. Jorda, K. Saigal, J. Hurley
Journal: Journal of Clinical Oncology (2011)

132 Background: Neoadjuvant endocrine therapy is increasingly used in the treatment of breast cancer. There is a need to define which patients will benefit the most from this form of therapy. Methods: Retrospective review of medical records from University of Miami/Jackson Memorial Hospital from 1998 to 2011. Response to neoadjuvant endocrine therapy was evaluated through comparison of palpable breast mass size at presentation with pathological tumor size in surgical specimens. Response was stratified as “No Response” (NR), indicating no change or increase in size, “Moderate Response” (MR) as up to 50% decrease in size, and “Good Response” (GR) &gt; 50% decrease in size. Data was analyzed by body mass index (BMI), type of endocrine therapy, race and histology. Results: Data from 62 postmenopausal, estrogen receptor-positive women who received neoadjuvant hormonal therapy was analyzed. Median age was 62 (range 50-91). Clinical stage: II 24.2%, IIIA 25.8%, IIIB 35.5%, IIIC 6.5%. Endocrine therapy used was tamoxifen (14.5%) or aromatase inhibitor (AI) (85.5%). Response rate was NR in 22.6%, MR in 43.5% and GR in 33.9%. Fifty two patients had available height and weight information. In patients receiving AI, BMI was significantly higher in the NR group vs. GR group (mean BMI 38.68 vs. 27.56, p=0.041). Mean BMI in MR was 32.18, not statistically different from either group. Analysis of both AI and tamoxifen treated patients yielded similar results (results not included). The rate of GR was higher in the Caucasian vs. African American population (40.4% vs. 14.3%, p=0.017). Inversely, the rate of NR was higher in African Americans (50.0% vs. 14.9%, p=0.017). There was a trend towards more favorable tumor size change in Caucasian vs. African American women (mean 36.19% reduction vs. 11.69% increase in tumor size, p=0.058). The mean tumor size change was more favorable in ductal vs. lobular carcinomas (34.75% decrease vs 8.69% increase, p=0.184). Conclusions: Lower BMI and Caucasian ethnicity were associated with higher frequency of GR (&gt; 50% decrease in tumor size) to neoadjuvant endocrine therapy. No association was found between response and stage, PR status or HER2 expression.
Randomized controlled phase II study of alternate-day S-1 as adjuvant chemotherapy for gastric cancer.
Authors: Seiichi Nakamura, Shigeru Tatebe, Tetsu Shimizu, Nariyuki Yamane, Hideaki Nishidoi, Yasuro Kurisu, Hirotomo Kanayama, Haruaki Ogawa, Shunichi Tsujitani, Masahide Ikeguchi
Journal: Journal of Clinical Oncology (2012)

114 Background: Based on the results of ACTS-GC, oral administration of S-1 for 1 year is considered standard postoperative adjuvant chemotherapy for gastric cancer in Japan. However, the 1-year treatment completion rate was only 65.8%, and completion of the treatment is a problem to be solved. On the other hand, we experienced in clinical practice that the alternate-day administration of S-1 reduced adverse effects and was tolerable for advanced gastric cancer patients unwilling to continue the standard daily administration. We therefore conducted a multi-center cooperative prospective study to compare daily with alternate-day administration of S-1 as postoperative adjuvant therapy for gastric cancer. Methods: Patients with Stage II or III gastric cancer who underwent curative surgery were randomly assigned to receive standard daily administration (group A: S-1 80-120 mg/day according to BSA, days 1 to 28, every 6weeks, for 1 year) or alternate-day administration of S-1 (group B: S-1 80-120 mg/day according to BSA, every other day, for 15 months). The primary endpoints were treatment completion rate and relative dose intensity. Secondary endpoints were safety, overall survival, and relapse-free survival. Results: A total of 73 patients were enrolled. As of August 30, 2011 analysis of the compliance data of 62 cases had been completed. The results showed a treatment completion rate of 74.2% in group A and 93.5% in group B and relative dose intensity of 72.1% in group A and 85.6% in group B, and compliance tended to be better in group B. Assessment of survival time showed a median follow-up time of 545 days, a 1-year survival rate of 93.8% in group A and 96.9% in group B and 1-year relapse-free survival rate of 79.5% in group A and 90.7% in group B. Digestive system adverse events were less frequent in group B than in group A. Conclusions: We will report the data from the final analysis at this meeting. The current data show improved compliance and mitigation of adverse effects with alternate-day administration of S-1, and it appears to be a more sustainable option for adjuvant chemotherapy for Stage II and III gastric cancer.
Cell-of-Origin Subtype Classification of Diffuse Large B-Cell Lymphoma Using the Lymph2Cx Assay Retains Relevance in the Context of BCL2 and MYC Expression Status
Authors: Samantha L. Kendrick, Katalin Tus, David W. Scott, George Wright, Elaine S. Jaffe, Andreas Rosenwald, Elías Campo, Wing Chung Chan, Joseph M. Connors, Rita M. Braziel, German Ott, Jan Delabie, James R. Cook, Dennis D. Weisenburger, Timothy C. Greiner, Kai Fu, Louis M. Staudt, Randy D. Gascoyne, Lisa M. Rimsza
Journal: Blood (2014)
Evaluation of tumor-associated macrophages as a prognostic indicator in patients with papillary renal cell carcinoma.
Authors: G. C. Hutterer, T. F. Chromecki, R. Zigeuner, T. Klatte, K. Kampel-Kettner, K. Pummer, M. Remzi, S. Mannweiler
Journal: Journal of Clinical Oncology (2011)

372 Background: Prognostic indicators in papillary renal cell carcinoma (PRCC) are not well defined. We evaluated the prognostic relevance of tumor-associated macrophages (TAM) in patients with PRCC. Methods: PRCC specimens were re-evaluated by one blinded pathologist (SM), with respect to pT-classification (TNM 2002), nodal status, Fuhrman grade (I-IV), tumor size, subtype (type 1 or 2), tumor necrosis, and presence of TAM. Presence of TAM was associated with pathological parameters (chi-square and fisher's exact tests). Impact of TAM on cancer-specific survival (CSS) was assessed (Kaplan-Meier method and log-rank test). A multivariate regression analysis including pT-stage, grade, vascular invasion, necrosis, tumor size, papillary subtype and TAM was performed with respect to CSS. Results: 177 patients operated for PRCC from 1984 to 2006, were evaluated. Presence of TAM was noted in 112/177 (63%) tumors and was significantly associated with favorable pathological parameters: low pT-classification (pT1a/b: 71/90, 79%; pT2: 14/31, 45%; pT3a/b: 27/56, 48%; p&lt;0.001), node negative tumors (Nx/pN0: 111/170, 65% vs. pN1/2: 1/7, 14%; p=0.01), low grade (G1: 35/45, 78%; G2: 67/110, 61%; G3: 10/22, 45%; p=0.025), absence of vascular invasion (V0: 106/153, 69% vs. V1/2: 6/24, 25%; p&lt;0.001), and papillary subtype (type 1: 64/87, 74% vs. 48/89, 54%; p=0.007), respectively. Median follow-up was 68.3 months. Five-year CSS probabilities for patients with TAM-positive tumors were 93.5%, compared with 72.5% in patients with TAM-negative tumors (p&lt;0.001). Median survival was not reached in both groups. Multivariate analysis revealed node positive tumors (HR=2.4, 95%CI=1.1-5.0; p=0.025), distant metastases (HR=8.7, 95%CI=2.6-29.3; p&lt;0.001), and tumor size (HR=1.2, 95%CI=1.0-1.3; p=0.03) as independent predictors of death from PRCC, whereas presence of TAM was independently associated with favorable outcome (HR=0.3, 95%CI=0.1-0.9, p=0.026). Conclusions: Presence of TAM was independently associated with a favorable outcome in patients with PRCC and was shown to reduce the risk of death from cancer by 66%. Presence of TAM should therefore be part of routine pathology reporting in PRCC. No significant financial relationships to disclose.
Brain and meningeal metastases (BMm) from castration-resistant prostate cancer (CRPC) in the era of docetaxel (DOC).
Authors: O. Caffo, A. Gernone, C. Ortega, T. Sava, G. Carteni, G. Facchini, P. Amadio, A. Veccia, A. Pagliarulo, E. Galligioni
Journal: Journal of Clinical Oncology (2011)

217 Background: The occurrence of BMm is usually viewed as an exceptional event in the history of prostate cancer (PC) patients (pts). In two large retrospective series the incidence of BMm in PC pts was about 0.5%. Since the introduction of DOC as first line treatment has improved survival of CRPC pts, we have retrospectively evaluated the occurrence of BMm in such setting of pts, to explore whether the incidence of BMm has changed. Methods: The clinical records of a series of 801 pts with CRPC treated from 2002 to 2010 were reviewed. All pts met the definition of CRPC according to international guidelines: all pts received or were eligible for DOC-based treatment. Results: We collected a series of 28 pts with BMm (incidence 2.9%). Sixteen pts had a median number of 1 brain metastases (range 1-8) and neurological symptoms were present in 11 cases. Teen cases presented meningeal metastases: in this case all but one pt were symptomatic. To date, no detailed information are available for the 2 remaining cases. After BMm diagnosis, local treatments were proposed in 16 pts: 5 pts underwent metastasectomy (M) + external brain irradiation (BI), 1 M alone, 9 BI alone, 1 gamma-knife. Eleven pts received chemotherapy after BMm, while the remaining received only best supportive care. The median interval from the PC diagnosis and the achievement of CRPC was 23 mos (range 7-141) while the appearance of BMm was documented after 6-173 mos (median 42) The median survival after BMm was 3 mos (range 1-29) with 6 pts surviving more than 1 year. These long-term survivors had brain metastases in 5 cases and meningeal metastases in 1 case and were managed with surgery in 3 cases, radiotherapy in 2 cases and DOC in 1 case. Conclusions: It appears from our data that in the DOC era 1) the incidence of BMm in CRPC pts is higher than in the historical reports; 2) the interval from PC diagnosis and the appearance of BMm is clearly longer (42 mos) compared to that reported in historical series (28 mos). These findings could be related to the changes in survival of CRPC, produced by DOC introduction in the clinical practice. A special attention should be reserved to the appearance of neurological symptoms in a long-term CRPC survivor due to a possible relation with BMm. No significant financial relationships to disclose.
Identification of Medical Patients Who Should Receive Venous Thromboembolism Prophylaxis.
Authors: Alexander T. Cohen, Raza Alikhan, Juan I. Arcelus, Jean-François Bergmann, Sylvia Haas, Geno J. Merli, Alex C. Spyropoulos, Victor F. Tapson, Alexander G.G. Turpie
Journal: Blood (2004)
Multicenter phase II study of triplet combination chemotherapy with paclitaxel, cisplatin, and S-1 for advanced gastric cancer (OGSG 0703).
Authors: Kazumasa Fujitani, Yutaka Kimura, Hiroshi Imamura, Masahiro Gotoh, Shohei Iijima, Shugo Ueda, Motohiro Imano, Masahide Oshita, Yukinori Kurokawa, Toshio Shimokawa, Hiroya Takiuchi, Toshimasa Tsujinaka, Hiroshi Furukawa
Journal: Journal of Clinical Oncology (2012)

124 Background: Docetaxel combined with cisplatin and 5-fluorouracil is active in advanced gastric cancer, but not generally accepted because of its substantial toxicities. We conducted a multicenter phase II study of triplet combination using paclitaxel, cisplatin and S-1 (PCS) as first-line treatment for advanced gastric cancer. Methods: Patients with previously untreated, locally advanced or metastatic measurable gastric cancer, a performance status &lt; 2, age of 20-75 years, and adequate organ functions were given intravenous paclitaxel at 70 mg/m 2 and cisplatin at 30 mg/m 2 on days 1 and 15, plus oral S-1 at 40 mg/m 2 b.i.d. on days 1 to 21, followed by 2-week rest, repeated every 5 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient refused the therapy. Study endpoints included overall response rate (ORR) as primary, progression free survival (PFS), overall survival (OS), and toxicity. Sample size of 40 patients was determined to reject the ORR of 55% under the expectation of 75% with a power of 80% and a one-sided α of 5%. Results: A total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. ORR was 46.9% (95% CI: 32.5-61.7%). The median PFS and median OS were 5.4 months (95% CI: 4.1-7.0) and 11.5 months (95% CI: 7.3-16.1), respectively. Frequent grade 3/4 toxicities were neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), diarrhea (8%) and fatigue (8%). There was no treatment-related death. Conclusions: Triplet combination chemotherapy with PCS demonstrated superior feasibility with promising antitumor activity, though which did not meet the statistical hypothesis, for advanced gastric cancer.
Clinical Implications of Pulmonary Function Tests in Allogeneic Stem Cell Recipients.
Authors: Joon Ho Moon, Byung Woog Kang, Shi Nae Kim, Soo Jung Lee, Yun Jeong Kim, Jang Soo Suh, Kun Soo Lee, Yoon Young Cho, Jae Hoo Park, Sang Kyun Sohn
Journal: Blood (2009)
Comparison of partial nephrectomy for tumors greater than 7 cm to radical nephrectomy and effect on overall survival.
Authors: S. Vourganti, W. Linehan, G. Bratslavsky
Journal: Journal of Clinical Oncology (2011)

323 Background: As growing evidence indicates the importance of renal functional preservation, there is an increased utilization of partial nephrectomy (PN) performed for small renal masses (SRM). The optimal cutoff size for PN has been based on historical observation of low metastatic rates for SRM and increasing metastatic potential with increase in size of the primary tumor. We aim to evaluate the outcomes of patients treated by PN or radical nephrectomy (RN) for tumors greater than 7 cm. Methods: SEER 17 database was queried to identify patients treated for kidney tumors between 1983 and 2007. We excluded cases treated for non-RCC histology, not treated surgically, and those without specified size. Patients were included if treated by PN or RN with tumor size between 7 and 20 cm. Demographic information included age, gender, and race. The comparison of RCC-specific and overall survival was performed for the entire cohort and stratified by SEER stage (localized, regional, or distant). The survival was compared using Kaplan-Meier method with log rank test to identify significant differences. Results: We identified a total of 18,927 patients treated for RCC that included 18,575 cases of RN and 352 treated with PN. There were no differences in age, gender, or race (Caucasian vs. non-Caucasian) between patients treated by RN or PN (p&gt;0.05). The mean size for tumors treated by PN was 9.7 cm vs. 10.2 cm for RN (p&lt;0.01) and there was more localized disease in the PN group (p&lt;0.01). The overall median survival for patients treated with PN was 108 months vs. 80 months for patients treated with RN (p&lt;0.01). The cancer-specific survival for the entire cohort treated with PN was 195 months vs. 145 months for RN (p&lt;0.01). When stratified by stage, there were no differences in the cancer specific survival between PN and RN groups (p&gt;0.05). Conclusions: PN for tumors 7 to 20 cm is not associated with inferior oncologic outcomes but may provide survival advantage. While patient selection may have influenced overall survival outcomes, PN may provide survival advantage by maximizing renal reserve. These findings may be best answered in a randomized trial to establish if there should be a size cutoff for nephron sparing surgery. No significant financial relationships to disclose.
Haploinsufficiency of Ebf1 Collaborates with BCR-ABL1 to Decrease the Latency of Acute Lymphoblastic Leukemia.
Authors: Salil Goorha, Noel T. Lenny, Christopher B Miller, S. Scott Perry, Xiaoping Su, Richard T Williams, Charles G Mullighan, James R. Downing
Journal: Blood (2008)
Clinical and Prognostic Significance of Epstein-Barr Virus in Diffuse Large B-Cell Lymphoma
Authors: Shinichiro Matsuda, Ritsuro Suzuki, Masaya Inoue, Ritsuko Seki, Koji Nagafuji, Hiroaki Miyoshi, Koichi Ohshima, Junji Suzumiya
Journal: Blood (2016)
Phase II Study of Cladribine and Low-Dose Cytarabine (AraC) Alternating with Decitabine in Older Patients with Acute Myeloid Leukemia (AML)
Authors: Tapan Kadia, Gautam Borthakur, Alessandra Ferrajoli, Naval Daver, Elias Jabbour, Naveen Pemmaraju, Srdan Verstovsek, Jan A. Burger, William G. Wierda, Marina Konopleva, Courtney D. DiNardo, Nitin Jain, Mark Brandt, Carla Tuttle, Xuemei Wang, Farhad Ravandi, Guillermo Garcia-Manero, Jorge E. Cortes, Hagop M. Kantarjian
Journal: Blood (2014)
Use of percent positive biopsy cores to predict prostate cancer–specific death in patients treated with dose-escalated radiotherapy.
Authors: Y. Qian, F. Y. Feng, S. Halverson, K. Blas, H. M. Sandler, D. A. Hamstra
Journal: Journal of Clinical Oncology (2011)

35 Background: The percent of positive biopsy cores (PPC)-considered a surrogate of local disease burden-has been shown to predict biochemical failure (BF) after external beam radiation therapy (EBRT), but most series have used conventional dose RT. Dose-escalated RT has been demonstrated to improve prostate cancer outcomes, but the value of PPC is unclear in the setting of RT doses high enough to decrease local failure. Methods: A retrospective evaluation was performed of 651 patients treated to ≥75 Gy with biopsy core information available. Patients were stratified for PPC by quartile, and differences by quartile in BF, freedom from metastasis (FFM), cause specific survival (CSS), and overall survival (OS) were assessed using the log-rank test. Receiver operated characteristic (ROC) curve analysis was utilized to determine an optimal cut-point for PPC. Cox proportional hazards multivariate regression was utilized to assess the impact of PPC on clinical outcome when adjusting for risk group. Results: With median follow-up of 62 months the median number of cores sampled was 7 (IQR: 6–12) with median PPC in 38% (IQR: 17%-67%). On log-rank test, BF, FFM, and CSS were all associated with PPC (p &lt; 0.005 for all), with worse outcomes only for the highest PPC quartile (&gt;67%). There was no observed difference in OS based upon PPC. ROC curve analysis confirmed a cut-point of 67% as most closely associated with CSS (p&lt;0.001, AUC=0.71). On multivariate analysis after adjusting for NCCN risk group and ADT use, PPC&gt;67% increased the risk for BF (p&lt;0.0001, HR:2.1 [1.4–3.0]), FFM (p&lt;0.05, HR:1.7 [1.1 to 2.9]), and CSS (p&lt;0.06 (HR:2.1 [1.0–4.6]). When analyzed as a continuous variable controlling for risk group and ADT use, increasing PPC increased the risk for BF (p &lt; 0.002), metastasis (p &lt; 0.05), and CSS (p &lt; 0.02), with a 1–2% increase in relative risk of recurrence for each 1% increase in the PPC. Conclusions: For patients treated with dose-escalated RT, the PPC adds prognostic value but at a higher cut-point then previously utilized. Patients with PPC &gt;67% remain at increased risk for failure even with dose-escalated EBRT and may receive benefit from further intensification of therapy. No significant financial relationships to disclose.
Analysis of Long-Term Outcomes, Management and Prevalence of Osteonecrosis in UKALL 2003: 3.5% of Adolescents and Young Adults over 10 Years of Age with Acute Lymphoblastic Leukaemia Required Hip Replacement
Authors: Nadia L Amin, Sally Kinsey, Richard Feltbower, Ajay J. Vora, Nicholas Goulden, Rachel Wade, Chris Mitchell, Rachael Hough, Clare Rowntree, Beki James
Journal: Blood (2015)