Acute encephalopathy with combination dabrafenib/trametinib therapy.

Biomarkers have improved the clinical application of numerous targeted agents used to treat solid tumors. In melanoma, the finding that approximately 60% of tumor cells harbor specific Val600 mutations of BRAF has increased the likelihood of response to certain agents aimed at inhibiting the mutant kinase. While dabrafenib is an effective anti-tumor agent with acceptable tolerability in patients with BRAF-mutated melanoma, we report the development (and outcome) of a previously unpublished acute toxic reaction observed in a patient receiving the drug.

Efficacy of solubilized vemurafenib administered via nasogastric tube.

Until only a few years ago, there was only one truly effective therapy for patients with metastatic melanoma. While long-term remission could be achieved in some patients, toxicities associated with high-dose IL-2 were significant. New insight related to molecular pathways of tumor cells indicated that an activating mutation of BRAF can be found in approximately 50-60% of all patients with melanoma. Proof-of-concept demonstrated in clinical trials of a drug targeting mutant BRAF led to the approval of vemurafenib by the US FDA in August 2011. Supplied in an oral dosage form, we provide an alternative method of administering vemurafenib in a patient unable to take anything by mouth.

Identification of a novel marker associated with risk for delayed chemotherapy-induced vomiting.

PURPOSE: Besides chemotherapy drugs, a number of patient-related factors (i.e., gender, age, history of alcohol consumption, and/or motion sickness) may be used to calculate the risk for chemotherapy-induced vomiting. We evaluated data with the intent of identifying a unique variable associated with delayed vomiting in patients receiving moderately emetogenic chemotherapy (MEC). METHODS: From an ongoing research study, the serotonin metabolite, 5-hydroxyindole acetic acid (5-HIAA), creatinine, and substance P were measured over a 72-h period in 25 patients receiving MEC. All patients were treated with a 5-hydroxytryptamine-3 receptor antagonist plus dexamethasone according to published guidelines; none received aprepitant prophylactically. Urine 5-HIAA/creatinine and serum substance P values were grouped according to the development (+) or absence (-) of delayed emesis. Baseline mean values associated with the two neurotransmitters were analyzed by analysis of variance. RESULTS: Eleven patients developed moderate to severe delayed vomiting; the other 14 were symptom-free. The pretreatment log (mean 5-HIAA/creatinine) was 1.22 and 1.81 in the (+) and (-) emesis groups, respectively, p = 0.0049; the pretreatment log (mean substance P) for the same respective groups was 5.33 and 4.09 pg/mL, p > 0.05. The log (mean ratio of substance P to 5-HIAA/creatinine) between-group difference in those with and without emesis was 4.53 and 2.52, respectively, p = 0.0002. The 5-HIAA/creatinine and ratio of substance P to 5-HIAA/creatinine data were also used to determine cutoff points which resulted in the optimal predictive accuracy. CONCLUSIONS: These preliminary findings suggest that an elevated pretreatment ratio of substance P to 5-HIAA/creatinine >70 is associated with the development of delayed vomiting induced by MEC.

Spoken and Unspoken Matters Regarding the Use of Opioids in Cancer.

Pain is among the most debilitating symptoms in patients with cancer. Except for their relatively frequent use during end-of-life care, opioids are often, though not routinely, prescribed during the course of the disease. Whereas the clinical phenomena of tolerance, dependence, and addiction are invariably recognized, the molecular mechanisms which effect these outcomes are not fully understood, even among health care professionals. Also uncertain is the possible unfavorable effect of these agents on cancer progression and survival, an association that may be related to the expression of opioid receptors in some tumors. An intriguing corollary of the latter finding is that cancer cells may also manifest equivalents of the three maladaptive phenomena. Accordingly, instead of re-addressing the societal and epidemiological impact of opioids, this paper has three alternative foci. The first, and most subordinate, focuses on the mu opioid receptor; the second, centers on the unresolved question regarding the potential adverse effect of opioids on tumor growth; the third, and most compelling, concentrates on the cellular apparatus and influences that modulate tolerance, dependence, and addiction in certain cancers exposed to opioids.

Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer.

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor's utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.

Capecitabine as Maintenance Therapy for High-Risk, Resected Colorectal Cancer.

INTRODUCTION: In 2020, colorectal cancer will be the fourth most frequently diagnosed malignant neoplasm and the second leading cause of site-specific, cancer-related deaths in the USA. Notably, 80% of the new cases are, by staging criteria, potentially curable even those with completely resected stage 4 disease. If slightly more than half the losses can be attributed to metastatic disease at presentation, then the remaining portion of deaths may be linked to disease relapse after surgery and, if applicable, adjuvant chemotherapy. The inference that these therapies are not curative for a significant number of subjects poses a role for maintenance therapy. OBJECTIVE: To assess event-free survival (EFS) of patients who received capecitabine as maintenance therapy following treatment according to current guidelines. METHODS: Clinical outcomes data were collected for 35 subjects treated with capecitabine as maintenance therapy. Descriptive statistical analyses were conducted on collective data related to duration of maintenance therapy and disease or clinical status from surgery to initial event. Kaplan-Meier method and log-rank test were used to analyze EFS and overall survival. RESULTS: Of the entire cohort, 26 subjects have no evidence of disease (NED), a median of 5.5 years from surgery. Kaplan-Meier analyses indicated a 5-year EFS rate of 74% (95% CI: 60-90%). Eighteen of these 26 patients received capecitabine ≥30 months. Eight of the 17 subjects treated with capecitabine therapy for <30 months developed progressive disease; the majority of the relapses occurred within 20 months of surgery. The difference between the two groups was statistically significant. Six subjects died, only two of who had metastatic disease at the time of death; the other four had NED at least 4 years from surgery. Five patients with resected stage 4 disease who received capecitabine as maintenance therapy were alive >5 years from surgery. CONCLUSION: The findings and analyses of this cohort of patients suggest that maintenance capecitabine therapy reduces the risk of disease progression and cancer-related death.

Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice.

OBJECTIVE: to review the scientific evidence related to serotonin and substance P and the clinical impact targeting these two neurotransmitters have had managing chemotherapy-induced nausea and vomiting (CINV). DATA SOURCE: a PubMed search (January 1968 to December 2008), restricted to English-language publications, was conducted using the key words antiemetics, cancer chemotherapy, cisplatin, serotonin, substance P, NK(1), and 5-HT(3). Abstracts emanating from the meetings of the American Society of Clinical Oncology and Multinational Association of Supportive Care in Cancer during the period May 2000 to June 2008 were also reviewed. DATA SYNTHESIS: two important outcomes emanated from well-conducted antiemetic clinical trials (Table 1): first, evidence that serotonin and substance P are major mediators of acute and delayed symptoms and second, improved, though not complete, control of CINV. CONCLUSION: serotonin-type 3 and neurokinin-1 receptor antagonists are the most effective agents currently available. In most cases, these agents are used in conjunction with glucocorticoids. The use of these three types of agents is incorporated into current clinical practice guidelines. Further understanding of the biological and biochemical basis of nausea and vomiting may enhance management of this potentially debilitating adverse effect.

Prevalence and factors associated with potentially inappropriate medication use in older medicare beneficiaries with cancer.

OBJECTIVE: To assess the factors related to potentially inappropriate medication (PIM) use in elderly patients with cancer, as well as to compare the PIM prevalence in older adults with and without cancer. METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare-linked base (2009-2011) were accessed to conduct a retrospective study comparing patients with cancers of the breast, colon/rectum, and prostate against a matched population of subjects without cancer. PIM use was defined based on the 2015 Beers Criteria and was quantified using prescription claims. Multivariable logistic regression models were used to assess the associations between the patients' characteristics, clinical factors, and PIM use in patients with cancer based on Beers criteria. Propensity score matching was applied to compare use of PIM in patients with versus without cancer. RESULTS: PIM usage rates in patients with colorectal and breast cancers were significantly higher than non-cancer-bearing adults; the difference in PIM usage rate was not significantly different in the prostate cancer-matched cohort. The prevalence of inappropriate medication use in the three types of cancers evaluated was directly correlated with number of medications prescribed, treatment with chemotherapy, and co-morbid medical problems. CONCLUSION: Patients diagnosed with cancer were more likely to use PIM compared with their non-cancer counterparts. The updated Beers criteria has the potential to serve as an important tool in geriatric oncology practice but it may still need to take into consideration different cancer types and their respective treatments.

Treatment of multiple myeloma in the targeted therapy era.

OBJECTIVE: To review the clinical trials that have impacted treatment standards of multiple myeloma (MM). DATA SOURCE: A PubMed search (1980-June 2008) restricted to English-language publications was conducted using the key words multiple myeloma, clinical trials, targeted therapy, thalidomide, lenalidomide, bortezomib, dexamethasone, melphalan, autologous stem-cell transplantation, and tumor biology. Abstracts emanating from the meetings of the American Society of Clinical Oncology and American Society of Hematology from June 2002 to June 2008 were also reviewed. DATA SYNTHESIS: Although hematopoietic stem-cell transplantation has improved the response rate and duration of overall survival, MM remains an incurable disease. However, focused research aimed at the molecular basis of the disease has led to a number of new treatment strategies. Evidence from clinical trials indicates that each of the 3 novel agents, thalidomide, lenalidomide, and bortezomib, is remarkably effective as first-line therapy. The data also suggest that clinicians may need to reevaluate the role of stem-cell transplantation in the disease. CONCLUSIONS: Thalidomide, lenalidomide, or bortezomib in combination with dexamethasone have replaced traditional chemotherapy such as melphalan, doxorubicin, and vincristine as initial therapy of patients with MM who are eligible for stem-cell transplantation. Furthermore, these novel drugs can be incorporated into regimens used to treat transplant-ineligible patients or those with relapsing disease.

Concordance between substance P levels and antiemetic guidelines.

Practice guidelines now include an antagonist of the substance P/NK1 (neurokinin 1) receptor pathway as part of the standard antiemetic regimen for patients receiving highly, as well as certain moderately, emetogenic chemotherapy regimens. Accumulated laboratory data were used to determine the degree of concordance between substance P levels and the current antiemetic guidelines. Five blood samples were collected over 72 hours from 22 adult patients treated with cisplatin-containing chemotherapy regimens. Overall, the mean baseline substance P level was 318 pg/mL. Although increases in substance P were observed during both phases of the emetic response, analysis by least squares means grouped by cisplatin dosage and vomiting phase was significantly different (P< 0.0001). Preliminary analysis of substance P levels appears to provide additional justification for including the NK1 receptor antagonist in the current antiemetic practice guidelines. In addition, these data provide biochemical justification for the cisplatin dosage criterion used in clinical trials.

Potentially inappropriate medication use and associated healthcare utilization and costs among older adults with colorectal, breast, and prostate cancers.

OBJECTIVES: To assess the association between Potentially Inappropriate Medication (PIM) use and healthcare utilization and costs among Medicare beneficiaries with breast, prostate, or colorectal cancer. MATERIALS AND METHODS: A retrospective cohort study was conducted using the SEER-Medicare linked database in older adults with breast (N = 17,630), prostate (N = 18,721), or colorectal cancer (female: N = 5652; male: N = 3768). PIM use was defined based on 2015 Beers Criteria and was measured using prescription claims. Count models were used to examine the association between PIM use and the number of inpatient and ER visits. Generalized linear models were utilized with the log-link function and gamma distribution to analyze associations between PIM use and medical expenditures. The Inverse Treatment Probability Treatment Weights were applied in the analyses. RESULTS: 61.7% of patients with breast cancer, 47.3% of patients with prostate cancer, and 66.3% (females: 68.0%; males: 63.8%) of patients with colorectal cancer were found to use one or more PIM. PIM use was positively associated with number of inpatient visits, number of ER visits, non-drug costs, and total medical costs in all three types of cancer, except for the number of inpatient visits among patients with colorectal cancer. CONCLUSION: PIM use was significantly associated with greater healthcare utilization and higher healthcare costs in this population. Future research should be undertaken to obtain additional evidence that can aid in the optimization of integrated interdisciplinary programs to facilitate effective management of care for older patients with cancer and other co-morbid medical problems.

Molecular Biology and Clinical Mitigation of Cancer Treatment-Induced Neuropathy.

Disruption of microtubule function is the antitumor mechanism of several classes of drugs used to treat cancer today. However, the significant beneficial effect on tumor outcomes is frequently counterbalanced by neurotoxic complications. Despite an abundance of scientific data, our under-standing of the biological mechanisms underlying this toxic reaction remains unclear, further hindering attempts to identify and develop effective preventive strategies. The primary goals of this review are to: (1) provide insight regarding the biology of the microtubule, (2) analyze the molecular and biochemical pathways that may be involved in the development of neurotoxicity, and (3) propose a unifying concept linking drug-induced neuropathy, microtubule dysfunction, and vitamin D.

Targeted therapies in oncology: in the crosshairs or at the crossroads?

Normal cellular behavior depends on functional integration of extracellular stimuli with intracellular signal transduction pathways. Coupling cell surface message reception to nuclear gene expression is no longer a linear model constructed with molecular components acting merely as conduits to relay signals that cascade toward the nucleus. What has emerged instead is a highly integrated circuit comprised of numerous molecular components harmoniously programmed to communicate a multitude of internal signals that controls cellular response. Despite increasing understanding of cell signaling, mutinous elements embedded in these pathways have defied complete resolution. Research indicates that propagation of signals emanating from the extracellular environment to the cell nucleus follows a complex internal circuit equipped with sophisticated molecular components that provide rigid control over a variety of cellular responses. Although increasing understanding of genetic aberrations and signaling pathway transgressions can lead to novel strategies for targeting cancer cells, the disappointing results from clinical trials suggest that the occult processes responsible for neoplastic transformation remain largely unexplained.

Exemestane: treatment of breast cancer with selective inactivation of aromatase.

The mechanism of action, pharmacology, and clinical efficacy and safety of exemestane in the treatment of metastatic breast cancer are reviewed. Endocrine strategies that deprive tumor cells of estrogens are effective therapeutic modalities for patients with hormone-dependent breast cancer. The efficacy and toxicities associated with tamoxifen and aminoglutethimide have contributed to the development of agents that selectively target aromatase, the enzyme responsible for conversion of androgens to estrogens. Exemestane, an orally active irreversible inhibitor of aromatase, was recently approved as second-line endocrine therapy of advanced hormone-sensitive postmenopausal breast cancer. Compared with megestrol acetate in patients with disease progressing on tamoxifen, a number of clinical endpoints, including a survival advantage, were significantly better in the exemestane-treated group. Preliminary data also indicate that cross-resistance is incomplete between exemestane and the reversible aromatase inhibitors. Even though suppression of aromatase activity is quantitatively similar regardless of the interactive mechanism between drug and enzyme, clinically relevant differences may become apparent with further application of these two types of aromatase inhibitors. Exemestane is effective as a second- or third-line treatment of advanced, estrogen-receptor positive breast cancer in postmenopausal patients.

Sex hormone receptor repertoire in breast cancer.

Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER) positive refers singularly to ER α . One of the oldest recognized tumor targets, disruption of ER α -mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ER α is widely accepted as the single most important predictive factor (for response to endocrine therapy), the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ER ß and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ER ß -mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

Adjudication of the alleged role of vitamin d in the antimicrobial pathway.

Dynamic interactions between microorganism and host have evolved in such a way that while microbial pathogens are the cause of many human infections, a symbiotic relationship is also known to exist. Another important anomaly is that exposure to pathogenic organisms does not necessarily result in development of clinical disease. The latter conclusion infers that susceptibility to infectious disease can be modified by host-related factors. Arguably the two most prominent factors are genetic variability and immunologic status of the exposed individual. Because of the Human Genome and the HapMap projects, developments in genotyping technology have brought the possibility of identifying associations between specific genetic alterations and common diseases closer to reality. In addition, a growing body of evidence suggests vitamin D has an important contributory role in the antimicrobial pathway.

A critical analysis of the (near) legendary status of vitamin D.

Labels such as food constituent, nutrient and supplement do not convey a sense of being essential. Yet these rather mundane descriptors, even if correct, belie the true significance of vitamin D. Long believed to be merely a functioning cofactor akin to vitamin C, deficiency of this secosteroid hormone is clearly associated with morbid complications of calcium and bone mineral metabolism, and because the hormonal effects are mediated by nuclear receptors that regulate the expression of many subordinate genes, the vitamin's pleiotropic mode of action can influence numerous metabolic pathways and, possibly, a number of different diseases. Although the vitamin is under intensive investigation, much still remains unknown, even in bone health, as the identity of osteoporosis susceptibility genes remains uncertain. This article focuses on various aspects of the basic science and molecular biology of the vitamin D endocrine system. The primary goal is to critically examine the evidence supporting its role in bone metabolism, diabetes and cancer.