tbuckley/cabot-search huggingface dataset:
Arterial spin labeling MRI detects early recurrence and anti-angiogenic drug effect in recurrent malignant gliomas
Authors: E. T. Wong, B. Appignani, J. K. Wu, A. Mahadevan, J. J. Joseph, D. Lee, A. Tam, J. Bloom, L. Barron, D. Hackney, D. Alsop
Journal: Journal of Clinical Oncology (2005)

1573 Malignant gliomas are characterized by three major physiological processes: growth/proliferation, angiogenesis, and invasion. Although incompletely understood, each physiological process is probably driven by independent but related signal transduction pathways. Assessment of anti-angiogenic drug effect has so far been based on stabilization of tumor size over time, as anti-angiogenic drugs are thought to have a predominant cytostatic effect. Unlike gadolinium-enhanced dynamic contrast MRI that has confounding blood perfusion and permeability variables, arterial spin labeling (ASL) measures primarily blood perfusion in tumors making this technique ideal for detecting early tumor recurrence and for measuring anti-angiogenic drug efficacy. We attempted to use serial ASL to follow a cohort of 6 patients with a history of malignant gliomas (1 glioblastoma multiforme, 1 anaplastic astrocytoma, and 4 anaplastic oligodendrogliomas). Four patients were in a trial with irinotecan, thalidomide, and doxycycline for recurrent malignant gliomas, while the other two were off therapy after adjuvant radiation and chemotherapy with temozolomide or PCV (procarbazine, CCNU, and vincristine). Although two patients died from probable pulmonary embolism, serial ASL in four patients detected increased blood flow one to two months before tumor recurrence based on conventional gadolinium enhancement criteria. Patients on irinotecan, thalidomide, and doxycycline also had serial ASL in addition to their conventional gadolinium-enhanced head MRI, and decreased ASL signal after 2 cycles of therapy suggests decreased blood perfusion in tumor. The pathology of recurrent tumor after irinotecan, thalidomide, and doxycycline treatment in two patients showed a myxoid appearance without vascular hyperplasia. Our data suggest that ASL could be used to monitor malignant gliomas for early detection of tumor recurrence, and for monitoring anti-angiogenic drug therapy. Supported in part by Celgene, Inc., Maurice and Abe Simon Brain Cancer Research Fund, and donations from the Mahoney family. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, General Electric Healthcare
Drug eluting beads versus conventional TACE for unresectable hepatocellular carcinoma: Survival benefits and safety
Authors: R. Dhanasekaran, D. A. Kooby, C. A. Staley, J. S. Kauh, H. S. Kim
Journal: Journal of Clinical Oncology (2009)

4524 Background: Conventional transarterial chemoembolization (TACE) has long been used as palliative transcatheter therapy for patients with unresectable hepatocellular carcinoma (HCC). Drug eluting beads (DEB) are a newer drug delivery system that can be loaded with doxorubicin. Though therapy with DEB is feasible, the survival advantage of this therapy over conventional TACE has not been established. Methods: Consecutive patients who received transcatheter therapy with Doxorubicin DEB or conventional TACE as sole therapy over a period of 1998 to 2008 were studied. Patients who underwent resection, transplantation, radioembolization or combination therapies have been excluded from the study. Statistical analysis was performed using Kaplan Meier Estimator with a log rank test, Chi-square and independent T-tests. Results: A total of 73 patients were included in the study, 47(64.4%) received therapy with DEB (group A) and 26(35.6%) underwent conventional TACE (group B). The demographic, tumor burden and liver reserve characteristics of patients in the two groups were statistically similar. Median survival from diagnosis of HCC in group A and B were 610 days(352–866) and 284 days(4–563) (p=0.03). Median survivals from the time of first transcatheter therapy in group A and B were 403 days(373–679) and 114 days (183–460)(p=0.01). The survival rates in group A and B at 6 months, 1yr and 2 yrs were 71%, 66%, 40% and 58%, 46%, 19%. On analysis of patients in Child Pugh class A and B, median survivals in group A and B were 390 days(298–491) and 114 days(41–187)(p=0.004). No difference in survival was found in Child Pugh class C. 6.4%(3/47) of patients treated with DEB and 7.7%(2/26) of patients treated with conventional TACE developed liver failure in the post procedure period. All patients who developed liver failure belonged to Child Pugh class C. No other major complications were reported in either group. Conclusions: In patients with unresectable HCC, transcatheter therapy with Doxorubicin eluting beads offers a survival advantage over conventional TACE. The safety profile of the two treatment modalities appears similar. No significant financial relationships to disclose.
Recombinant soluble prostate-specific membrane antigen (rsPSMA) vaccine: Preliminary findings of a Phase I safety/immunogenicity trial
Authors: J. P. Gardner, S. F. Slovin, D. M. Morrissey, G. P. Donovan, K. G. Surowitz, W. C. Olson, H. I. Scher, R. J. Israel
Journal: Journal of Clinical Oncology (2004)

2584 Background: Prostate-specific membrane antigen (PSMA) is an ∼100 kDa transmembrane glycoprotein that is abundantly and preferentially expressed in prostate cancer, including recurrent and hormone-refractory cases. We have developed a subunit vaccine based on a novel rsPSMA protein that represents the entire extracellular domain of PSMA (Schulke et al., PNAS 100:12590, 2003). The vaccine comprises purified rsPSMA protein formulated with Alhydrogel® adjuvant. In preclinical studies, rsPSMA elicited high-titer antibodies that strongly cross-reacted with prostate cancer cells. Methods: The first-in-man trial was an ascending, multiple-dose, safety and tolerance study in cohorts of 6 patients each. Patients received four subcutaneous injections of rsPSMA vaccine at weeks 1, 2, 3 and 7. The study included assessments of PSMA-specific immune responses and serum PSA levels. Inclusion criteria included biochemically progressive prostate cancer following definitive local therapy with or without an adequate course of hormonal therapy. Patients with radiographic evidence of disease progression were excluded from the study. Results: The vaccine was well tolerated in this patient population, and no dose-limiting toxicities were observed. Whereas no patient had detectable levels of PSMA-reactive antibodies at baseline, vaccination elicited PSMA-reactive antibodies as measured by ELISA, and the anti-PSMA antibody titers increased with repeat immunizations. Conclusions: PSMA-specific sero-conversion has been observed without dose-limiting toxicity in patients treated to date. The results support further testing of rsPSMA vaccine alone and in heterologous prime-boost combinations with vaccines that elicit high-titer cellular immune responses to PSMA. A viral-vector vaccine (PSMA-VRP) based on the alphavirus Venezuelan equine encephalitis virus is expected to enter Phase I testing in 2004. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Progenics Pharmaceuticals, Inc.
K-<i>ras</i> and <i>p16</i> Aberrations Confer Poor Prognosis in Human Colorectal Cancer
Authors: M. Esteller, S. González, R. A. Risques, E. Marcuello, R. Mangues, J. R. Germà, J. G. Herman, G. Capellà, M. A. Peinado
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways. PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated. RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered. CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.
Stage I nonseminomatous germ cell tumors of the testis: Clinical outcome of 45 patients on a surveillance protocol after orchiectomy alone at a single institution in Japan
Authors: K. Kakimoto, Y. Ono, N. Meguro, K. Takezawa, T. Yoshida, Y. Arai, M. Usami
Journal: Journal of Clinical Oncology (2009)

e16165 Background: In Japan, risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis (NSGCTT) has been performed in very few institutions. This retrospective study was performed to evaluate histopathologic prognostic factors with stage I NSGCTT for whom careful follow-up with a surveillance protocol was possible at a single institution. Methods: We included 45 patients with a median age of 31 years (range 16 - 58) who were managed with a surveillance strategy after orchiectomy in our department between 1972 and 2006. Mean duration of follow-up was 8.1 years (range 1.4 –30). The patients were monitored at follow-up evaluation for tumor marker (AFP, beta-hCG) levels and by abdominal CT scan, chest x-ray, and physical examination. Primary testis tumor samples were assessed for prognostic factors including lymphatic and/or vascular (LV) invasion and pathological components such as the presence of embryonal carcinoma. Log-rank analyses were performed to identify prognostic factors. Results: All patients were alive and disease-free. Relapses occurred in 16 (35.6%) patients after a median follow-up of 5.7 months (range 3–45). In 11 patients (68.8 %), relapse was detected in the retroperitoneal lymph nodes. Two patients (12.5%) had metastases in the retroperitoneal lymph nodes and lungs, two patients (12.5%) had metastases in the lungs alone, and one patient (6.2%) had metastases in the retroperitoneal lymph nodes, lungs, and brain. LV invasion was identified in 17 patients, 53% of whom had relapsed, and relapse was found in 25% of 28 patients without LV invasion (p&lt;0.01). Of 31 patients with an embryonal carcinoma component, 13 patients (42%) developed metastases, whereas 21% of those without an embryonal carcinoma component developed metastases (p=0.04). After chemotherapy and/or surgical treatment for relapse, the 5-year overall survival rate was 100%. Conclusions: As in previous reports, the presence of an embryonal carcinoma component and LV invasion appeared to be factors suggesting a high likelihood of relapse. The surveillance protocol described here is a reliable strategy for stage I NSGCTT patients if careful long-term follow-up is possible. No significant financial relationships to disclose.
Abstract 9414: RyR2 Stabilization by Inhibiting Aberrant Ca2+ Release Mediated by CaMKII Signaling Within the Increase of Ca2+ Buffering Capacity Suppress Arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy
Authors: Shinichi Okuda, Takayoshi Kato, Masakazu Fukuda, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
Journal: Circulation (2014)

Backgrounds:  Familial Hypertrophic Cardiomyopathy (FHC) caused by Cardiac troponin T (cTnT) mutations leads to sudden cardiac death. Ca2+ sensitivity in myofilaments was increased, however, the underlying mechanism by which the cTnT mutations lead to lethal arrhythmia and the therapeutic approach remains elusive. Here, we investigated the pathogenic role of aberrant Ca2+ release via the cardiac ryanodine receptor (RyR2) and the therapeutic effects of RyR2 stabilization by inhibition of phosphorylating activity, or dantrolene, which was found to correct inter-domain interactions of RyR2 directly in failing hearts (i.e. unzipping to zipping), in transgenic mouse (TG) model with FHC-related cTnT mutation (delta160E).   Methods and results:  In 6thmonths of age, there was no appreciable difference in the structural or functional features of the hearts between non-TG and TG. In response to isoproterenol (ISO; 10 nmol/L), the Ca2+ spark frequency (SpF:s-1·100μm-1; by fluo4) was much higher in TG cardiomyocytes (ISO-TG: n=11: 7.9±0.6; p   Conclusions:  In FHC-linked cTnT mutated hearts, aberrant local Ca2+ release through defective RyR2 was induced by beta-adrenergic stimulation, presumably due to mutation-linked, increased Ca2+ buffering capacity, and subsequent CaMKII activation. RyR2 stabilization by inhibiting CaMKII-mediated aberrant Ca2+ release could be a new therapeutic approach to prevent the development of arrhythmias in FHC.
Clinical development of huARH460–16–2: A therapeutic antibody targeting the CD44 cancer stem cell antigen on high-incidence adenocarcinomas
Authors: S. E. Hahn, L. A. da Cruz, A. Gupta, B. Mak, L. Popp, D. S. Pereira, D. B. Rubinstein, D. S. Young
Journal: Journal of Clinical Oncology (2008)

14581 Background: CD44, a membrane glycoprotein instrumental in cell adhesion and tumor progression, is a cancer stem cell target in solid tumors and leukemias. ARH460–16–2, an antibody targeting a unique epitope of CD44, has been shown to be effective in various pre-clinical cancer models. For example, it suppresses tumor growth and extends survival in breast cancer xenograft models. To enable the development of this antibody for human clinical trials, a non-GLP toxicology study was done with chimeric ARH460–16–2 (chARH460–16–2) in cynomolgus monkeys. In addition, efficacy and mechanism of action studies were performed with the clinical molecule, humanized ARH460–16- 2. Methods: IHC was performed with chARH460–16–2 on human and cynomolgus monkey tissues. Thereafter, dose-ranging toxicology was carried out in cynomolgus monkeys. In the first phase, monkeys (2 per group) were given a single 1 hr infusion of 10, 30, or 95 mg/kg of chARH460–16–2. A second cohort of 3 monkeys received 25 mg/kg of chARH460–16–2 weekly for 2 doses. Results: Limited binding of chARH460–16–2 to normal human tissues was observed: while the Ab bound myeloid elements, there was no binding to erythroid cells, megakaryocytes, endothelium, fibroblasts, smooth muscle, eye, heart, liver, ovary or colon epithelium. A similar pattern was seen in cynomolgus tissues with differences in intensity. In toxicology studies, there were no drug-related effects on clinical chemistry, coagulation, or hematology parameters. Histopathology of the repeat-dose group demonstrated no findings in bone marrow or lung sections. In one high-dose monkey and in all repeat-dose subjects, transient skin reddening resolved within days. huARH460–16–2 generated in CHO cells was confirmed to be similar to chARH460–16–2 by binding to CD44 and CD44+ cancer cell lines, in induction of apoptosis, and in tumor regression in a breast cancer xenograft model. Conclusions: ARH460–16–2 inhibits growth in CD44+ adenocarcinomas, and demonstrates no limiting toxicity at therapeutically applicable doses in cynomolgus monkeys. These results and the role of CD44 in cancer stem cells strongly support clinical development of huARH460–16–2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Arius Research Inc. Arius Research Inc. Arius Research Inc.
Management of acute oxaliplatin-related peripheral sensory neuropathy with magnesium and calcium
Authors: S. Pederiva, C. B. Caspar
Journal: Journal of Clinical Oncology (2004)

3715 Background: Oxaliplatin is an effective anticancer agent in the treatment of colorectal cancer. However, it is associated with chronic peripheral sensory neuropathy, an often dose-limiting side effect, which occurs after 4–6 cycles of chemotherapy. Furthermore, an acute, cold-induced syndrome with dysesthesia and sometimes myoclonia occurs in most patients (85–95%) which is reversible but possibly very painful. Recent data showed that magnesium- and calcium-infusions (mg/ca-) before oxaliplatin reduce the acute neuropathy1. Methods: We administered magnesiumsulfat (mg) 1.25g (= 5 mmol = 24.3mg ionised Mg) and calciumgluconat (ca) 1.375g (= 90mg ionised Calcium) infusions (mixed in 100ml normal saline over 30 min before chemotherapy) in 11 patients with acute sensory neuropathy receiving an oxaliplatin-based chemotherapy. Results: 11 patients received 3–18 doses of oxaliplatin (median =10) preceeded by mg/ca-infusions. There were no side effects nor changes in electrolytes caused by the mg/ca-infusions. Only minimal neuropathy was reported by the patients with mg/ca-infusions. In patients with marked acute neuropathy during previous cycles, the pretreatment with mg/ca-infusions dramatically reduced the dysesthesias (e.g. during exposure to cold in the refrigerator). In one of the patients the infusion of oxaliplatin had to be interrupted because of severe acute neuropathy but could be resumed without any problems after application of a mg/ca-infusion (up to now for a total of 18 doses of oxaliplatin). However, the mg/ca-infusions do not influence the cumulative and often dose-limiting chronic neuropathy. Discussion: Our data indicate that the prophylactic treatment of acute sensory neuropathy with mg/ca-infusions is safe, inexpensive and effective. There is no change in blood electrolytes. However, this treatment does not seem to prevent the oxaliplatin-related chronic neuropathy. 1 Lainé-Cessac P et al. Acute oxaliplatin neurotoxicity dramatically improved with intravenous calcium and magnesium salts. Ileme Congrés Annuel de la Société Francaise de Pharmacologie, Nancy, France, 1998. No significant financial relationships to disclose.
Prevention of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) in the levrat rat model of EAC by treatment with a smoothened (SMO) inhibitor.
Authors: M. K. Gibson, A. H. Zaidi, J. M. Davison, B. Hough, A. F. Sanz, T. Foxwell, T. Hoppo, Y. Komatsu, K. S. Nason, C. Rotoloni, U. Malhotra, A. Atasoy, C. Smith, J. D. Luketich, B. A. Jobe
Journal: Journal of Clinical Oncology (2011)

4129 Background: EAC from BE is increasing and the prognosis is poor. The benefit from prevention of BE and EAC is great. The Sonic Hedgehog (Shh) pathway, a mediator of foregut development, may play a role in development of BE/EAC. The Levrat model of gastroduodenojejunal reflux mimics progression from normal to BE to EAC. We studied the activity of a SMO inhibitor (BMS 833293) in prevention of BE/EAC in the Levrat’s rat model. Methods: Gastroduodenojejunal reflux was induced in 6-8 wk old male Sprague–Dawley rats, as approved by the Institutional Care and Use Committee. Esophagus was mobilized, preserving the vagus, and a loop of jejunum was identified. The gastroesophageal junction (GEJ) was divided and ligated, and an end-to-side anastomosis was constructed. The incidence of BE/EAC at 28 wks is 90%/70%. To attain a 42% reduction in incidence of EAC vs controls (70%) at 28 weeks, 32 rats/group (a = 0.05) were included. PK evaluation in operated rats yielded a dose of 10mg/kg. Oral dosing daily started at 10 wks post-op on weeks 10-16, 18-22 and 24-28. One pathologist (JD) evaluated all samples. Results: Surgical survival=90%. Dose schedule was daily; however, by 6 wks, rats lost 10-15% of their BW, necessitating an interrupted schedule. All animals have been sacrificed; however, data is available for a subset. Treatment toxicities included: wt loss at 6 weeks of 10-15%, porphyria and UGI bleeding. Specimens from 11 control and 14 treated animals were evaluated by JD. Control: BE=11/11 and EAC=4/11. Treatment: BE=7/14 and EAC=0/14. Samples also showed ulcerative esophagitis in: 11/14 treated and 0/11 controls. Review of remaining samples is underway. Conclusions: The Levrat model for evaluation of inhibition of BE/EAC by the smoothened inhibitor, BMS 833293, is feasible. Preliminary data suggest a treatment effect. Full data available at the meeting will include PD and Shh gene expression.
An algorithm for screening and treatment of breast cancer-related lymphedema.
Authors: T. R. Lopez Penha, E. M. Heuts, S. Tuinder, R. van der Hulst, M. F. von Meyenfeldt
Journal: Journal of Clinical Oncology (2011)

256 Background: Currently, there is no clear-cut regimen for the treatment of breast cancer related lymphedema. There is evidence advocating both conservative and micro surgical therapy, with treatment effectiveness being dependent on the lymphedema stage. We propose a multidisciplinary screening program with the aim of preventing breast cancer related lymphedema progression and ensure disease regression by early identification and treatment initiation. This approach would ultimately reduce the negative functional, psychosocial and cosmetic consequences resulting from (chronic) lymphedema. Methods: All women with early stage breast cancer are included in this screening program. We use preoperative and sequential postoperative bilateral upper limb circumference measurements and patient perception to identify lymphedema. A difference of &gt; 2cm between post-operative and baseline circumference and patient perception of (refractory) swelling constitutes a diagnosis of lymphedema. Upon lymphedema diagnosis, patients are referred to a lymph therapist for initiation of conservative therapy in the form of complex decongestive physiotherapy. Therapy effect is evaluated after 1 month. In case of unsatisfactory symptom or limb circumference reduction, the patient is considered for surgical treatment. A plastic surgeon evaluates the possibility of microsurgical lymph vessel repair in the form of lymphatic-venous anastomoses or lymphatic-venous-lymphatic anastomoses. This minimal invasive surgery can improve lymph flow in the affected limb. If despite this, symptom improvement and patient satisfaction remains minimal, autologous lymph node transplantation is considered. Results: The aimed outcome parameters are 1) limb circumference reduction, 2) perceived symptom improvement: (refractory) swelling, 3) quality of life improvement, 4) limb range of motion improvement, 5) strength and sensory improvement, 6) restoration/improvement of lymph flow visualized by lymphoscintigraphy. Conclusions: A structured approach for a multidisciplinary treatment of breast cancer related lymphedema is proposed to reduce the negative functional, psychosocial and cosmetic consequences resulting from (chronic) lymphedema.