Effect of Erdafitinib on the Pharmacokinetics of Midazolam and Metformin in Patients With Advanced Solid Tumors Harboring FGFR Gene Alterations.

Erdafitinib, an oral pan-FGFR inhibitor, is used in locally advanced or metastatic urothelial carcinoma for adults with FGFR3 genetic alterations and whose disease progressed following prior systemic therapy. This drug-drug interaction substudy evaluated the effect of erdafitinib on the pharmacokinetics of midazolam (cytochrome P450 3A4 substrate), and metformin (organic cation transporter 2 substrate). Twenty-five patients with advanced solid tumors harboring FGFR gene alterations received pretreatment with single doses of midazolam and metformin, followed by a daily dose of erdafitinib. Drug-drug interaction assessments were performed at erdafitinib steady state following coadministration of single doses of midazolam and metformin, respectively. Geometric mean ratios for maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were estimated using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). The 90% confidence intervals of geometric mean ratios for maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity of midazolam (86.3%, 88.5%, and 82.1%), 1-OH midazolam (99.8%, 97.4%, and 101.5%), and metformin (108.7%, 119.0%, and 113.9%) were either contained or slightly outside the 80%-125% interval and not considered clinically meaningful. Adverse events were consistent with the known erdafitinib safety profile; no new safety signals emerged. Thus, repeated dosing of erdafitinib had no clinically meaningful effect on the pharmacokinetics of midazolam or metformin.

Subcutaneous versus Intravenous Amivantamab, both in Combination with Lazertinib, in Refractory EGFR-mutated NSCLC: Primary Results from the Phase 3 PALOMA-3 Study.

PURPOSE: Phase 3 studies of intravenous amivantamab demonstrated efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed following osimertinib and platinum-based chemotherapy were randomized 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS: Overall, 418 patients underwent randomization (subcutaneous group, n=206; intravenous group, n=212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27-1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42-0.92; nominal P=0.02). Fewer patients in the subcutaneous group experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) versus the intravenous group. Median administration time for first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab from 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

Prognostic and Predictive Value of Fibroblast Growth Factor Receptor Alterations in High-grade Non-muscle-invasive Bladder Cancer Treated with and Without Bacillus Calmette-Guérin Immunotherapy.

BACKGROUND: Limited data are available on the prognostic and predictive value of fibroblast growth factor receptor alterations (FGFRa) relative to clinical outcomes in patients with non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To determine whether FGFRa may be clinically useful in stratifying for treatment response in a real-world cohort of patients with pT1 NMIBC treated and untreated with bacillus Calmette-Guérin (BCG) instillation therapy. DESIGN, SETTING, AND PARTICIPANTS: A pooled dataset of matched clinical and genomic data (1992-2015) for pT1 NMIBC patients was assessed by the Bladder Cancer Research Initiative for Drug Targets in Germany consortium. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Key efficacy outcomes were recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS), which were estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model. RESULTS AND LIMITATIONS: In this retrospective study of 263 patients with high-grade NMIBC, at a median follow-up of 63 mo, 32% showed recurrence and 15% progressed to muscle-invasive bladder cancer. FGFRa were found in 43% of patients, including 39% mutations and 5.7% fusions. FGFRa were associated with lower rates of concomitant carcinoma in situ. Among patients with or without FGFRa, there was no significant difference in PFS, RFS, and DSS in those who were BCG treated or BCG naive, or in the overall population. Limitations include the retrospective design from a single-center setting. CONCLUSIONS: In patients with high-risk NMIBC, FGFRa were frequently observed. Patients with FGFRa who often exhibit recurrence/relapse after BCG treatment have a high unmet need. PATIENT SUMMARY: Our retrospective study suggests that fibroblast growth factor receptor alterations (FGFRa) occur frequently in non-muscle-invasive bladder cancer (NMIBC). Outcomes were similar with or without FGFRa in patients with NMIBC, both overall and for standard bacillus Calmette-Guérin (BCG) treatment.

Prolonged duration of response in lenvatinib responders with thyroid cancer.

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2%; 95% confidence interval (CI) 54.2-66.1) was 30.0 months (95% CI 18.4-36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99% CI 0.17-0.35; nominal P < 0.0001). In lenvatinib responders, median PFS was 33.1 months (95% CI 27.8-44.6) vs 7.9 months (95% CI 5.8-10.7) in non-responders. The median DOR of 30.0 months seen with patients who achieved complete or partial responses with lenvatinib (60.2%) demonstrates that lenvatinib responders can have prolonged, durable and clinically meaningful responses. Prolonged PFS (33.1 months) was also observed in these lenvatinib responders.

A prospective study on red blood cell transfusion related hyperkalemia in critically ill patients.

BACKGROUND: Transfusion-associated hyperkalemic cardiac arrest is a serious complication in patients receiving packed red blood cell (PRBC) transfusions. Mortality from hyperkalemia increases with large volumes of PRBC transfusion, increased rate of transfusion, and the use of stored PRBCs. Theoretically, hyperkalemia may be complicated by low cardiac output, acidosis, hyperglycemia, hypocalcemia, and hypothermia. In this study, we focus on transfusion-related hyperkalemia involving only medical intensive care unit (MICU) patients. METHOD: This prospective observational study focuses on PRBC transfusions among MICU patients greater than 18 years of age. Factors considered during each transfusion included patient's diagnosis, indication for transfusion, medical co-morbidities, acid-base disorders, K(+) levels before and after each PRBC transfusion, age of stored blood, volume and rate of transfusion, and other adverse events. We used Pearson correlation and multivariate analysis for each factor listed above and performed a logistic regression analysis. RESULTS: Between June 2011 and December 2011, 125 patients received a total of 160 units of PRBCs. Median age was 63 years (22 - 92 years). Seventy-one (57%) were females. Sixty-three patients (50%) had metabolic acidosis, 75 (60%) had acute renal failure (ARF), and 12 (10%) had end-stage renal disease (ESRD). Indications for transfusion included septic shock (n = 65, 52%), acute blood loss (n = 25, 20%), non-ST elevation myocardial infarction (NSTEMI) (n = 25, 20%) and preparation for procedures (n = 14, 11%). Baseline K(+) value was 3.9 ± 1.1 mEq/L compared to 4.3 ± 1.2 mEq/L post-transfusion respectively (P = 0.9). During this study period, 4% of patients developed hyperkalemia (K(+) 5.5 mEq/L or above). The mean change of serum potassium in patients receiving transfusion ≥ 12 days old blood was 4.1 ± 0.4 mEq/L compared to 4.8 ± 0.3 mEq/L (mean ± SD) in patients receiving blood 12 days or less old. Sixty-two patients (77.5%) that were transfused stored blood (for more than 12 days) had increased serum K(+); eight (17.7%) patients received blood that was stored for less than 12 days. In both univariate (P = 0.02) and multivariate (P = 0.04) analysis, findings showed that among all factors, transfusion of stored blood was the only factor that affected serum potassium levels (95% CI: 0.32 - 0.91). No difference was found between central and peripheral intravenous access (P = 0.12), acidosis (P = 0.12), ARF (P = 0.6), ESRD (P = 0.5), and multiple transfusions (P = 0.09). One subject developed a sustained cardiac arrest after developing severe hyperkalemia (K(+) = 9.0) following transfusion of seven units of PRBCs. Multivariate logistic regression showed linear correlation between duration of stored blood and serum K(+) (R(2) = 0.889). CONCLUSION: This study assesses factors that affect K(+) in patients admitted to MICU. Results from the study show that rise in serum K(+) level is more pronounced in patients who receive stored blood (> 12 days). Future studies should focus on the use of altered storage solution, inclusion of potassium absorption filters during transfusion and cautious use of blood warmer in patients requiring massive blood transfusions.

The evolution of Clostridium difficile infection in cancer patients: epidemiology, pathophysiology, and guidelines for prevention and management.

Clostridium difficile infection (CDI) has emerged as a significant challenge to the healthcare system. The availability of anti-cancer chemotherapeutic regimens has contemporaneously resulted in a larger population of patients who are susceptible to CDI. The outbreak of a novel, hypervirulent, resistant strain, NAP-1/027 as well as resistance to antibiotic therapy have further contributed to an increase in prevalence as well as in disease severity. Recent data show high fatality rates in cancer patients with CDI. In this review, we have discussed the incidence, epidemiology, pathophysiology, clinical signs and symptoms and therapeutic guidelines for patients who are on chemotherapy and present with CDI and highlighted clinical reports documenting severe CDI associated with chemotherapeutic agents such as methotrexate, 5FU, cisplatin, carboplatin, paclitaxel, vinorelbine and cyclophosphamide. The review article also has the discussion of patents pertaining to infections caused by Clostridium difficile in cancer patients. We underscore the urgent need for early recognition and diagnosis of CDI in cancer patients and for the design and implementation of randomized clinical trials of new treatment modalities in the management of chemotherapy- associated CDI.

Warfarin: implementing its safe use in hospitalized patients from nursing homes and community through a performance improvement initiative.

INTRODUCTION: Warfarin is increasingly used to prevent thromboembolism but adverse drug events (ADEs) are common. The National Safety Goals (3E) 2008 recommend that institutions develop processes to monitor the safe use of warfarin. Despite these guidelines, adverse events (bleeding) are common. This initiative, in an academic hospital, tracked warfarin use before and after using a PI process aimed at improving safe use of warfarin in hospitalized adults. METHODS: Retrospective (PRE-initiative, September-December 2007) and prospective (POST-initiative, January-December 2008) data were collected on in-hospital and prior warfarin use, demographics, medical history, initial and in-hospital warfarin maintenance dosing, hematocrit, International Normalized Ratio (INR), hepatic and renal function and adverse events related to warfarin use. Education on the appropriate use of warfarin was provided through formal and informal sessions and during daily hand-off sessions. RESULTS: A total of 308 patients receiving oral warfarin were examined (mean age 70 ± 17(SD) years, 47% males, 36% from nursing homes). Age, sex ratios, and place of residence were similar PRE- versus POST-initiative. Overall initial and maintenance warfarin doses were significantly lower POST-initiative (P = .0129 and P = .0319, respectively) and these decreases occurred exclusively in patients with supratherapeutic INR levels (>3.0). During the POST-period, the prevalence of high INR levels and bleeding events during hospitalization also decreased significantly (P = .015 and P < .0005, respectively). Finally, concomitant use of anticoagulant and/or antiplatelet drugs was significantly decreased POST-initiative (P = .028). CONCLUSIONS: Most hospitalized patients (PRE- and POST-) presented with INRs in the sub- or supratherapeutic ranges (<2 and >3, respectively), requiring warfarin dose adjustments. Education through this initiative resulted in significantly lower average maintenance doses of warfarin, less use of concomitant anticoagulant or antiplatelet drugs, fewer supratherapeutic range INRs, and fewer adverse events during warfarin therapy. Education through a PI initiative is a simple and effective means to implement safer use of warfarin in the in-hospital setting.

Emerging therapies in the treatment of locally advanced squamous cell cancers of head and neck.

Head and neck squamous cell cancers (HNSCCs) represent 4 to 5% of all solid malignancies. Despite improvements in diagnostic techniques, 60% of patients will present with locally advanced HNSCCs with a median survival of about 12 months and 5-year overall survival of approximately 10-40%. Recent clinical trials have altered the treatment landscape by refining existing forms of radiation, incorporation of IMRT, choice of chemotherapeutic agents, introduction of biological and targeted therapy, immunotherapy and gene therapy. Cetuximab, a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR), has recently been approved in combination with RT in patients with locally advanced HNSCCs. Antiangiogenic therapies and tyrosine kinase inhibitors (gefitinib and erlotinib) have also shown promise in the clinical trials. Vandetanib, an antagonist of both vascular endothelial growth factor receptor (VEGFR) and the EGFR is currently being tested in phase II trial. New patents on hypoxia-inducible factor 1 alpha, mesenchymal-epithelial transition factor, insulin-like growth factor or the PI3K/AKT/mTOR pathway, farnesyl transferase inhibitors have shown promise in the management of HNSCCs. Nevertheless, identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from them. However, increase in efficacy comes at the cost of increased toxicity. The current review focuses on insight into recent patents and updates on the clinical trials using new investigational agents in the management for HNSCCs.

Clostridium difficile infection following chemotherapy.

Clostridium difficile infection (CDI) is a major concern for health care system and clinicians. Interest in C. difficile infection has increased recently due to an ongoing C. difficile epidemic with a hypervirulent strain and mortality. Disease due to C. difficile is responsible for substantial strain on the hospital system by increasing patients' length of stayand increasing costs. Present studies have demonstrated chemotherapeutic agents as an independent risk factor for CDI potentially leading towards serious morbidity and mortality. However, the current strategies lack randomized trials on management in chemotherapy-associated CDI. The changing face of the disease, emergence of more resistant strains, and the rising cancer incidence have heightened the need for identification of risk factors, rapid diagnosis including prompt identification of toxins, and management algorithms. This review focuses on recent insights on the epidemiology, diagnosis, current management, recent patents, and advances on treating strategies of CDI with reference to current studies.

Novel management of pruritus in patients treated with IL-2 for metastatic renal cell carcinoma and malignant melanoma.

Pruritus has been a side effect, associated with several biologic response modifiers, most commonly interferons and interleukins. Reports of pruritus are anecdotal and have not been a focus of attention. Itch fibers are essentially pain fibers, and gabapentin is used for neuropathic pain. This has led to our formal investigation of gabapentin for interleukin-2 (IL-2)-related pruritus. Clinical records of 54 patients treated with high-dose IL-2 from January 2005 to December 2006 were reviewed. Among 30 patients, who complained of pruritus, 17 patients were given gabapentin. These 17 patients were interviewed using a specific IRB approved questionnaire, which quantified pruritus according to CTCAE v3.0 criteria. According to CTCAE scale, the mean pruritus before gabapentin was 2.41, which decreased to 0.65 after gabapentin treatment and was statistically significant (P<0.0005). IL-2 therapy is frequently associated with varying degrees of peripheral eosinophilia. Relationship between pruritus and the degree of eosinophilia was also analyzed. Patients grouped into mild eosinophilia (eosinophil count<1500/mL) and moderate to severe eosinophilia (eosinophil count>1500/mL) during HDIL-2 therapy was evaluated for pruritus. χ² test for independence of variable between degree of eosinophilia and pruritus was 0.714 with no statistically significant correlation. To summarize, gabapentin is used in our facility with excellent response against pruritus. Hypothesizing the likely mechanism of pruritus in patients treated with IL-2, we suggest that gabapentin should be considered an effective and safe treatment in IL-2-related pruritus, and this concept could be applied to pruritus encountered in similar clinical settings.

Adverse clinical sequelae after skin branding: a case series.

INTRODUCTION: Branding refers to a process whereby third degree burns are inflicted on the skin with a hot iron rod or metallic object. Branding employs the phenomenon of "counter irritation," and is widely used by faith healers in developing countries for therapeutic purposes. Some methods, which are very crude and inhuman, carry a large risk of complications. The purpose of this study is to present a series of complications and to familiarize clinicians with this dangerous method of treatment. CASE PRESENTATION: Four Pakistani patients, three male and one female, ranging from 25 to 60 years of age "branded" with a red hot iron rod for various medical reasons presented with severe medical complications to our tertiary care hospital. The mean duration between the procedure and presentation to the hospital was 6 days. At the time of admission, two patients had septic shock, one patient had cavernous sinus thrombosis and one patient had multiple splenic abscesses. All patients received standard care for wound management and systemic infections. Two patients eventually died during the course of treatment. CONCLUSION: Severe complications from branding are troublesome and the potential risks of this treatment outweigh its benefits. Globally, there is a great need for heightened awareness about the dangers of branding among patients and physicians, as this will have an important effect on patients who seek branding for various medical conditions.