tbuckley/cabot-search huggingface dataset:
Zoledronic acid impairs geranyl-geranylation but not farnesylation of small GTP-ases in prostatic cell lines
Authors: Sophie Séronie-Vivien, Marine Goffinet, Anne Pradines, Isabelle Lajoie-Mazenc, Jean-Charles Faye
Journal: Cancer Research (2004)

4756  Nitrogen-containing bisphosphonates (N-BPs) are potent inhibitors of osteoclast-mediated bone resorption. They have demonstrated clinical utility in the treatment of bone metastases particularly in breast and prostate cancers with no major side-effects. Moreover, extensive in vitro and in vivo pre-clinical evidence shows that N-BPs have an anti-tumor activity and can reduce skeletal tumor burden. In osteoclasts as well as in many tumor cell lines, pharmacodynamic effects of N-BPs have been proposed to be predominantly mediated by interference with the mevalonate pathway. So, we intended to characterize the effects of a late-generation N-BP, zoledronic acid (ZOL), on cell proliferation and protein isoprenylation in prostatic cell lines (LnCAP, PC-3, PNT1-A). ZOL induced a dose-dependent inhibition of proliferation of all three cell lines. The inhibition of proliferation induced by 20 μM ZOL was reversed in the three cell lines by geranyl-geraniol but not by farnesol, squalene or mevalonate. These results argue for an inhibition of the synthesis of geranyl-geranyl-pyrophosphate (GGPP) by ZOL in prostatic cell lines with no impact on farnesyl-pyrophosphate (FPP) production. After a 24-hour treatment of PC-3 cells with ZOL 20 μM, geranyl-geranylation of the small GTPase Rap1A was abolished whereas farnesylation of both farnesylated proteins HDJ-2 and H-Ras was conserved. Unlike inhibition of geranyl-geranylation by a geranyl-geranyl transferase inhibitor (GGTI), inhibition of Rap1A geranyl-geranylation by ZOL was reversed by GGOH. To investigate if inhibition of cell geranyl-geranylation by ZOL may impair the biological activity of small G proteins, we studied the LPA-induced formation of stress fibers, which is mediated by RhoA, an exclusively geranyl-geranylated small GTPase. Indeed, similar to treatment with GGTI or Y27632, a specific inhibitor of Rho-associated kinase, a 48-hour treatment of PNT1-A cells with 20 μM ZOL prevented the formation of stress fibers induced by 20 μM LPA. So, in prostatic cell lines, ZOL inhibits proliferation by impairing GGPP production and impedes both geranyl-geranylation and biological activity of small GTPases with no impact on farnesylation.
States Worse Than Death—Reply
Authors: Emily B. Rubin
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Combination therapy of a novel oral fluorouracil derivative S-1 with low-dose cisplatin for unresectable and recurrent gastric cancer: JFMC27–9902 phase I trial
Authors: B. Nakata, A. Tsuji, Y. Mitachi, S. Yamamitsu, K. Hirata, T. Shirasaka, S. Saji, K. Inokuchi, K. Hirakawa
Journal: Journal of Clinical Oncology (2004)

4128 Background: The Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) conducted a phase I trial to examine the tolerability, clinical efficacy, and serum concentration of 5-FU and cisplatin by administering a combination therapy of S-1 with low-dose cisplatin for patients with unresectable or recurrent gastric cancer. Methods: S-1 was given orally at 80–120 mg/body per day, depending on body surface area. Low-dose cisplatin was administered intravenously on days 1–5, 8–12, 15–19, and 22–26 of each course. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. The dose escalation of cisplatin began with an initial dose of 1 mg/m2 per day as level 1, and was stepped up to 2, 3, 4, and 6 mg/m2 per day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses. Results: Twenty-four patients were enrolled. At level 5, consisting of five evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. Therefore, the maximum tolerated dose (MTD) of cisplatin was estimated to be 6 mg/m2 per day. The recommended dose of cisplatin of 4 mg/m2 per day was decided, because the dosage was one level under the MTD. There was no treatment-related death. All three patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The high serum concentrations of 5-FU were obtained after 4 h of the standard dose of S-1 (mean ± SD, 141.7 ± 56.1 ng/ml). The serum concentrations on day 26 of cisplatin at level 4 and 5 were 918 ± 92 ng/ml and 1306 ± 261 ng/ml, respectively. Conclusions: S-1 with low-dose cisplatin regimen may be one of the treatments showing a high efficacy with acceptable toxicity in cases of unresectable and recurrent gastric cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Taiho Pharmaceutical Co., Ltd.
Subcutaneous (SQ) amifostine (A) during radiation or chemoradiation for the treatment of head and neck cancers
Authors: R. Wang, R. Kagan, M. Tome
Journal: Journal of Clinical Oncology (2004)

8154 BACKGROUND: We have previously reported that SQ A. was safe and effective in 24 patients (pts) receiving chemoradiation (CR) for SCCA of the H & N (SCCHN). Our expanded experience includes 19 more pts with SCCHN. Our initial CR report showed a 46% grade 3 mucositis and a 21% treatment break. We expected to observe decrease in morbidity with A. METHODS: From May 2001 to December 2003, a total of 45 pts (42 males and 3 female, median age 55) were given SQ A. as a flat dose of 500 mg dissolved in 2.5 ml of saline solution, divided into 2 insulin syringes and injected into the deltoids, abdomen or thighs 30 minutes prior to daily radiotherapy (RT). Recently, we switched to only 1 SQ injection. CR was used in 17 pts, adjuvant RT in 26 pts with SCCHN and 1 with NHL, 1 pt had definitive RT. Our protocol involves pre-medication with Ondansetron 2 hours prior to SQ A. Fexofenadine 60 mg bid was given prophylactically during the entire course of A. treatment to prevent allergic reactions in the last 29 pts. Pts were instructed on oral hydration prior to treatment. Multiple blood pressure measurements were taken before and after A and RT. The median follow-up was 12 months. RESULTS: Overall, SQ A was well-tolerated. Nausea and hypotension were rarely observed. Cutaneous reactions were seen in 9 pts, 5 local and 4 systemic. The 4 pts with systemic reactions also developed fever and discontinued A. They were treated with antihistamines and recovered without sequelae. Localized skin reactions resolved in 5 pts after being given antihistamines and rotating the injection sites. The following table shows the outcome of pts treated with SQ A. CONCLUSION: This study confirms our prior experience that SQ A is safe and effective in the treatment of H & N malignancies treated with RT or CR. The treatment related morbidities were decreased with the use of A. compared to our historical controls. SQ A. is well- tolerated with the proper pre-medication regimen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune Oncology MedImmune Oncology
Predictors of recurrence in postmastectomy patients with one to three positive lymph nodes.
Authors: Tracy-Ann Moo, Robert McMillan, Michele Lee, Michelle Stempel, Sujata Patil, Alice Y. Ho, Mahmoud El-Tamer
Journal: Journal of Clinical Oncology (2012)

1118 Background: Although the role of post mastectomy radiation therapy (PMRT) is well established in women with ≥ 4 positive axillary lymph nodes (ALN), its indications in patients with 1-3 positive ALN is controversial. A recent large meta-analysis suggested a survival benefit in patients with 1-3 positive ALN who received PMRT. However, because recurrence rates in this group are low, identifying a subgroup of patients at higher risk for locoregional recurrence (LRR) could aid decision-making about PMRT. Methods: From an institutional database, 1,333 breast cancer patients who underwent mastectomy between 1996 and 2006 and had 1-3 positive ALN were identified. Among these, T3/T4 tumors and those who received PMRT were excluded. 926 patients were analyzed. The Kaplan-Meier method and Cox regression was used to explore clinicopathologic features that predicted LRR, distant metastases (DM), and recurrence-free survival (RFR). Results: Median follow-up was 7yrs. LRR occurred in 49 patients and DM in 126 patients. LRR and/or DM occurred in 146. On univariate analysis, factors significantly affecting LRR recurrence were increasing tumor size (p=0.04), age &lt;50 (p=0.003), histologic grade (p=0.03), nuclear grade (p=0.008), lymphovascular invasion (LVI) (p&lt;0.0001), and macroscopic ALN metastases (p=0.02). On multivariate analysis, age &lt;50 (p=0.0012) and the presence of LVI (p&lt;0.0001) predicted a higher LRR; increasing tumor size (p=0.0005), age &lt;50 (p=0.04), higher histologic grade (p=0.01), number of positive ALN (p=0.04), LVI (p=0.02), macroscopic ALN metastases (p=0.02), and no chemotherapy (p=0.02) predicted a significantly lower RFR. Conclusions: Pts with T1-2 tumors and 1-3 positive ALN are at low risk of isolated LRR; however, patients &lt;50 and with LVI may have additional risk that warrants consideration of PMRT.
Vascular Imaging With 18 F-Fluorodeoxyglucose Positron Emission Tomography Is Influenced by Hypoxia
Authors: Francis R. Joshi, Roido Manavaki, Tim D. Fryer, Nichola L. Figg, Judith C. Sluimer, Franklin I. Aigbirhio, Anthony P. Davenport, Peter J. Kirkpatrick, Elizabeth A. Warburton, James H.F. Rudd
Journal: Journal of the American College of Cardiology (2017)

This study was funded by a programme grant (RG/10/007/28300) from the British Heart Foundation (BHF). Dr. Joshi was supported by a BHF Clinical Research Training Fellowship (FS/12/29/29463), a British Atherosclerosis Society Binks Trust Travel Award, and a Raymond and Beverly Sackler PhD Studentship. Dr. Manavaki is funded by the NIHR Cambridge Biomedical Research Centre. Dr. Rudd is partially supported by the NIHR Cambridge Biomedical Research Centre, the BHF, The Wellcome Trust, and the EPSRC Cambridge Centre for Mathematical Imaging in Healthcare.
Melanoma risk in women with previous breast cancer
Authors: R. Weitzen, G. Harari, A. Achiron, R. Catane, M. Mandel
Journal: Journal of Clinical Oncology (2004)

7553 Background: Four cases of double primaries (melanoma and breast cancer), which were treated in our institute, raised our attention to the risk of both tumors in women. Our objective was to determine the risk for development of melanoma or breast cancer as second primary tumor in women with either one of them. Methods: We considered 51,000 breast cancer women patients and 6248 malignant melanoma women registered by the Israel Cancer Registries (6,000,000 inhabitants) and followed up from 1960 to 2000. Results: Overall, 276 malignant melanoma women were observed in the subpopulation of breast cancer versus 157 expected [standardized incidence ratio (SIR): 1.76; 95% confidence interval (CI) 1.50–2.05]. The incidence for breast cancer (276) in the sub population of melanoma females was as expected (267) with SIR 1.03 (95% CI 0.91 -1.17). Interestingly most women had been diagnosed with the second primary within the 12 months after diagnosing the first primary. The SIR for melanoma in the sub population of females with breast cancer (43 observed versus 19 expected) during 1 year after diagnosis of breast cancer was 2.28 (95% CI 1.39 –3.50). The SIR for breast cancer (44 observed versus 20 expected) in subpopulation of females up to one year after diagnosing of melanoma was 2.21 (95% CI 1.36 –3.35). Conclusions: We report excess risk of melanoma in women with breast cancer. Most of the cuetaneous tumors were discovered during the first year after diagnosis of the breast cancer. Although there is no excess risk for breast cancer in melanoma patients we observed that during the first year after diagnosing the melanoma there were double observed cases than expected. These findings suggest the possibility that more intense follow up lead to diagnosis of both second primary tumors. Genetic susceptibility might be responsible for the excess risk. Recommendation: Women with either breast cancer or melanoma and their clinicians should be aware of the reciprocal higher risk for both tumors. Skin and breast examination should be performed after diagnosing one of the primaries. No significant financial relationships to disclose.
Influenza-associated Aspergillosis in Critically Ill Patients
Authors: Frank L. van de Veerdonk, Eva Kolwijck, Pieter P. A. Lestrade, Caspar J. Hodiamont, Bart J. A. Rijnders, Judith van Paassen, Pieter-Jan Haas, Claudy Oliveira dos Santos, Greetje A. Kampinga, Dennis C. J. J. Bergmans, Karin van Dijk, Anton F. J. de Haan, Jaap van Dissel, Hans G. van der Hoeven, Paul E. Verweij, Janette C. Rahamat-Langendoen, Bart-Jan Kullberg, Mihai G. Netea, Roger J. Brüggeman, Astrid W. Hoedemaekers, Willem J. G. Melchers, Wieke Freudenburg, Nienke Roescher, W. Joost Wiersinga, Charlotte H. S. B. van den Berg, Alieke G. Vonk, Carla van Tienen, Ben van der Hoven, Martha T. van der Beek, Lennie P.G. Derde, Coretta van Leer, Heleen Aardema, Astrid Oude Lashof, C. Wim Ang
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Lymphatic mapping and sentinel lymphadenectomy (LM/SL) in thin (pT1≤1mm) and thick (pT4 &gt; 4mm) primary cutaneous melanoma (CM) patients (pts)
Authors: P. Rutkowski, Z. I. Nowecki, A. Nasierowska-Guttmejer, Z. Zurawski, W. Ruka
Journal: Journal of Clinical Oncology (2004)

7539 Background: The benefit of LM/SL in thin (≤1 mm pT1) and thick (>4 mm - pT4) CM pts is controversial. We analyzed the results of LM/SL in these pts at one institution. Methods: We analyzed a group of consecutive pts with CM thickness ≤ 1 mm (A, 176 pts, range: 0.5mm to 1mm) and > 4mm (B, 223 pts, range: 4.1 - 58.0mm) selected from database of 832 pts who underwent LM/SL using the technetium radiocolloid combined with blue dye technique from 06/1996 to 04/2003. The median follow-up time was 30 months. Results: The sentinel node(s) (SLN) were successfully identified in 98.3% of pts in A and in 96.9% in B. SLN metastases in A were found in significantly (p<0.0001) lower number of 14 pts (7.9%, the thickness for positive SLN ranged from 0.75 mm to 1.0 mm and only 2 pts had evidence of ulceration) as compared with 79 pts (35.4%) in B (thickness for positive SLN ranged from 4.2 mm to 35.0 mm and 69 pts with ulceration). The false-negative LM/SL rate was 1.9% (3/162) in A and 6.2% (9/144) in B (p=0.048). All node-positive pts underwent radical lymph node dissection. Lymph nodes other than SLNs were found to contain metastases in 21.4% (3/14) in group A and in 45.6% (36/79) in group B (p=0.09). The estimated 5-year overall survival (OS) rate was 94% for A and 58% for B (p<0.0001). In A we did not detect statistically significant differences for OS between SLN-positive and negative pts (5-year OS rate 95% and 93%, respectively), however SLN positive pts had significantly lower disease free survival - DFS (5-year ratio: 94%% and 85%, respectively, p=0.01). In B 5-year OS rate was 75% for SLN negative pts and 31% for SLN positive pts (p=0.00001) and 5-year DFS ratio was 63% and 33% (p=0.00002). SLN status was an independent prognostic factor for both OS and DFS by univariate and multivariate analyses in B, but not in A. Conclusions: LM/SL should be offered to all pts with thick (pT4 > 4 mm) CM, as well as to pts with pT1 CM thicker than 0.75 mm. In thick CM the regional lymph node status is the strongest predictor for survival. LM/SL in thick CM is connected with a higher false negative results rate when compare with thin CM, what can be explained by wider excision of advanced primaries. No significant financial relationships to disclose.
Pulmonary Hypertension Prevalence and Prognosis in a Cohort of Patients with Hereditary Hemorrhagic Telangiectasia Undergoing Embolization of Pulmonary Arteriovenous Malformations
Authors: Mwelwa Chizinga, Anastasiia A. Rudkovskaia, Katharine Henderson, Jeffrey Pollak, Guadalupe Garcia-Tsao, Lawrence H. Young, Wassim H. Fares
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
A phase I study of BMS-936558 plus sunitinib or pazopanib in patients with metastatic renal cell carcinoma.
Authors: Hans J. Hammers, Brian I. Rini, Gary R. Hudes, Marc S. Ernstoff, Christian K. Kollmannsberger, Yun Shen, Ian Waxman, Arindam Dhar
Journal: Journal of Clinical Oncology (2012)

TPS2614 Background: Standard treatments for metastatic renal cell carcinoma (mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib, pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus, everolimus). However, most patients (pts) develop resistance and complete responses are rare. Upregulation of programmed death-1 (PD-1) in tumor infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for mRCC. In preliminary results of a phase I trial, the anti-PD-1 monoclonal antibody BMS-936558 had antitumor activity in pts with advanced tumors, including objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a phase I study planned to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of BMS-936558, when combined with sunitinib or pazopanib in pts with mRCC. Methods: This open-label study will have two parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558 plus pazopanib) conducted in two parts (dose escalation and dose expansion). Pts must have received ≥1 prior systemic therapy to be eligible for dose escalation. Only treatment-naïve pts will be eligible for dose expansion. Up to 36 pts (18 per arm) will be treated in the dose-escalation phase. After determining the MTD of BMS-936558, treatment-naïve pts will be enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed on Days 1 and 22 and sunitinib or pazopanib given according to product label. Adverse events will be graded according to NCI CTCAE v4.0. Disease will be assessed every 6 weeks for the first four assessments and then every 12 weeks until disease progression. Pts will be treated until unacceptable toxicity, disease progression, or withdrawal of consent. The safety profile in pts treated at the MTD will be used to determine the recommended phase II study dose of BMS-936558 in each combination arm. Secondary objectives will include OR rate and duration of response based on RECIST 1.1. Exploratory analyses will investigate predictive biomarkers of BMS-936558.
Compliance to chemotherapy with oxaliplatin and 5 fluorouracil in patients with advanced rectal cancer who have received prior high-dose pelvic radiotherapy
Authors: A. Makris, R. Glynne-Jones, D. Sebag-Montefiore, L. Samuel, S. Myint, M. Harrison, A. Martin, J. Dixon
Journal: Journal of Clinical Oncology (2004)

3747 Background: Pelvic radiotherapy (RT) may compromise the compliance and effectiveness of future chemotherapy (CT). Patients and Methods: 20 patients (15 male, 5 female), mean age 69 yrs (range 51–75) were studied in a prospective, multicenter, phase II study. All patients had recurrent or metastatic diease. All had received previous pelvic RT: 45Gy 25 fx (15), 45 Gy 30 fx (3), 45 Gy 20 fx (2) and 25 Gy 5 fx (1) at a 16 months prior to this study. Most patients had received concurrent chemoradiation (CRT). Patients were treated with a schedule consisting of oxaliplatin 85 mg/m2 on day 1 and 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv 22hour infusion with folinic acid on day 1 and 2. A maximum of eight cycles of CT were administered every two weeks. Results: A median number of 7 cycles of CT was given (range 3–8), with 132 cycles being given in total. There were 8 episodes of grade III neutropaenia (1 with sepsis). There were 4 episodes of grade III/IV diarrhoea, two of which required hospitalisation, but all resolved. In 18 evaluable patients patients the overall response rate was 33% (3 CR; 3 PR), with 2 patients having SD. Conclusion: This study shows that the combination of oxaliplatin, 5FU and folinic acid after high-dose pelvic RT is well tolerated and has comparable efficacy to that seen in other metastatic studies and a dose intensity equal to that achieved in adjuvant studies. Based on the results of this study, adjuvant oxaliplatin is being delivered in a randomised phase III study (CHRONICLE) following CRT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Sanofi