Few epidemiologic studies describe longitudinal liver chemistry (LC) elevations in cancer patients. A population-based retrospective cohort was identified from 31 Phase 2-3 oncology trials (excluding targeted therapies) conducted from 1985-2005 to evaluate background rates of LC elevations in patients (n=3998) with or without liver metastases. Patients with baseline liver metastases (29% of patients) presented with a 3% prevalence of alanine transaminase (ALT) ≥3x upper limits normal (ULN) and 0.2% prevalence of bilirubin ≥3xULN. During follow-up, the incidence (per 1000 person-months) of new onset ALT elevations ≥3xULN was 6.1 (95% CI: 4.5, 8.0) and 2.2 (95% CI: 0.9, 4.5) in patients without and with liver metastases, respectively. No new incident cases of ALT and bilirubin elevations suggestive of severe liver injury occurred among those with liver metastases; a single case occurred among those without metastasis. Regardless of the presence of liver metastases, LC elevations were rare in cancer patients during oncology trials, which may be due to enrolment criteria. Our study validates uniform thresholds for detection of LC elevations in oncology studies and serves as an empirical referent point for comparing liver enzyme abnormalities in oncology trials of novel targeted therapies. These data support uniform LC stopping criteria in oncology trials.
Copyright © 2016. Published by Elsevier Inc.

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On March 31, 2016 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a clinical stage biotechnology company focused on developing targeted therapies for cancer and diabetes using its live-cell encapsulation technology, Cell-in-a-Box, reported the final design of its clinical trial for patients with advanced pancreatic cancer (Press release, PharmaCyte Biotech, MAR 31, 2016, View Source [SID:1234510778]). The clinical trial design was developed with Translational Drug Development (TD2), America’s premier oncology Contract Research Organization, as well as with renowned pancreatic cancer specialists consulting with PharmaCyte.

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PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, stated, "The trial is designed to determine if PharmaCyte’s pancreatic cancer treatment (the combination of micro-capsules that contain genetically modified human cells which convert the cancer prodrug ifosfamide into its "cancer-killing" form at one-third the normal dose) can satisfy a clear unmet medical need that exists for patients with locally advanced, inoperable pancreatic cancer who no longer respond to the current standard of care. Most of these patients are initially treated with the combination of nab-paclitaxel (Abraxane) plus gemcitabine or the four-drug combination known as FOLFIRINOX. When these patients’ tumors no longer respond to treatment with these regimens, the next standard of care offers little to no benefit. It is then that these patients are often treated with the combination of the anticancer drug capecitabine plus radiation therapy. However, this combination is only marginally effective in stopping the progression of the disease. In PharmaCyte’s clinical trial, our pancreatic cancer therapy will be compared "head to head" with the capecitabine/radiation combination to demonstrate that it is clearly superior in treating these patients while maintaining a superior quality of life during the therapy."

Major factors in the overall trial design are:

The clinical trial will be international (United States, Europe and possibly Australia), multi-site, open-label and randomized.

Study sites under consideration in the United States include the Mayo Clinic in Scottsdale, Arizona, the Beth Israel Deaconess Cancer Center and the Dana-Farber Cancer Institute both in Boston, Massachusetts, the Baylor Cancer Center in Dallas, Texas, the City of Hope Cancer Center in Los Angeles, California, and sites in Germany and Spain.

The randomization ratio of patients between the two study groups will be 1:1 (an equal number of patients will be randomly assigned to the capecitabine + radiation group and the PharmaCyte pancreatic cancer therapy group).

As many as 84 patients will be required to complete the study, although fewer may be required based upon the data developed during the trial.

Only patients who have locally advanced, non-metastatic, inoperable cancers and whose tumors no longer respond after 4-6 months of treatment with either the nab-paclitaxel (Abraxane) + gemcitabine or FOLFIRINOX regimens will be eligible for the study.

Unlike the earlier clinical trials using PharmaCyte’s pancreatic cancer therapy where patients received only two doses of ifosfamide, multiple cycles of ifosfamide will be given to those being treated with PharmaCyte’s pancreatic cancer therapy. This will continue until the patients’ tumors no longer respond to PharmaCyte’s therapy or until treatment-related toxicity accumulates to unacceptable levels.
Mr. Waggoner concluded, "We feel that the major factors that needed to be considered for the development of a complete clinical trial protocol have now been addressed. Of course, as we continue to move toward our clinical trial, slight changes that benefit the overall trial design could certainly be addressed and lead to further refinement of the trial. Special appreciation for reaching this point must be given to the renowned pancreatic cancer experts who have played such a major role in the trial design. With these developments, we are yet another step closer to the commencement of our clinical trial which we believe will satisfy the clear unmet medical need experienced by patients with locally advanced, but inoperable, pancreatic cancer who no longer respond to the gold standard of care."

The objective of this study was to examine the source of advanced cancer patients’ information about their prognosis and determine whether this source of information could explain racial disparities in the accuracy of patients’ life expectancy estimates (LEEs).
Coping With Cancer was a prospective, longitudinal, multisite study of terminally ill cancer patients followed until death. In structured interviews, patients reported their LEEs and the sources of these estimates (ie, medical providers, personal beliefs, religious beliefs, and other). The accuracy of LEEs was calculated through a comparison of patients’ self-reported LEEs with their actual survival.
The sample for this analysis included 229 patients: 31 black patients and 198 white patients. Only 39.30% of the patients estimated their life expectancy within 12 months of their actual survival. Black patients were more likely to have an inaccurate LEE than white patients. A minority of the sample (18.3%) reported that a medical provider was the source of their LEEs; none of the black patients (0%) based their LEEs on a medical provider. Black race remained a significant predictor of an inaccurate LEE, even after the analysis had been controlled for sociodemographic characteristics and the source of LEEs.
The majority of advanced cancer patients have an inaccurate understanding of their life expectancy. Black patients with advanced cancer are more likely to have an inaccurate LEE than white patients. Medical providers are not the source of information for LEEs for most advanced cancer patients and especially for black patients. The source of LEEs does not explain racial differences in LEE accuracy. Additional research into the mechanisms underlying racial differences in prognostic understanding is needed. Cancer 2016;000:000-000. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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The present global, open-label, single-arm, multicenter, phase IIb study was designed to determine the efficacy and tolerability of oral vorinostat combined with standard doses of bortezomib in patients with multiple myeloma considered refractory to novel myeloma agents.
Eligible patients were age ≥ 18 years, had received ≥ 2 previous regimens, had disease refractory to ≥ 1 previous bortezomib-containing regimen, and had received ≥ 1 dose of an immunomodulatory drug (thalidomide or lenalidomide)-based regimen. The patients received 21-day cycles of bortezomib (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11) plus oral vorinostat (400 mg/d on days 1-14). Oral dexamethasone, 20 mg, on the day of and the day after each dose of bortezomib could be added for patients with progressive disease after 2 cycles or no change after 4 cycles. The primary endpoint was the objective response rate.
The objective response rate was 11.3% (95% confidence interval, 6.6%-17.7%), and the median duration of response was 211 days (range, 64-550 days). The median overall survival duration was 11.2 months (95% confidence interval, 8.5-14.4 months), with a 2-year survival rate of 32%. The frequently reported adverse events were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%); the overall safety profile was consistent with that of bortezomib and vorinostat.
The combination of vorinostat and bortezomib is active in patients with multiple myeloma refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population (ClinicalTrials.gov identifier, NCT00773838).
Copyright © 2016 Elsevier Inc. All rights reserved.

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Inflammation is a response of body tissues to injury and infection. Compounds that can inhibit inflammation have been shown to have potential therapeutic clinical application. Gambogenic acid (GEA) has potent antitumor and anti-inflammatory activities. Herein, the molecular mechanisms of GEA’s anti-inflammatory effect were investigated in lipopolysaccharide (LPS)-stimulated macrophage cells. The results showed that pretreatment with GEA could markedly inhibit interleukin (IL)-1α, IL-1β, tumor necrosis factor-α, IFN-β, IL-12b, and IL-23a production in a dose-dependent manner in LPS-induced model. Furthermore, this drug significantly reduced the release of nitric oxide (NO), and impaired the protein level of inducible NO synthase and the cyclooxygenase 2. The finding also showed that the effect of GEA may be related to the suppression of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway. These results indicate that GEA could suppress LPS-simulated inflammatory response partially by attenuating NO synthesis and NF-κB and MAPK activation, suggesting that it may become a potent therapeutic agent for the treatment of inflammatory diseases.
© The Author 2016. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

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