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Introduction: Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib, are approved for first-line treatment of metastatic renal cell carcinoma (mRCC). Pembrolizumab/axitinib is associated with superior progression free survival (PFS), objective response rate (ORR), and overall survival over sunitinib. However, to date, the activity and safety of pembrolizumab/axitinib in later lines of therapy has not been reported., Materials and Methods: Clinical data of consecutive patients receiving pembrolizumab/axitinib in the second-line or beyond for mRCC at Yale-New Haven Hospital were retrospectively collected. Best objective response was assessed using RECIST 1.1 criteria. Kaplan-Meier function was used to analyze survival., Results: Thirty-eight patients were included. Median age was 64, 92.1% had clear cell mRCC, 18.4% had sarcomatoid dedifferentiation; 94.7% had prior ICI and 39.5% had prior VEGF-R-TKI. Pembrolizumab/axitinib was administered as second-line therapy in 21 (55.5%) patients, third-line in 5 (13.2%) and beyond in 12 (30.2%). Adverse events (AEs) occurred in 86.8% of patients. Grade 3-4 AEs attributed to pembrolizumab and axitinib were seen in 18.4% and 6.4% of patients, respectively. No grade 5 AEs occurred. At a median follow up of 17.1 months, median PFS was 9.7 months (95% CI, 4.1-15.3). Amongst 36 response evaluable patients, the ORR was 25.0% (all partial) and disease control rate (including stable disease for at least 6 months) was 66.6%. The most frequent treatment sequence was first-line nivolumab/ipilimumab followed by second-line pembrolizumab/axitinib (n = 17, 44.7%); among this cohort, median PFS with pembrolizumab/axitinib was 11.1 (95% CI, 8.4-13.7) months, with an ORR of 31.4%., Conclusion: Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line. Prospective studies evaluating ICI-VEGF-R-TKI combinations beyond first-line are warranted to identify the most beneficial treatment sequencing in mRCC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction/background: Durvalumab is a programmed cell death ligand 1 (PD-L1) inhibitor indicated for stage III, unresectable non-small cell lung cancer (NSCLC) consolidation therapy following concurrent platinum-based chemoradiation based on results of the PACIFIC trial. Safety data of durvalumab demonstrates an increased risk of immune-related adverse effects (irAEs), most notably pneumonitis. Pneumonitis is a serious and potentially fatal complication of immunotherapy. It is important to investigate the incidence of pneumonitis in clinical practice to evaluate the generalizability of published data. The objective of this study is to assess and characterize real-world incidence of pneumonitis in patients with NSCLC receiving durvalumab., Materials and Methods: This retrospective study included patients who were initiated on durvalumab for unresectable stage III NSCLC from February 2018 through November 2019. The data analysis utilized descriptive statistics to determine the incidence of pneumonitis associated with durvalumab., Results: Of the 83 patients who were evaluated, 21 patients (25.3%) experienced pneumonitis, with 5 cases (6%) being grade 3/4. Seven patients were re-challenged with durvalumab, while 14 patients permanently discontinued durvalumab. There were no clearly identifiable risk factors leading to an increased incidence of pneumonitis., Conclusion: The results of this study indicate that real-world incidence of pneumonitis in stage III NSCLC patients receiving durvalumab consolidation therapy is congruent with the incidence reported in the PACIFIC trial., Competing Interests: Disclosure Darren Luon has served as a consultant for Heron Therapeutics. Other authors have no conflicts of interests to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Proteinuria monitoring is required for patients receiving bevacizumab. Nonetheless, the frequency of monitoring is not specified in the package insert. A 2014 quality improvement study performed at Yale New Haven Health System (YNHHS) found that proteinuria occurred in 15% (all grade) of the 162 patients evaluated. These results led to decreasing the frequency of proteinuria monitoring from every treatment to every other treatment. The objective of this study is to assess the safety of the extended interval for urine protein (UP) monitoring., Methods: Patients receiving at least four bevacizumab treatments at YNHHS from January to June 2017 were randomly selected and retrospectively reviewed. The following data were collected: baseline patient characteristics, comorbidities, medication history, and proteinuria monitoring. The grade, prevalence and management of proteinuria were evaluated. The minimum necessary sample size was determined to be 384 treatments to achieve a 95% confidence interval., Results: Fifty-five patients and 388 bevacizumab treatments were evaluated. Urine protein was assessed in 52.5% of treatments. The incidence of proteinuria among patients was 7.2% (grade 2) and 0% (grade 3). Cumulative dose and the number of total bevacizumab doses did not affect the timing for onset or severity of proteinuria. Two patients with UP ≥ 2+ were further monitored using a 24-h urine collection test with negative results. No treatments were held due to proteinuria., Conclusion: Monitoring proteinuria every other treatment does not increase the frequency of adverse events. Urine protein is now monitored prior to every third bevacizumab treatment, reducing unnecessary labs and chair time.

Background: The advent of anti-PD1 therapy for cancer treatment has led to improvements in response rates and overall survival. However, anti-PD1 therapy has the potential to cause immune-related adverse events (irAEs), which can be treated with corticosteroids if severe. The clinical implications of concomitant immunotherapy and systemic steroids remain unclear, as short courses of steroids do not significantly suppress T-cell function. The primary objective of this study is to determine if the use of concomitant steroids impacts the efficacy of anti-PD1 therapy., Methods: This retrospective, single-center study reviewed adult patients who received at least four cycles of nivolumab or pembrolizumab for the treatment of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma from November 2014 to February 2016. Patients who received steroids (prednisone equivalent >10 mg) during anti-PD1 therapy were divided into two main cohorts based on the duration of steroid administration of ≤2 weeks or >2 weeks. Time to disease progression, overall response, and overall survival were assessed., Results: Twenty-seven of 55 patients (13 melanoma, 11 NSCLC, 3 renal cell carcinoma) required steroids during anti-PD1 therapy. In patients who received steroids, median time to disease progression was 5.6 months for melanoma, 5.8 for NSCLC, and 2.0 for renal cell carcinoma. The overall response rate (ORR) was 3/13 (23%) for melanoma, 6/11 (54%) for NSCLC, and 1/3 (33%) for renal cell carcinoma. Median overall survival was 11.9 months for melanoma, 9.9 for NSCLC, and not reached for renal cell carcinoma. Thirteen patients who had received steroids expired; 11 of these patients had received prednisone >10 mg/day for >2 weeks., Conclusion: High-dose steroids for long durations during anti-PD1 therapy may be associated with poorer survival outcomes.

Many medical centers in the United States have implemented pharmacogenomics (PGx) programs to integrate PGx into clinical practice. The roles of pharmacists in optimizing medication use based on genetic testing results are emergently evolving. A literature search was conducted to assess pharmacists' roles in pharmacogenetics/pharmacogenomics or precision/personalized medicine programs. Fifteen PGx pharmacy practice models implemented in eleven hospitals and one community pharmacy in the U.S. were selected for evaluation. Pharmacists perform results interpretation, genotype-guided medication selection and adjustment, medication acquisition, adverse reactions monitoring, and patient education. Institutions that are interested in implementing a PGx program should plan the strategies to overcome the challenges, such as educational knowledge gaps, informatics, and reimbursement issues. Strong institutional support, well-defined goals, standardized procedures, and strategies to educate clinicians and patients are the prerequisites to comprehensively deliver genomic data for individualized drug therapy.

Purpose To evaluate and compare the rate of hypersensitivity reactions between two low-dose steroid pre-medication regimens for paclitaxel-based treatments. Methods This was a single-center, retrospective, descriptive study, comparing the incidence of hypersensitivity reactions in two different dexamethasone pre-medication regimens that took place between July 2013 to December 2014. Patients who were paclitaxel-naïve with a diagnosis of breast or gynecological cancers were included. Patients in the early termination protocol were pre-medicated with a standard pre-medication regimen and if tolerated with no hypersensitivity reaction occurrence, all pre-medications were discontinued after the first two infusions. Patients in the low-dose steroid continuation protocol were pre-medicated with lower doses of dexamethasone, and if the infusion was tolerated with no hypersensitivity reaction, dexamethasone doses were further reduced after the first two infusions. Results A total of 120 patients were included for data analysis. The hypersensitivity reaction rate in the early termination protocol group was 7% (4 out of 60 patients). The hypersensitivity reaction rate in the low-dose continuation protocol group was 5% (3 out of 60 patients). All hypersensitivity reactions occurred during the first infusion, with no hypersensitivity reactions occurring once the dexamethasone pre-medications were discontinued or dose-reduced. All of the patients who experienced a hypersensitivity reaction were successfully re-challenged with paclitaxel and were able to continue their therapy uninterrupted. Conclusion Discontinuing dexamethasone pre-medication altogether after two uneventful infusions or decreasing the dose of dexamethasone paclitaxel pre-medication are both safe alternatives to high-dose steroid pre-medications recommended in product labeling.

The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P = 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P = 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P = 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died.

Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers. These include ASPSCR1-TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs. Here we examined the functional properties of the ASPSCR1-TFE3 fusion oncoprotein, defined its target promoters on a genome-wide basis and performed a high-throughput RNA interference screen to identify which of its transcriptional targets contribute to cancer cell proliferation. We first confirmed that ASPSCR1-TFE3 has a predominantly nuclear localization and functions as a stronger transactivator than native TFE3. Genome-wide location analysis performed on the FU-UR-1 cell line, which expresses endogenous ASPSCR1-TFE3, identified 2193 genes bound by ASPSCR1-TFE3. Integration of these data with expression profiles of ASPS tumour samples and inducible cell lines expressing ASPSCR1-TFE3 defined a subset of 332 genes as putative up-regulated direct targets of ASPSCR1-TFE3, including MET (a previously known target gene) and 64 genes as down-regulated targets of ASPSCR1-TFE3. As validation of this approach to identify genuine ASPSCR1-TFE3 target genes, two up-regulated genes bound by ASPSCR1-TFE3, CYP17A1 and UPP1, were shown by multiple lines of evidence to be direct, endogenous targets of transactivation by ASPSCR1-TFE3. As the results indicated that ASPSCR1-TFE3 functions predominantly as a strong transcriptional activator, we hypothesized that a subset of its up-regulated direct targets mediate its oncogenic properties. We therefore chose 130 of these up-regulated direct target genes to study in high-throughput RNAi screens, using FU-UR-1 cells. In addition to MET, we provide evidence that 11 other ASPSCR1-TFE3 target genes contribute to the growth of ASPSCR1-TFE3-positive cells. Our data suggest new therapeutic possibilities for cancers driven by TFE3 fusions. More generally, this work establishes a combined integrated genomics/functional genomics strategy to dissect the biology of oncogenic, chimeric transcription factors., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Pancreatic cancer is one of the most devastating solid tumor malignancies. Majority of patients have metastatic disease upon diagnosis. Five-year survival is less than 5% for all stages of pancreatic cancer combined. Gemcitabine has been the standard palliative therapy for advanced pancreatic cancer over the past decade. Many studies attempted to develop combination regimens, but they failed to improve overall survival in the metastatic settings. The combination of gemcitabine and erlotinib was the first combination regimen to show improvements in survival benefit compared with gemcitabine alone and became the first-line combination therapy in advanced pancreatic cancer. The search for better treatment strategies to prolong survival in this deadly disease is very much needed and is a worldwide effort. There were many studies presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting focused on first-line therapy in metastatic pancreatic cancer. This article highlights a few phase III and II studies that have demonstrated encouraging results.

Pancreatic cancer represents the 4th leading cause of cancer deaths in the United States. Surgical resection remains the only potential curative approach. Current standard adjuvant therapy is gemcitabine monotherapy for 6 months. This year several trials investigated other combinations with or without molecular target agents, with or without concurrent radiation attempting to optimize adjuvant therapy. Several abstracts presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting are highlighted here and will be further discussed in this review article. Abstracts #4012, #4059, and TPS226 added immunotherapy to adjuvant treatment. Abstract #4034 demonstrated lack of efficacy by adding either cetuximab or bevacizumab to known adjuvant therapies. Abstract e14625 combined S-1 to gemcitabine and abstract #4113 demonstrated a positive correlation between symptoms and CA 19-9 levels with the length of survival.

Majority of pancreatic cancers are unresectable upon diagnosis. Palliative chemotherapy is usually administered in an attempt of prolonging survival potentially and providing quality of life. Gemcitabine has been the solo player in the field of pancreatic cancer treatment after replacing 5-FU since 1997. How to treat a patient with advanced pancreatic cancer failing to respond or progressing after gemcitabine is a true challenge. No established second-line treatment exists yet. Chinese herbal medicine PHY906 provides cytoprotective effects without dampening the anti-tumor activity of chemotherapeutic agents. Several combinations such as S-1/gemcitabine, GTX, FOLFIRINOX showed promising results in retrospective studies. Among single agents, erlotinib and Src inhibitor failed to show seemingly benefit, while abraxane and pemetrexed deserve further investigation.

Pancreatic cancer is sometimes called a "silent killer" because it is often not diagnosed until it is advanced. It remains the fourth leading cause of cancer-related death in the United States. Gemcitabine has been the front line therapy for advanced pancreatic cancer over the past 10 years. Over this time period, survival benefit has not been able to improve substantially from studies of gemcitabine-based combination therapy. A breakthrough to improve treatment options in this setting is needed. In the 2010 ASCO Gastrointestinal Cancers Symposium in Orlando, Florida, USA, several abstracts were presented to explore new agents or combinations as first-line therapy in locally advanced or metastatic settings. In this article, we review and summarize the findings from these studies.

Objectives: Recent meta-analysis has demonstrated that nesiritide may worsen renal function (RF) in patients with acute decompensated heart failure (ADHF). A nesiritide utilization evaluation (NUE) performed in our institution reflected that belief of RF preservation was one reason leading to nesiritide overuse. This study examined the effect of nesiritide on RF in patients evaluated in this NUE., Research Design and Methods: Nesiritide patient records from October 1, 2003 to March 31, 2004 were reviewed (n = 162). Pertinent demographics, laboratory and medication utilization data were obtained., Main Outcome Measures: Changes in creatinine clearance (CrCl) and percentage of patients demonstrating worsening RF (decrease in CrCl > or = 25%) during diuretics therapy before nesiritide initiation and during nesiritide initiation and during nesiritide therapy were compared using Wilcoxon Signed-Ranks test and Chi-Square respectively., Results: Overall, the addition of nesiritide to IV furosemide did not clinically change RF as compared to the use of IV furosemide alone (% change in CrCl: 0 vs. -2.13 mL/min, p = 0.023), although the difference was statistically significant. When categorized into different RF, there is no different in CrCl changes between the nesiritide group and the IV furosemide alone group. There is also no difference in terms of number of patients experiencing > or = 25% reduction in CrCl overall. Changes in RF were also not correlated to dose or duration of therapy., Conclusion: Nesiritide did not demonstrate significant impact in RF. Larger studies that examine RF in a more systematic and controlled manner and relate changes in RF to clinical outcomes are necessary to further elucidate the risk versus benefit profile of nesiritide.

Background and Objectives: Nesiritide is a new vasodilator approved for decompensated heart failure (DHF). Compared with nitroglycerin, nesiritide improves haemodynamics and symptoms in the first 3 h of therapy. However, nesiritide is more expensive than nitroglycerin (US$380-1500 daily vs. US$2-5 daily). Since its approval in the US in late 2001, nesiritide use has increased dramatically in our institution. Nesiritide has become a focus of our multidisciplinary drug utilization initiative, aimed at performing a nesiritide utilization evaluation (NUE) and developing a nesiritide usage guideline., Methods: Medical records of patients who received nesiritide from 1 October 2003 to 31 March 2004 were reviewed. Nesiritide utilization pattern was presented to the initiative group for guideline development., Results: A total of 162 records were reviewed. A 22.6% of inappropriate usage was reported. The most significant inappropriate usage was in patients who received the agent for precardiac valvular surgery optimization, followed by those for diuresis in non-cardiac-related fluid overload states. The median duration of nesiritide therapy was 6 days (range 1-94). The median length of stay (LOS) in our institution was 14 days (National statistics DHF LOS: 5.3 days). Eliminating inappropriate nesiritide usage can lead to a potential of US$141 886 savings per year., Conclusion: Based on the results, a 48-h nesiritide restriction policy was implemented. Usage beyond 48 h requires Heart Failure Service approval. Future NUE will evaluate the effectiveness of this policy. The overall management of DHF also needs to be evaluated to improve efficiency of care.