Defining the impact of the use of granulocyte colony stimulating factors on the incidence of chemotherapy-induced neutropenia in patients with gynecologic malignancies.

Purpose The objectives of this study were to characterize the incidence of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) with specific chemotherapy agents commonly used in the treatment of gynecologic malignancies, as well as defining the impact of granulocyte colony stimulating factors (G-CSF) on the prevention of CIN and FN in this patient population. Methods This retrospective analysis was conducted from a database of 635 gynecologic cancer patients who received chemotherapy between 1 September 2007 and 31 August 2008. A logistic regression analysis was conducted to determine the impact of potential covariates on the overall incidence of CIN. Results Overall, 28.3% of patients experienced CIN with one or more cycles chemotherapy, and 13.1% had treatment delays or dose reduction associated with CIN. The use of G-CSF prior to administration of chemotherapy resulted in a decrease in the incidence of CIN from 29.8% to 19.6% compared to no G-CSF use. No difference was observed in number of treatment delays or dose reductions in the 46 (7.2%) of gynecologic cancer patients that received G-CSF prophylaxis. Multivariate analysis found that both age and the number of current cycles jointly may predict risk of CIN. Conclusions Patients with gynecologic malignancies appear to be at a higher risk of development of neutropenia when treated with chemotherapy. The proactive use of G-CSF did decrease the risk of CIN by over 30%. Prospective study is warranted to determine the impact of G-CSF to reduce CIN in patients with gynecologic malignancies receiving chemotherapy.

Evaluation of pegylated liposomal doxorubicin dose on the adverse drug event profile and outcomes in treatment of recurrent endometrial cancer.

OBJECTIVE: This study aims to determine factors that may increase the likelihood of adverse drug events (ADEs) in patients with recurrent endometrial cancer treated with pegylated liposomal doxorubicin (PLD) as well as this agent's impact on clinical outcomes. METHODS: The treatment records of patients with endometrial cancer who received PLD at The University of Texas, MD Anderson Cancer Center, from 1996 to 2006 were reviewed. Patient demographics, PLD dose, ADEs, use of supportive care interventions, disease progression, and survival were extracted. Logistical regression analysis was used to identify factors that were associated with higher incidence of ADEs and that influenced survival. RESULTS: A total of 60 patients with recurrent endometrial cancer were identified who experienced 122 ADEs. The most commonly reported ADEs were nausea (18.9%), palmar-plantar erythrodysesthesia (PPE; 16.4%), muscle weakness (12.3%), mucositis (10.7%), and peripheral neuropathy (9.8%). Seventeen patients (28%) required a dose reduction because of ADEs. However, only 5 (8.3%) patients discontinued therapy because of toxicity. Cooling mechanisms were used in 19 patients to prevent PPE, although 9 of these patients still experienced PPE. Treatment with 6 or more cycles of PLD was associated with increased incidence of neutropenia (P = 0.045), peripheral neuropathy (P = 0.004), and PPE (P < 0.001). No differences in progression-free survival or time to progression were found between the doses of PLD; however, there was an assessable trend toward increased survival with doses of 40 mg/m(2). CONCLUSIONS: Although there was no association with dose level and ADEs, more cycles received increased the incidence of toxicities, including PPE and neuropathy. There was no association between different doses of PLD and progression-free survival or time to progression.

Defining the role of echinocandin catechol functional groups in the development of secondary hepatocellular carcinoma.

OBJECTIVES: To determine whether the catechol functional group on echinocandins decreases the catechol-O-methyltransferase (COMT) metabolism of catechol oestrogens (CEs) and the potential role of this functional group in the development of hepatocellular cancer. METHODS: Human COMT expression was measured by RT-PCR in a panel of selected human cancer cell lines and human hepatocytes. An ex vivo human hepatocyte model was employed to evaluate the metabolism of 17-ß-oestradiol to CEs in the presence of a catechol (B(0)C) versus a non-catechol echinocandin (B(0)) compound. COMT inhibition assays were conducted to evaluate the metabolism of CEs in the presence of B(0)C or B(0). Oestrogen receptor expression in human hepatic carcinoma cells was evaluated by RT-PCR and western blotting. Cell proliferation assays were used to evaluate the impact of B(0) or B(0)C on cancer cell growth. RESULTS: MCF-7 and Hep-G2 cells and human hepatocytes expressed variant Met/Met COMT. At clinically relevant concentrations, only B(0)C significantly increased CE levels in the COMT inhibition assays, to 90.0 µM compared with 79.8 µM in the untreated controls (P = 0.032). A high concentration (500 µg/mL) of B(0)C decreased COMT expression to 79%, 94% and 90% of untreated, baseline control levels in the three cell lines, respectively. B(0)C and B(0) did not increase cell growth in the cancer cell lines evaluated. CONCLUSIONS: At clinically achievable concentrations only B(0)C significantly inhibited COMT activity and increased CE concentrations. Short-term exposure did not alter the rate of cancer cell growth. Confirmation is needed to determine the clinical impact of long-term exposure to and the use of echinocandins with catechol functional groups.

An Evaluation of the Use of Corticosteroids for the Management of Immune-Mediated Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have gained prominence for the treatment of a variety of malignancies. However, they are associated with the development of immune-mediated adverse events (IMAEs). Appropriate management of IMAEs and subsequent rechallenging of patients with ICI therapy remains an important area of research. The primary endpoint of this study was to evaluate the efficacy of current prescribing practices and adherence to guideline recommendations for IMAE management. The incidence of symptom resolution, number of patients reinitiated with ICI therapy, and IMAE recurrence upon ICI therapy reinitiation were explored as secondary endpoints. A retrospective chart review within the Allegheny Health Network was conducted in cancer patients treated with ICI therapy who developed a documented ICI-associated IMAE and subsequently received corticosteroid therapy. IRB approval was obtained for this study. Descriptive statistics were used to analyze both primary and secondary endpoints. The study sample was made up of 81 patients. Overall, 50 out of 81 patient cases (62%) were found to be discordant with guideline recommendations; the primary factors identified were inappropriate starting corticosteroid dosing (64%), initiation of a corticosteroid taper prior to IMAE resolution to at least grade 1 severity, and condensed corticosteroid taper (74%). The main IMAEs identified were colitis (28%), pneumonitis (27%), and skin-related inflammation (12%). 76 out of the 81 patients (94%) achieved IMAE resolution; 41 patients (54%) were rechallenged with ICI therapy, of which 14 patients (34%) developed IMAE recurrence. Future studies may focus on evaluating different immunosuppression strategies to optimize IMAE management.

Synthesis and pharmacological evaluation of 1,2,3,4-tetrahydropyrazino[1,2-a]indole and 2-[(phenylmethylamino)methyl]-1H-indole analogues as novel melatoninergic ligands.

Two novel series of melatonin-derived compounds have been synthesized and pharmacologically evaluated at the MT(1) and MT(2) subtypes of melatonin receptors. Compounds 12b-c are non-selective high-affinity MT(1) and MT(2) receptor ligands (K(i)=7-11 nM). Compound 12b had little intrinsic activity at the MT(1) receptor and no intrinsic activity at the MT(2) receptor. Compound 20d displayed the highest MT(2) binding affinity (K(i)=2 nM) and moderate selectivity toward the MT(2) subtype (K(i) MT(1)/MT(2) ratio=8) behaving as MT(2) antagonist and MT(1) agonist (IC(50)=112 pM). The findings help define SARs around the positions 1 and 2 of melatonin with respect to binding affinity, MT(2) selectivity, and intrinsic activity.

Synthesis and pharmacological evaluation of pentacyclic 6a,7-dihydrodiindole and 2,3-dihydrodiindole derivatives as novel melatoninergic ligands.

The synthesis of novel melatonin analogues 3a and 4a-c designed as melatonin receptor ligands is described. Among the newly synthesized ligands, 2-((S)-2-hydroxymethylindolin-1-ylmethyl)-melatonin 4b displayed the highest affinity for MT(1) receptors (K(i)=9.8 nM) and for MT(2) subtype (K(i)=7.8 nM), whereas the rigid pentacyclic ligand 3 showed the highest selectivity towards the MT(2) receptor subtype (K(i)=319.3 nM for MT(1) and K(i)=65.2 nM for MT(2)).

Potential Obstacles in the Acquisition of Oral Anticancer Medications.

PURPOSE: To determine the amount of time elapsed between prescriber order and patient receiving oral anticancer medication. PATIENTS AND METHODS: Adult patients with a diagnosis of cancer were prospectively identified in three outpatient oncology clinics when oral anticancer agents were prescribed during a 4-month observation period. For each patient, time to obtain medication was analyzed by the following time points: date of prescription, date of submission to insurance, date prior authorization was obtained, date financial assistance was received, date prescription was processed by pharmacy, and date patient received medication. Out-of-pocket cost and time spent by clinic staff to facilitate the medication acquisition process were recorded. RESULTS: Thirty-four patients were prescribed oral anticancer medication during the data collection period. For the 27 patients who were eligible for the primary end point, medication acquisition required a median of 10 days (range, 3 to 28 days). Overall, the rate-limiting step for medication acquisition was processing by the pharmacy, with a median of 6 days (range, 1 to 27 days). Most patients' prescription insurance plan covered a portion of medication cost, and the majority of patients considered their out-of-pocket expense to be affordable. Clinic staff spent a median of 2 hours per prescription to facilitate medication acquisition. CONCLUSION: Patients may encounter process barriers in acquiring oral therapy, particularly because of pharmacy processing time, as well as high copays. Time to treatment initiation may have implications for patients' clinical outcomes. Adequate staff with dedicated time to facilitate this process should be used in the ambulatory oncology practice setting.

Evaluating the potential effect on fetal tissue after exposure to granisetron during pregnancy.

The objective of this study was to elucidate the possible toxic effects on the fetal tissues after exposure to two clinically relevant concentrations of granisetron. Primary cells were isolated from human fetal organs of 16-19 weeks gestational age and treated with 3 ng/mL or 30 ng/mL of granisetron. Cell cycle progression was evaluated by flow cytometry. ELISA was used to detect alterations in major apoptotic proteins. Up to 10% apoptosis in cardiac tissue was observed following treatment with 30 ng/mL granisetron. Neither concentration of granisetron caused alteration in cell cycle progression or alterations in apoptotic proteins in any of the other tissues. At 30 ng/mL granisetron concentration had the potential to induce up to 10% apoptosis in cardiac tissue; clinical significance needs further evaluation. At granisetron 3 ng/mL there was no detectable toxicity or on any fetal tissue in this study. Further research is needed to confirm these preliminary findings and determine if clinically significant.

Evaluation of the maternal-fetal transfer of granisetron in an ex vivo placenta perfusion model.

The objective of this study was to estimate maternal-fetal transplacental passage of granisetron in an ex vivo placental perfusion model. Term human placentas (N=8) were collected immediately after delivery. A single cotyledon from each placenta was perfused granisetron concentration to mimic systemic maternal peak plasma concentrations following either IV (50ng/mL) or transdermal administration (5ng/mL). To assess drug transfer and accumulation, samples were collected from maternal and fetal compartments. In the 50ng/mL open model, the mean transport fraction was 0.21±0.08 with clearance index of 0.53±0.66. Fetal peak concentrations achieved was 5.6±6.6ng/mL with mean accumulation of 5.35±6.4ng/mL. No drug was detected in the fetal compartment with the 5ng/mL models. Transplacental passage of granisetron was inconsistent at the 50ng/mL concentration that achieved with IV dosing. However, there consistently was no detectable passage in all the placentas evaluated of the granisetron at 5ng/mL concentration that would be achieved after transdermal patch administration.

Clinical perspectives on the role of the human papillomavirus vaccine in the prevention of cancer.

The role of human papillomavirus (HPV) in the genesis of cervical cancer has been well documented, and an increasing body of literature exists with regard to the role of HPV in other cancers, including cancers of the head and neck. With the recent expansion of the United States Food and Drug Administration's approval of the quadrivalent HPV virus-like particle vaccine to include men and boys and approval of the bivalent vaccine this year, the controversies regarding who should be vaccinated, at what age is vaccination most appropriate, and the limitations of the available HPV vaccines are increasing. Health care providers are challenged with evaluating the current, but continually changing, clinical evidence when making critical decisions for their patients. A literature search of MEDLINE and SciVerse Scopus was conducted for articles published from 1998-April 2010 regarding HPV, HPV-related cancers, and HPV vaccines. Although both HPV vaccines were greater than 90% effective in the prevention of cervical cancer precursors in an according-to-protocol cohort, both vaccines were significantly less effective in the intent-to-treat population. In patients who achieved seroconversion, the geometric mean titers decrease dramatically within the first 2 years after vaccination, and then continue to decline at a slower rate. No effective antibody titer has been defined for either vaccine, and no studies have been conducted with documented HPV exposure after vaccination. With low efficacy rates in an intent-to-treat population and the potential for waning immunity, it is imperative for women to continue to receive regular Pap tests and gynecologic examinations. Although vaccine administration was shown to be cost-effective when administered to adolescent girls, many of these simulations overestimated the durability of protection, efficacy rates in sexually active women, impact of incomplete vaccination, or necessity of boosters in the future. Whereas the introduction of the HPV vaccine was an enormous advancement in the cancer prevention research arena, optimization of its clinical use is still needed.

2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists.

A novel series of 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues has been prepared to probe the steric and electronic properties of the binding pocket of the MT(2) receptor accommodating the "out-of-plane" substituent of MT(2)-selective antagonists. The acetamide (6b) bearing an usubstituted indoline moiety displayed an excellent binding affinity and selectivity toward the MT(2)-subtype (MT(2), K(i) = 1 nM; MT(1), K(i) = 115 nM), behaving as a competitive antagonist. 5-Me, 5-OMe, 5-Br, 6-NH(2), and 6-NO(2) substitution of the indoline moiety reduced both MT(2) affinity and selectivity, indicating that hydrophobic interactions play a decisive role in binding the out-of-plane substituent. The cyclobutanecarboxamide (6e) showed a biphasic binding pattern at MT(2) receptors, indicating the presence of two MT(2) binding sites, a high affinity (K(i) = 1 pM) and a low affinity (K(i) = 148 nM), while MT(1) binding affinity was very low (K(i) = 1.4 microM). Functional analysis of 6e revealed it to be an antagonist at MT(1) receptors and a partial agonist, at best, at MT(2) receptors.

Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole analogues as melatonin receptor ligands.

A structure for the self-condensation product of 2-(1H-indol-2-yl)ethyl tosylate 2a, previously proposed as 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5-b]diindole 3a, was revised based on the (13)C-2D-INADEQUATE experiment, and proved to be 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole 4a. A mechanism for the unexpected formation of this novel hexacyclic heterocycle was proposed and its NMR solution structure was elucidated. Five derivatives of the title ring skeleton 12-16 designed as melatonin receptor ligands were synthesized and their affinities for the human MT(1) and MT(2) receptors were determined. Both butyramides 13 and 15, as well as the non-methoxy acetamide 12 exhibited micromolar binding affinities for both receptors being slightly MT(2) selective. The methoxy acetamide 14 showed the best pharmacological profile exhibiting a five times higher affinity for MT(1) (K(i) = 49 nM) than for MT(2) (K(i) = 246 nM) receptor.