tbuckley/cabot-search huggingface dataset:
iMTD (individualized maximal tolerated dose) protocol: A clinical strategy to address interindividual heterogeneity to antiangiogenic therapy
Authors: V. W. Li, W. W. Li
Journal: Journal of Clinical Oncology (2006)

13130 Background: The determination of optimal biological dose is critical to the successful development of antiangiogenic agents. Recent studies suggest that genetic heterogeneity of angiogenesis and interindividual variations in efficacy response to angiogenic inhibitors and their side effects exist. Imiquimod, approved to treat skin cancer, is a topical immune response modifier with antiangiogenic effects mediated by interferons and interleukins. Although efficacy is associated with increased dosing frequency, adverse events are dose limiting. In clinical studies, imiquimod had a 75% efficacy rate in treating basal cell carcinoma (BCC) when dosed 5×/week × 12 weeks, but moderate to severe local inflammation was seen in up to 50%. Methods: The dose frequency that results in gross clinical skin inflammation is one marker of individual heterogeneity. To optimize efficacy while minimizing side effects, we devised a treatment algorithm termed Individualized Maximal Tolerated Dose (iMTD) to determine the optimal treatment frequency per patient. Imiquimod was applied in an incremental titrating fashion to BCC neoplasms (N=52): 2×/wk × 2 wks escalating to 3×/wk × 2 wks, then M-F × 2 wks, then daily × 2 wks. Dose frequency was increased until the threshold of inflammation, then lowered to the last best-tolerated dose. Tumor response and the maximal required/tolerated dose frequency (MTD) for each patient was recorded. Results: The iMTD protocol resulted in 52/52 complete responses with 0/52 cases of undesired inflammation. In order to achieve these results, a significant interindividual variation in dose tolerance was observed: 62% (32/52) required/tolerated 3×/week dosing for complete clearance, 29% (15/52) daily treatment, and 8% (4/52) 5×/week treatment. Conclusions: Because interindividual heterogeneity to response is not addressed in most clinical trial protocols, a single dose frequency among study cohorts generates outcomes that includes both responders and non-responders. When therapy is titratable by dose scheduling, the iMTD strategy may optimize clinical results while minimizing toxicities, a goal of antiangiogenic therapy. No significant financial relationships to disclose.
P09.01 * NEUROLOGICAL COMPLICATIONS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION
Authors: G. Berzero, L. Diamanti, A. L. Di Stefano, L. M. Farina, S. Bastianello, L. Calafiore, M. Zecca, M. Ceroni, E. Marchioni, A. A. Colombo
Journal: Neuro-Oncology (2014)

INTRODUCTION: Allogeneic bone marrow transplantation (BMT) has now become a common procedure in the treatment of a variety of hematologic disorders. Neurological complications after BMT are a frequent event, including subtle relapses of hematologic malignancy and a number of pleomorphic conditions, ranging from CNS infections to cerebrovascular diseases, radiation-induced and toxic encephalopathies and acute/chronic graft versus host disease (GVHD). Diagnosis may be challenging due to the variety of disorders involved, and timeliness of treatment is crucial, as most of these complications may be life-threatening. We present our decennial experience in the field through a number of iconic cases, and propose an algorithm to guide the neurologist in the complex process of differential diagnosis. MATERIAL AND METHODS: Patients were recruited among our two institutions (Neuro-oncology/ General Neurology Unit, C. Mondino Institute, Pavia; Haematology and Transplantation Unit, Policlinico San Matteo, Pavia), and data collected retrospectively from clinical records referring to the period from January, 2010 to March, 2014. RESULTS: We selected eight patients with a history of bone marrow transplantation for different hematologic malignancies (acute lymphocytic or myeloid leukaemia and non-Hodgkin lymphomas). Neurological symptoms occurred between 1 month and 7 years after BMT, and were pleomorphic. In one patient the final diagnosis was of localization of the malignancy to the peripheral nervous system. Two patients had infectious complications: one acute limbic encephalitis by HHV-6, and one neuro-toxoplasmosis. Two other patients had autoimmune disorders of the CNS (one neuromyelitis optica and one chronic GvHD). One patient presented with PRES, and the final two with toxic encephalopathies induced respectively by radiotherapy and intrathecal chemotherapy. Complications occurred with a characteristic timing after engraftment, with PRES and limbic encephalitis being the earliest to occur and autoimmune disorders the latest. CONCLUSIONS: The timely and accurate diagnosis of neurological complications after BMT is a diagnostic challenge, that involves a multidisciplinary expert team. The definition of diagnostic algorithms could help to quicken the process of diagnosis, thus reducing the severe morbidity and mortality associated with these complications. We present our experience in the field and propose a joint prospective multicentric collection of data to address this unresolved issue.
Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: an outpatient multicenter trial.
Authors: N J Vogelzang, A Lipton, R A Figlin
Journal: Journal of Clinical Oncology (1993)

PURPOSE A prospective multicenter phase II trial was undertaken to define the activity of a low-dose subcutaneous regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN) in patients with metastatic renal cancer. PATIENTS AND METHODS Between December 1990 and October 1991, 42 patients with metastatic renal cancer who had received no prior immunotherapy were treated with IL-2 (4 x 10(6) U) days 1 through 4 and IFN (9 x 10(6) U) day 1 and 4 each week of a 4-week treatment course followed by a 2-week rest period. Maximum duration of therapy was 1 year. Concomitant therapy with acetaminophen, diphenhydramine, and indomethacin was recommended. Treatment was administered on an outpatient basis. RESULTS With a median follow-up duration of 18 months, responses occurred in five of 42 patients (12%; 95% confidence interval [Cl], 2% to 22%). One pathologic complete remission, one surgical complete remission, and three partial remissions occurred. Toxicity was modest, with a symptom complex of rash, fever, anorexia, fatigue, mild weight loss, lymphocytosis, and eosinophilia occurring in 85% to 90% of patients. Renal dysfunction (creatinine &gt; 2 mg/dL) occurred in 19% of patients, while three patients (7%) refused further IL-2 and IFN. No toxic deaths occurred. The median survival duration was 14.5 months. CONCLUSION This outpatient low-dose subcutaneous regimen induced mild toxicity, a modest response rate, and an excellent median survival duration in previously untreated patients. Phase III trials are now needed to compare IL-2 plus IFN with IL-2 alone or to various IL-2/IFN regimens. However, the major task is to identify unique new agents with activity in renal cancer.
First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction
Authors: Morie A. Gertz, Heather Landau, Raymond L. Comenzo, David Seldin, Brendan Weiss, Jeffrey Zonder, Giampaolo Merlini, Stefan Schönland, Jackie Walling, Gene G. Kinney, Martin Koller, Dale B. Schenk, Spencer D. Guthrie, Michaela Liedtke
Journal: Journal of Clinical Oncology (2016)

Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264).
Treatment of Diabetes Mellitus
Authors: J. D. N. Nabarro
Journal: BMJ (1959)

Less than 50% of patients with diabetes mellitus need insulin for the control of their condition.Evidence is accumulating to show that the remainder have no true deficiency of this hormone.It has long been recognized on clinical grounds that diabetics may be divided into two groups: on the one hand the thin patients who quickly become ketotic in the absence of insulin treatment, and on the other those who are or have been obese and, although they have hyperglycaemia, show no tendency to develop ketosis.It has been suggested that the former are insulin-
Physical Activity vs Health Education for Cognition in Sedentary Older Adults
Authors: Marc J. Poulin, Gail A. Eskes, Michael D. Hill
Journal: JAMA (2016)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models
Authors: P. J. Beltran, P. Mitchell, G. Moody, Y. Chung, E. Cajulis, B. Belmontes, R. Radinsky, F. Calzone
Journal: Journal of Clinical Oncology (2008)

4617 Background: Binding of IGF-1 or IGF-2 to the type I insulin-like growth factor receptor (IGF-1R) activates intracellular signals important in the growth and survival of pancreatic tumors. AMG 479 is a fully human monoclonal antibody against IGF-1R currently in phase II clinical trials. AMG 479 exerts its anti-tumor activity by blocking ligand binding and inducing receptor downregulation in vivo. Methods: IGF-1R and Insulin Receptor (IR) levels were determined using FACS analysis or Meso Scale Detection (MSD). Level of IGF-1R and AKT phosphorylation were measured using MSD. Animal experiments were performed by injecting 5 million MiaPaCa or BxPC-3 cells subcutaneously into female athymic nude mice. Treatment began when xenografts (n=10/group) were approximately 200 mm3 and continued for the length of the experiment. AMG 479 and gemcitabine were dosed 2x/week intraperitoneally. Erlotinib was dosed orally every day. Repeated measures ANOVA was used to compare the efficacy of the treatment groups. Results: The ratios of IGF-1R to IR were 60:1 and 1.5:1 in the BxPC-3 and MiaPaCa cell lines, respectively. In vitro, AMG 479 blocked IGF-1 induced IGF-1R and AKT activation in both cell lines. In vivo, AMG 479 blocked IGF-1 induced IGF-1R activation in both cell lines but could only block AKT activation in the BxPC-3 cell line. Dose- dependent tumor growth inhibition by AMG 479 was observed in both human pancreatic carcinoma xenograft models. Maximal inhibition (70%) was achieved with a 300 μg/dose, 2x/week schedule. Analysis of tumor xenografts following AMG 479 treatment revealed significant down- regulation of IGF-1R expression (>60%). Since the survival signals driven by IGF-1R have been shown to convey resistance to traditional therapies, we tested the ability of AMG 479 to enhance the efficacy of gemcitabine or erlotinib in vivo. Both gemcitabine and erlotinib were significantly more effective in combination with AMG 479. Furthermore, the triple combination of optimal doses of AMG 479, erlotinib and gemcitabine resulted in tumor stasis and regression. Conclusions: These results demonstrate that IGF-1R blockade by AMG 479 inhibits AKT signaling and enhances the in vivo anti-tumor effects of approved therapies for the treatment of pancreatic carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen
Deconstructing IκB kinase
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

On page 1677, Ruocco et al. show that the formation of bone-resorbing osteoclasts is crippled when the β subunit of the NF-κB–activating IκB kinase (IKK) complex is missing. The absence of IKKβ also protected mice against inflammatory-induced bone loss, a complication of inflammatory diseases such as rheumatoid arthritis (RA) that is caused by excessive activation of osteoclasts.

The osteoclast growth factor RANKL (receptor activator of NF-κB ligand) activates the transcription factor NF-κB, which promotes osteoclast development. NF-κB activation requires the upstream IKK complex (IKKα, β, γ), which releases NF-κB from its inhibitor protein. Although a recent report showed that the IKK complex is required for osteoclast development, the relative importance of the two catalytic subunits of IKK (α, β) in this process remained unclear.






Figure 

The β subunit of the IκB kinase complex is required for inflammation-induced bone loss (arrows).




Ruocco et al. now show that mice lacking IKKβ were unable to generate osteoclasts and developed severe osteopetrosis (increased bone formation), whereas those lacking IKKα activity had no apparent bone abnormalities. The IKKβ-deficient mice failed to transmit RANKL signals and had increased TNF-induced apoptosis in osteoclast precursors. Osteoclast formation was partially restored in mice that lacked both IKKβ and the type I TNF receptor.

IKKβ-deficient mice were also resistant to inflammatory bone loss and this resistance was dependent on TNF-derived signals. Thus the authors suggest that drugs designed to block IKKβ may prevent bone loss in patients. However, they caution that such drugs, if developed, should perhaps not be combined with anti-TNF therapy (commonly used to treat RA) as the combination may not be effective.
A psychoanalytic approach to a therapeutic impasse with an impulsive adolescent: permission to speak the unspeakable
Authors: A Hoffer, R Goettsche, F Linden
Journal: American Journal of Psychiatry (1980)

The authors describe an impasse in the therapy of an impulsive, intermittently psychotic adolescent boy and demonstrate the usefulness of understanding the impulsive behavior according to the classical psychoanalytic definition of "acting out." Rather than being viewed as a random breaking through of impulses, this impulsive behavior can best be understood and clarified in the course of intensive psychotherapy as classical acting out under the influence of the therapy and the transference. With impulsive patients of this type they have observed a strong tendency to abandon this basic psychoanalytic formulation and the use of the verbal interventions that follow from them. Such patients often need encouragement to remember and express their painful feelings in words instead of repeating the entire emotional experience in action. The authors also describe the resistances within the treatment team that interfered with the development and utilization of this basic psychoanalytic formulation.
Extra Chromosome 7 in Cells Cultured From Cervical Carcinoma2
Authors: C. C. Lin, P. B. Dent, E. J. Ward, P. B. McCulioch
Journal: JNCI Journal of the National Cancer Institute (1973)

Chromosome analysis with quinacrine fluorescence and modified Giemsa banding tech. niques were completed on 3 cultured cervical carcinomas. Whereas 2 cultures had apparently normal karyotypes, 75% of the cells in the third possessed an extra chromosome #7.
Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis
Authors: Kosei Nakajima, Dhong Hyo Kho, Takashi Yanagawa, Yosuke Harazono, Victor Hogan, Wei Chen, Rouba Ali-Fehmi, Rohit Mehra, Avraham Raz
Journal: Cancer Research (2016)

Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158-175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.
Phase I clinical and pharmacokinetic study of oral etoposide phosphate.
Authors: C Sessa, M Zucchetti, T Cerny, O Pagani, F Cavalli, M De Fusco, J De Jong, D Gentili, C McDaniel, C Prins
Journal: Journal of Clinical Oncology (1995)

To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate.In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days.Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%.The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.
Functional Tuning of Intrinsic Endothelial Ca <sup>2+</sup> Dynamics in Swine Coronary Arteries
Authors: Michael Francis, Joshua R. Waldrup, Xun Qian, Viktoriya Solodushko, John Meriwether, Mark S. Taylor
Journal: Circulation Research (2016)

Recent data from mesenteric and cerebral beds have revealed spatially restricted Ca(2+) transients occurring along the vascular intima that control effector recruitment and vasodilation. Although Ca(2+) is pivotal for coronary artery endothelial function, spatial and temporal regulation of functional Ca(2+) signals in the coronary endothelium is poorly understood.
Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-bevacizumab (CP-B) in advanced (stage III-IV) or recurrent endometrial cancer: The MITO END-2 trial.
Authors: Domenica Lorusso, Gabriella Ferrandina, Nicoletta Colombo, Sandro Pignata, Vanda Salutari, Giuseppina Maltese, Carmela Pisano, Maria Lapresa, Antonella Savarese, Pierosandro Tagliaferri, Roberto Sorio, Saverio Cinieri, Enrico Breda, Roberto Sabbatini, Stefano Lepori, Carmine Conte, Sabrina Chiara Cecere, Francesco Raspagliesi, Giovanni Scambia
Journal: Journal of Clinical Oncology (2015)

5502 Background: The prognosis of advanced or recurrent endometrial cancer (AEC) is dismal. The antiangiogenic drug Bevacizumab (B) has reported activity in AEC with response rates ranging from 13 to 22% and 6-month disease control up to 40%. The This randomized phase II trial was designed to compare CP vs CP-B in the treatment of AEC in terms of progression free survival (PFS).(EUDRACT Number 003301-16) Methods: Eligible pts had advanced (stage III-IV) or recurrent (progression > 6 months after completion of previous platinum chemotherapy) endometrial cancer, and ≤ 1 prior CT lines. All patients had measurable or evaluable disease and both type 1 and 2 endometrial cancers were eligible. Pts were randomized 1:1 to receive CP standard dose for 6-8 cycles with or without Bevacizumab 15 mg/kg in combination and maintenance until progression or unacceptable toxicity. Results: From January 2012 to October 2014, 108 pts were randomized (CP: 54 pts; CPB 54 pts). Overall, 2 out of 3 of pts presented with recurrent disease; almost 60% of cases had endometrioid histology, and 55% were G3. PS was < or 1 in 83% and 15% of case, respectively. Vascular comorbidity was documented in 57% of pts. There was no difference in clinico-pathological features according to arm allocation. As on March 2015, median duration of follow up was 13 months; outcome data are summarized in the table. As far as toxicity, Grade 3 cardiac toxicity was documented in 4 cases in arm B versus no cases in arm A. 13 serious adverse events (SAE) were documented in 8 patients: 3 DVTs, 3 retinal artery thrombosis, 2 intracardiac thrombus, 1 silent myocardial infarction, and 1 cerebrovascular accident. Conclusions: The addition of B to CP significantly increased PFS in recurrent endometrial cancer. Cardiovascular toxicity should be carefully evaluated in a population with pre-existing cardiovascular risk factors. Clinical trial information: EUDRACT Number 003301-16. CP (N = 48) CP-B (N = 48) PFS (IRC*) Events, n (%) 31 (35.4) 27 (43.8) HR (95% CI) 0.57 (0.34, 0.96) Log-rank p = 0.036 Median, mo (95% CI) 8.7 (6.3-11.2) 13.0 (9.2-16.8) ORR (IRC), % (54.3)§ (39.9-68.7) (72.7)° (59.5-85.9) §Calculated on 46 cases; ° calculated on 44 cases.