tbuckley/cabot-search huggingface dataset:
Lapatinib-based therapy for women with advanced/metastatic HER2+ breast cancer.
Authors: Jamal M Zekri, Meteb Owaish Al-Foheidi, Mohamed Mokhtar Ibrahim, Tarek Darwish, Mervat Mahrous, Maged Mansour, Azhar J Rizvi, Turki Mohammad Al Fayea
Journal: Journal of Clinical Oncology (2014)

e11543 Background: Lapatinib (L) in combination with capecitabine (C) is approved for patients withadvanced/metastatic Her2+ breast cancer (A/MHer2+BC) after progression on Trastuzumab (T) based therapy. Single agent L and L in combination with other agents are also in use. Here we report our experience with L based therapy in this setting. To our knowledge there are no previous reports from the Middle East investigating this treatment strategy in multi-centre setting. Methods: 67 consecutive patients from 5 centres in western province of Saudi Arabia received L based therapy. 58 (87%) received L with C, 7 (10%) with other agents and 2 (3%) as single agent. The first patient started treatment with LC in February 2008 and the last in June 2013. Starting dose of L was 1250 mg daily and of C 1250 mg/m2 twice a day on days1-14 every 3 weeks. Data was collected from patients’ records retrospectively. Results: Median age at primary diagnosis of breast cancer was 46 (22-70) years. 38 (57%) received adjuvant chemotherapy and 26 of them (68%) received adjuvant T based chemotherapy. 58/67 (87%) received palliative chemotherapy regimens (1-3 lines) prior to L (57/58: were T based regimens). 64 patients were evaluable for response to L based therapy. 5 (8%) had CR, 36 (56%) had PR, 11 (17%) had stable disease and 12 (19%) had PD.Objective response to LC combination in evaluable patients was 36/56 (64%). Median PFS was 10 months (95% CI: 7.8-12.2). Median OS was 27 months (95% CI: 12-41). 13 (19%) patients required L dose delay for > one week and 9 (13%) required L dose reduction. At final analysis, 36 patients progressed and remained on FU. 19/36 (53%) received at least one subsequent line of chemotherapy with 26% objective response rate. Conclusions: In this small retrospective study, L based therapy is an effective treatment for women with A/MHer2+BC after prior exposure to T. In this setting, it yields meaningful response rates, PFS and OS. Dose delay is required for a relatively small subset of patients. L based therapy does not limit feasibility of subsequent chemotherapy and its benefit.
Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment
Authors: Tina Wang, Brian Tsui, Jason F. Kreisberg, Neil A. Robertson, Andrew M. Gross, Michael Ku Yu, Hannah Carter, Holly M. Brown-Borg, Peter D. Adams, Trey Ideker
Journal: Genome biology (2017)

Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans.We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls.This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.
Prevalence of vitamin D insufficiency and falls in older cancer patients.
Authors: Xiaotao Zhang, Ming Sun, Jay Bakul Shah, Colin P.N. Dinney, Uday R. Popat, Richard E. Champlin, Vicente Valero, Debu Tripathy, Ann-Marie Hedberg, Beatrice Jara-Almonte Edwards
Journal: Journal of Clinical Oncology (2017)

138 Background: More than 60% of cancer patients are older adults. Such patients undergo age and cancer therapy related changes. Older adults also have geriatric risk factors for falls such as frailty, cognitive impairment (mild cognitive impairment [MCI] and dementia), and malnutrition-including vitamin D deficiency. Objective: To assess the prevalence of vitamin D insuffiency and risk factors for falls in older cancer patients. Retrospective cohort study. Methods: Patients underwent prospective data collection and retrospective analysis. Patients underwent a comprehensive geriatric assessments, including cognitive, functional, nutritional, physical, and comorbidity assessment. Vitamin D was assayed. Bone densitometry was performed. Analysis: Descriptive statistics, and multivariable logistic regression. Results: We enrolled 318 patients and 305 patients with complete data were included for final analysis. Patients were undergoing active cancer care. Patients had gastrointestinal, urologic, breast, lung and gynecologic cancers. The mean age was 78.4 ± 6.9 years. Low bone mass and osteoporosis were very common (80%) in this cohort. Twenty-six percent had one or more falls in the preceding six months. Dementia and mild cognitive impairment were seen in 33% and 37% of patients, and 53% presented frailty. In 256 patients, 48.8% (n = 125) had Vitamin D insufficiency ( &lt; 30 ng/ml). In univariate analysis, co-morbidity (p = 0.05), frailty (p &lt; 0.01), and cognitive impairment (0 = 0.02) were significantly associated with falls, while in multivariate analysis, frailty remained significantly associated with falls (OR = 3.51, 95%CI = 1.88, 6.52). Conclusions: Older cancer patients have a high prevalence of falls, osteoporosis and vitamin D insufficiency, raising the possibility of injurious falls (fractures). Frailty was found to be the most prominent risk factor for falls in this cohort. Greater awareness and targeted interventions such as vitamin D replacement, physical therapy, nutrition interventions, and therapy for low bone mass/osteoporosis will be effective preventing injurious falls.
Discharge to a skilled nursing facility as the strongest modifiable risk factor for readmissions following pancreaticoduodenectomy.
Authors: Katelin Anne Mirkin, Christopher S Hollenbeak, Amanda Beth Cooper, Niraj Jaysukh Gusani
Journal: Journal of Clinical Oncology (2017)

435 Background: Pancreaticoduodenectomy is a technically difficult and notoriously morbid procedure. As payers begin to link reimbursement to readmission rates, there is growing interest in understanding and preventing readmissions. The objective of this study was to evaluate factors contributing to 30-day readmission rates for patients undergoing pancreaticoduodenectomy. Methods: Data from the Pennsylvania Health Care Cost Containment Council (PHC4) were reviewed for patients undergoing pancreaticoduodenectomy from 2011-2014 (n = 1,552). Outcomes included 30-day readmission and length of stay (LOS). Univariate comparisons were performed between characteristics of those readmitted (n = 404) and not readmitted (n = 1,148). Readmission and LOS were modeled using multivariate logistic regression and linear regression, respectively. Results: Of the 404 (26.0%) patients who were readmitted, the most common causes for readmission were post-operative infection (26.2%), anastomotic complications (8.0%), and dehydration (5.7%). Patients who were readmitted were more likely to be discharged to a skilled nursing facility (SNF) and were associated with a longer LOS of index admission (p &lt; 0.001, both). In multivariate analysis, black race (HR 1.96, p = 0.001), discharge to a SNF (HR 1.73, p = 0.006) and increased LOS (HR 1.36, p = 0.019), were associated with increased odds of readmission. After controlling for patient, admission, and facility characteristics, black race, urgent and emergent admissions, and discharge to a SNF or home with home healthcare, were predictive of a longer LOS (p &lt; 0.05). High surgeon volume, and high hospital volume were associated with a shorter LOS (p &lt; 0.05). Conclusions: The most common causes of readmission following pancreaticoduodenectomy in Pennsylvania from 2011-2014 were post-operative infection, anastomotic complications, and dehydration. Patients with a longer initial hospital stay and those discharged to a SNF were associated with higher odds of readmission. Understanding the interplay of these factors may result in opportunities to prevent readmissions, and improve outcomes in patients undergoing this complex surgery.
Clinicopathological Significance of Taz and VGLL1 Expression in Early Stage Ovarian Cancer. A study by Spanish Group for Ovarian Cancer Research (GEICO).
Authors: Jose Antonio Lopez-Guerrero, Ana Gutierrez Pecharroman, José Palacios, Eva Maria Cristobal Lana, Ignacio Romero, David Hardisson, Francisco Vera-Sempere, Carmen Illueca, BegoÃÂ±a Vieites, Angel Garcia, Javier Ibarra de la Rosa, Sofia Hakin Alonso, Rosa Guarch Troyas, Encarna Andrada, Santiago Montes, Francisco Pastor, Maria Carmen Gomez, Maria Amparo Torroba, Emanuela D'Angelo, Andres Poveda
Journal: Journal of Clinical Oncology (2015)

e16583 Background: The Hippo signaling pathway has emerged as an important regulatory pathway in cancer. Two final transducer effectors of this pathway are the oncoproteins TAZ and VGLL1. In breast cancer, the expression of these two proteins occurs mainly in triple negative tumors. The aim of this study is to analyze the role of TAZ and VGLL1 in ovarian cancer (OC). Methods: We studied a total of 212 FFPE samples belonging to the GEICO Early Stage (I-II) OC Registry. All cases were reviewed centrally by two independent pathologists after the evaluation of WT1, p53, p16, progesterone receptor and napsin A expression to confirm histological type. Final diagnosis was achieved by consensus and compared with diagnosis of origin (DO). TAZ and VGLL1 were evaluated by immunohistochemistry on tissue microarrays (TMAs) and their impact on prognosis was analyzed by log-rank tests being relapse free survival (RFS) the clinical endpoint. Results: OC were classified as following: high-grade serous (HGS, n = 44), low-grade serous (LGS, n = 23), high-grade endometrioid (HGE, n = 20), low-grade endometrioid (LGE, n = 48), clear cell (CCC, n = 50) and mucinous (M, n = 27). TAZ and VGLL1 were overexpressed in 30% and 9% of tumors, respectively. TAZ was expressed by 43% of HGS and 52% of CCC being negative in M (p < 0.001), whereas VGLL1 has not a significant histotype predilection (p = 0.08) being expressed in 20% of CCC. Concordance with DO was of 77% (Kappa = 0.722; p < 0.0001). Median follow-up was 87 months (range: 0-217) and 43 (20%) recurrences were reported. The univariate analysis showed a 5-years RFS of 67% for those cases expressing VGLL1 vs 85% of the negative (p = 0.038); a 73% for HGS and HGE vs. 88% of other histotypes (p = 0.001). TAZ expression was not reported as prognostically relevant. The multivariate analysis showed that higher stage [HR = 3.9 (1.4-10.6); p = 0.008], age > 55 yrs [HR = 2.1 (1.1-4.3); p = 0.03] and p53 expression [HR = 2.4 (1.2-4.8); p = 0.015] constituted independent poor prognostic factors. Conclusions: This is the first study demonstrating the expression and the prognostic impact of TAZ and VGLL1 in OC. These results suggested an important role of the Hippo pathway, particularly in CCC.
Erratum: Late development of antidesmoglein 1 antibodies in pemphigus vulgaris: Correlation with disease progression (British Journal of Dermatology (1999) 141 (1084-1088))
Authors: S. Miyagawa, M. Amagai, T. Iida, Y. Yamamoto, T. Nishikawa, T. Shirai
Journal: British Journal of Dermatology (2000)
Genetic difference between multicentric carcinogenesis and intrahepatic metastasis of multiple hepatocellular carcinoma.
Authors: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani
Journal: Journal of Clinical Oncology (2017)

307 Background: Multiple hepatocellular carcinoma (HCC) is categorized into 2 types; multicentric carcinogeneis (MC) and intrahepatic metastasis (IM). Although discrimination of the types of multiple HCC is of clinical importance, it is difficult to determine it correctly even after histological diagnosis. Methods: In order to classify multiple HCC into MC and IM, we compared pairs of multiple HCC and matched non-tumoral liver samples from 22 patients who were clinically diagnosed MC and 8 patients with IM with regard to molecular aberrations using next generation sequencer. Results: Exome sequence showed that among the 22 patients with clinical MC, 7 patients were genetically determined as having IM (gIM) because of the concordance of mutations, while all the patients with clinical IM were as having MC (gMC). In 15 patients with gIM, 125 mutations (90.6%) per patient were common, which were consistent with the result of a pair of primary HCC, and only a few passenger mutations were different between IM specimens suggesting that IM pairs developed from the common ancestor. On the other hand, 138 somatic mutations per tumor, and no common somatic mutations were identified in the 15 patients with gMC. Clinically, vascular invasion was significantly frequent in gIM group ( P = 0.007). On the other hand, after a median follow-up of 2.56 years (range; 0.27−6.32 years), the median overall survivals were 3.7 years (95%CI, 1.26–6.14) and 3.37 years (2.02−6.32, P = 0.712) in the patients with IM and MC, respectively. The 3-year rates of overall survival were 71.7% and 65.1% in the two groups, respectively. Conclusions: Taken together, genetic comparison of mutations in a pair of HCCs makes it possible to classify MC and IM, which is available to make treatment plan for multiple HCC patients.
Abstract 1446: Central Role of Calcium-Dependent Tyrosine Kinase PYK2 in eNOS-Mediated Vascular Function and Angiogenic Response -Unmasked by PYK2 Knockout Mice-
Authors: Akihiro Matsui, Mitsuhiko Okigaki, Asako Katsume, Shinsaku Matsunaga, Hiroyuki Yamada, Hiroaki Matsubara
Journal: Circulation (2007)

Background: Endothelial nitric oxide synthase (eNOS) is activated by PI3-kinase/Akt or Ca 2+ -dependent CaM kinases, whereas the involvement of Ca 2+ -dependent tyrosine kinase PYK2 remains to be determined. Methods and Results: We newly generated the PYK2-deficient (−/−) mice and investigated the effects of PYK2 on NO-mediated vascular functions and angiogenic response. The PYK2−/− mice exhibited a significant reduction in the basal eNOS phosphorylation and VEGF- or Acetylcholin-mediated response in the aorta and aortic endothelial cells (ECs) compared with the wild-type mice, and blood flow recovery and neovessel formation after hindlimb ischemia were reduced with affecting mobilization of endothelial progenitors. Acetylcholin-mediated aortic vasorelaxation and cGMP production were decreased (54% and 44%, P&lt;0.01, respectively) and blood pressure in the PYK2−/− mice is higher than the wild-type mice (mean 97 vs. 86 mmHg, P&lt;0.05). In the PYK2−/− mice, VEGF-mediated Akt phosphorylation, NO production and cytoplasmic Ca 2+ mobilization were markedly decreased. And also the phosphorylation of c-Src and PLCγ1, interaction of c-Src/PLCγ1 were clearly reduced. VEGF-dependent migration, tube formation and actin cytoskeletal reorganization were markedly inhibited in PYK2−/− ECs, while addition of L-arginine or cGMP-dependent kinase activator reversed the attenuated response. Conclusion: These findings demonstrate that PYK2 is involved in the receptor-activated signaling events leading to the phosphorylation of eNOS and thus regulates eNOS-mediated vasoactive function and angiogenesis.
Multimodality management of synovial sarcoma: Review of single institutional experience.
Authors: N.M.L. Manjunath, S. V. S. Deo, N. K. Shukla, Sameer Bakhshi, Dayanand Sharma
Journal: Journal of Clinical Oncology (2013)

e21506 Background: Soft tissue sarcomas (STS) are rare malignancies constituting 1% of all solid tumors. Synovial sarcoma (SS) constitutes 5-10% of all sarcomas. Histopathologically SS is classified as Monophasic, Biphasic and Poorly differentiated varieties and majority are high grade. There is paucity of literature pertaining to SS from developing countries. Methods: Study population was selected from a prospectively maintained STS database at the department of Surgical Oncology, Dr BRAIRCH, AIIMS. All patients with pathological diagnosis of SS were included for the analysis. Results: A total of 446 patients of STS were treated from 1995 to 2009 and 80 cases of pathologically proven SS were selected. Median age at diagnosis was 33 years. There were 53 males (66.3%) and 27 females (33.8%). Most common site was proximal lower limb, majority involving thigh. Sixty one patients presented with prior inadequate interventions including intralesional excision or marginal excision. Sixty seven cases had tumors more than 5 cm in size and 27 more than 10 cm. Lymph nodes were seen in 9 patients (11.3%) but only 4 showed pathological involvement. According to MSKCC staging 83% had stage III disease and stage I and II constituted 10.5%. Ten patients had metastasis at presentation and all of them had lung metastasis. Among the extremity sarcoma, 35 (43.8%) patients had limb salvage surgery and the rest required amputations due to advanced nature of disease. Overall 15% of cases required reconstruction and only 6 had positive margin. Postoperatively 35 patients received radiotherapy and 52 received chemotherapy (Adriamycin Ifosamide based). At a median follow up of 59 months,10 patients had local recurrence and 34 (42.5%) patients had systemic relapse mainly in the lungs (27 patients). At last follow up, 58 patients were alive of which 44 were disease free. The overall 5 year survival was 52%. Conclusions: SS is a rare tumor involving younger age group. Due to lack of awareness among patients and physician, majority present with suboptimal surgical intervention or advanced stage in developing countries resulting in a low limb salvage rate. Most common site of relapse is lung despite multimodality management resulting in a modest 5-year survival of 52%.
Glucocorticoid receptor (GR) expression in circulating tumor cells (CTCs) to prognosticate overall survival (OS) for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with androgen receptor signaling inhibitors (ARSi).
Authors: David Wise, James Kelvin, Ryon Graf, Nicole A. Schreiber, Brigit McLaughlin, Luisa Fernandez, Normy Rivera, Bianca Petines, Melissa Harvey, Linda Nguyen, Aaron Oh, Lee Horiuchi, Ryan Vance Dittamore, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

194 Background: Upregulation of GR protein expression in metastatic biopsies from pts with CRPC has previously been shown to correlate with resistance to enzalutamide and has been validated as a therapeutic target in pre-clinical studies. We sought to determine whether upregulated GR protein expression in CTCs from pts with progressing mCRPC predicted clinical outcomes following treatment with enzalutamide (E) or abiraterone (A). Methods: Pre-therapy blood samples from 54 pts with progressing mCRPC were subjected to CTC analysis using the Epic Sciences platform. Samples were examined to identify CK+ (CK+, CD45- cells, with intact nuclei, morph distinct) CTCs for GR protein expression. GR+ CTCs were defined as having expression greater than the 95 th percentile of GR expression in the GR negative LNCAP cell line. Kaplan-Meier analysis was used to test the impact of GR+ CTCs on OS following treatment with A or E. A Cox proportional hazards model with CTC number and GR positivity was used in a multivariate analysis. Results: 37 out of 54 pts (69%) had detectable and viable CK+ CTCs. 28 out of 37 pts (76%) had CTCs with upregulated GR staining with a median of 6 GR+/CK+ cells/ml per patient (range 0.7 – 244 cells/ml). The OS of patients with GR+ CTCs treated with ARSi was significantly worse than that of patients without detectable GR+ CTCs (11.4 mo. vs NA, p &lt; 0.01), an effect independent and additive to the presence of viable CTCs, a previously described prognostic biomarker (see Table). Conclusions: GR protein upregulation in CTCs can be detected in a significant percentage of pts with progressing mCRPC and the presence of GR+ CTCs predicts worse OS in response to ARSi. The data supports previously reported pre-clinical data proposing a pathogenic role for GR in mediating resistance to ARSi therapy. Detection of GR in patient CTCs may be a useful predictive biomarker to guide GR-directed therapies. [Table: see text]
Assessment of sarcopenia as predictor of response and outcome after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC).
Authors: Petros Grivas, Homi Zargar, Cesar Emilio Ercole, Evan Kovac, Erick M. Remer, Wadih Karim, Hamid Emamekhoo, Andrew J. Stephenson, Amr Farouk Fergany, Michael C. Gong, Steven C. Campbell, Ryan Kent Berglund, Robert Dreicer, Brian I. Rini
Journal: Journal of Clinical Oncology (2015)

e15512 Background: Sarcopenia (loss of skeletal muscle mass) at the time of RC has been associated with lower cancer-specific and overall survival (OS) in bladder cancer patients. Change in muscle volume during NAC has not been well studied. We assessed change in total psoas muscle volume (TPMV) before and after NAC and evaluated if such change was associated with pathologic response at cystectomy, 2-year recurrence-free rate (2yRFR) or OS. Methods: During the period 2009-2013, patients with pure/mixed urothelial MIBC undergoing NAC and RC at Cleveland Clinic with pre and post NAC (prior to RC) cross sectional CT images available were selected from our IRB-approved RC database. Bilateral TPMV was obtained from pre and post NAC images by one observer (Radiology). The proportion of TPMV change was calculated by dividing the change in TPMV by pre-NAC TPMV. Univariate and multivariate analysis for assessment of factors predicting pathologic complete response (pCR, pT0N0), partial response (pPR, ≤ pT1N0), 2yRFR and OS were performed. Results: From the total 130 patients receiving NAC during the study period, 60 patients had adequate radiological data available for analysis. Mean age was 61.7 years, 86.7% were men and 96.7% had ECOG performance status 0-1; 88.3% received cisplatin-based NAC. pCR rate was 28.3%, pPR rate was 48.3%, 2yRFR was 73%, median follow-up was 15.5 months. Median pre-NAC TPMV and body mass index (BMI) were 423.5 cm3 and 29.8 kg/m2, respectively, weakly correlated with each other (r = 0.4 p = 0.001) but not with pPR, pCR, 2yRFR or OS. Median time interval between the two images was 128 days. Proportions of post-NAC TPMV and BMI decline were statistically significant, 4.9% (p < 0.001), and 0.05 % (p = 0.03), respectively, and weakly correlated with each other (r = 0.33 p = 0.01). On multivariable analysis (age, clinical T stage, gender, chemotherapy regimen, proportion of TPMV loss, BMI change) the proportion of TPMV loss or BMI change after NAC was not associated with pPR, pCR, 2yRFR or OS. Conclusions: In our cohort of patients with urothelial MIBC, proportion of changes in TPMV and BMI after NAC was not associated with pathologic response to NAC, 2yRFR or OS.