Association of Higher-Dose Fluoroquinolone Therapy With Serious Adverse Events in Older Adults With Advanced Chronic Kidney Disease.

Importance: Population-based data are needed to inform the safe prescribing of fluoroquinolone antibiotics to patients with advanced chronic kidney disease (CKD). Objective: To quantify the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event in patients with advanced CKD newly prescribed a fluoroquinolone at a higher vs a lower dose. Design, Setting, and Participants: This population-based cohort study in Ontario, Canada (January 1, 2008, to March 17, 2020) used linked health care data to identify new users of fluoroquinolone antibiotics. Participants included adults 66 years or older with advanced CKD (an estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 but not receiving dialysis). Data analysis was performed from January 1 to April 30, 2021. Exposures: A new prescription for a higher-dose fluoroquinolone (ciprofloxacin, 501-1000 mg/d; levofloxacin, 501-750 mg/d; or norfloxacin, 401-800 mg/d) vs a lower-dose fluoroquinolone (ciprofloxacin, 500 mg/d; levofloxacin, 250-500 mg/d; or norfloxacin, 400 mg/d). Main Outcomes and Measure: The primary outcome was the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event. Secondary outcomes included a hospital visit with sepsis, retinal detachment or other tendinopathies, all-cause hospitalization, all-cause mortality, and sudden cardiac death. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on baseline health. Weighted risk ratios and risk differences were obtained using modified Poisson regression and binomial regression, respectively. Results: Of 11 917 patients (median age, 83 years [IQR, 77-89 years]; 7438 women [62.4%]; median eGFR, 25 [IQR, 21-28] mL/min/1.73 m2) included in the analysis, 5482 (46.0%) received a higher-dose and 6435 (54.0%) received a lower-dose fluoroquinolone. After weighting, the primary composite outcome-a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event-occurred in 68 of 5482 patients (1.2%) treated with a higher-dose fluoroquinolone and in 47 of 5516 (0.9%) treated with a lower-dose fluoroquinolone (weighted risk ratio, 1.45 [95% CI, 1.01-2.08]; weighted risk difference, 0.39% [95% CI, 0.01%-0.76%]). The risk of sepsis, retinal detachment, all-cause hospitalization, all-cause mortality, and sudden cardiac death did not differ significantly between groups. Conclusions and Relevance: These findings suggest that older patients with advanced CKD who were prescribed a fluoroquinolone at a higher-than-recommended dose were significantly more likely to experience the composite outcome of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event, although the absolute risk of these events was less than 2%.

Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators.

Deferoxamine (DFO) is an FDA-approved iron-chelating agent which shows good therapeutic efficacy, however, its short blood half-life presents challenges such as the need for repeated injections or continuous infusions. Considering the lifelong need of chelating agents for iron overload patients, a sustained-release formulation that can reduce the number of chelator administrations is essential. Here, injectable hydrogel formulations prepared by integrating crosslinked hyaluronic acid into Pluronic F127 for an extended release of DFO nanochelators are reported. The subcutaneously injected hydrogel shows a thermosensitive sol-gel transition at physiological body temperature and provides a prolonged release of renal clearable nanochelators over 2 weeks, resulting in a half-life 47-fold longer than that of the nanochelator alone. In addition, no chronic toxicity of the nanochelator-loaded hydrogel is confirmed by biochemical and histological analyses. This injectable hydrogel formulation with DFO nanochelators has the potential to be a promising formulation for the treatment of iron overload disorders.

Phase I Study of Lenvatinib and Capecitabine with External Radiation Therapy in Locally Advanced Rectal Adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation. METHODS: In this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer. RESULTS: A total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes. CONCLUSION: The combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified. CLINICAL TRIAL REGISTRATION: NCT02935309.

Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models.

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Pharmacogenomic-based personalized medicine: Multistakeholder perspectives on implementational drivers and barriers in the Canadian healthcare system.

Pharmacogenomics (PGx)-based personalized medicine (PM) is increasingly utilized to guide treatment decisions for many drug-disease combinations. Notably, London Health Sciences Centre (LHSC) has pioneered a PGx program that has become a staple for London-based specialists. Although implementational studies have been conducted in other jurisdictions, the Canadian healthcare system is understudied. Herein, the multistakeholder perspectives on implementational drivers and barriers are elucidated. Using a mixed-method qualitative model, key stakeholders, and patients from LHSC's PGx-based PM clinic were interviewed and surveyed, respectively. Interview transcripts were thematically analyzed in a stepwise process of customer profiling, value mapping, and business model canvasing. Value for LHSC located specialist users of PGx was driven by the quick turnaround time, independence of the PGx clinic, and the quality of information. Engagement of external specialists was only limited by access and awareness, whereas other healthcare nonusers were limited by education and applicability. The major determinant of successful adoption at novel sites were institutional champions. Patients valued and approved of the service, expressed a general willingness to pay, but often traveled far to receive genotyping. This paper discusses the critical pillars of education, awareness, advocacy, and efficiency required to address implementation barriers to healthcare service innovation in Canada. Further adoption of PGx practices into Canadian hospitals is an important factor for advancing system-level changes in care delivery, patient experiences, and outcomes. The findings in this paper can help inform efforts to advance clinical PGx practices, but also the potential adoption and implementation of other innovative healthcare service solutions.

Regorafenib, an investigational agent for the treatment of cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma is a prevalent gastrointestinal cancer with a high mortality rate. A limited number of cholangiocarcinoma patients are diagnosed with early-stage disease but unfortunately, most patients present with an advanced-stage disease which is not amenable to curative surgical resection. AREAS COVERED: We discuss regorafenib, a multi-kinase inhibitor, which has been investigated as a therapeutic agent in advanced stage biliary tract cancer patients in phase II trials. We examined the efficacy and toxicity of this agent and its potential in this patient population in the future. We also provide further insights on novel approaches to optimize the efficacy of regorafenib in cholangiocarcinoma patients. EXPERT OPINION: The recent phase II trials of single-agent regorafenib in advanced stage biliary tumors revealed a modest activity in non enriched patient population and is currently part of the national comprehensive cancer network (NCCN) guidelines (Level 2B) in the refractory setting. However, more opportunities for this agent exist in combination approaches with other therapeutics such as immune checkpoint inhibitors. It is also important to recognize that the paradigm has significantly shifted for targeted therapy to more specific and more potent tyrosine kinase inhibitors targeting specific actionable genes.

Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

Using the Multitheory Model to Predict Initiation and Sustenance of Physical Activity Behavior Among Osteopathic Medical Students.

CONTEXT: The multitheory model (MTM) is a newly developed fourth-generation theoretical framework that addresses both initiation and sustenance of health behavior change. Studies have shown that the MTM is efficacious in predicting a range of health behaviors. OBJECTIVE: To assess the utility of the MTM in predicting initiation and sustenance of physical activity behavior among osteopathic medical students. METHODS: In this cross-sectional study, a volunteer convenience sample was recruited from an osteopathic medical school student population at a university in the southeastern region of the United States. An online survey was used to collect self-reported data on sociodemographic information and MTM constructs. Multiple linear regression using the enter method for modeling was performed to determine the predictive ability of the MTM constructs. RESULTS: Of the 135 participants, 52.6% were women and 67.7% were white. The initiation model explained 25.8% of the variance (adjusted R2=0.238). Behavioral confidence was a statistically significant predictor of initiation of physical activity behavior change. The sustenance model explained 41.7% of the variance (adjusted R2=0.402). Changes in social environment and emotional transformation were statistically significant predictors of sustenance of physical activity behavior change. CONCLUSION: The MTM appears to be a robust theoretical framework for designing behavior change interventions to increase physical activity among osteopathic medical students.

The Role of Angiogenesis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers and is the second leading cause of cancer-related deaths worldwide. The hypervascular nature of most HCC tumors underlines the importance of angiogenesis in the pathobiology of these tumors. Several angiogenic pathways have been identified as being dysregulated in HCC, suggesting they may be involved in the development and pathogenesis of HCC. These data provide practical targets for systemic treatments such as those targeting the vascular endothelial growth factor receptor and its ligand. However, the clinical relevance of other more recently identified angiogenic pathways in HCC pathogenesis or treatment remains unclear. Research into molecular profiles and validation of prognostic or predictive biomarkers will be required to identify the patient subsets most likely to experience meaningful benefit from this important class of agents.

Single Institute Experience With Methylphenidate and American Ginseng in Cancer-Related Fatigue.

BACKGROUND: Single therapy with methylphenidate or American ginseng contributes to the reduction in cancer-related fatigue (CRF) with different pharmacologic mechanisms and is relatively safe. However, the safety and efficacy of treating CRF with methylphenidate and AG combination therapy is unknown. AIM: The primary objective was to assess the clinical safety and the change in fatigue with numerical rating scale (NRS) on the Edmonton Symptom Assessment Scale (ESAS) after intervention with methylphenidate and AG combination therapy. METHODS: We reviewed the electronic medical records of 857 patients seen in our Palliative Medicine outpatient clinic between February 1, 2015, and December 31, 2015. Fatigue was assessed by NRS on ESAS. Toxicity was reviewed on clinician's documents. RESULTS: We identified 28 patients who were prescribed a combination of methylphenidate (10-40 mg/d) and AG (2000 mg/d). Ten patients did not comply with the combination therapy. Three patients had stage 2 adverse effects. Fifteen patients completed prescribed combination therapy per instructions. The mean time interval between pre- and postintervention follow-up was 30.5 days (standard deviation [SD]: 7.78). There was a significant reduction in the fatigue score (mean score 6.93-4.13) from the pre- to postscore records (mean: -2.8; SD: 1.61; P < .0002* [*refers to statistically significant]). Sixty percent of patients reported significant reduction in fatigue (cutoff value: ≥3; reduction in fatigue score from baseline: 80% ≥2, 60% ≥3, and 46.7% ≥4). CONCLUSION: In our retrospective medical record review, the combination treatment of methylphenidate and AG had no discernible associated toxicities and showed potential clinical benefit in CRF.

Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers.

INTRODUCTION: Aromatase inhibitors (AIs) are routinely used for the adjuvant treatment of women with hormone receptor-positive early breast cancer. AIs are widely prescribed in the postmenopausal setting, as they are effective at preventing recurrence. However, their use is complicated by significant adverse effects, particularly arthralgia, noted in up to 50% of treated patients, and thereby affects quality of life and AI compliance. The mechanism by which AIs cause arthralgia is largely unknown, although there is a growing body of literature which suggests that there may be multiple intersecting mechanisms. Areas covered: This review describes the evidence for the mechanistic basis of AI arthralgia as well as potential pathways that could contribute to the development of AI associated arthralgia. Expert opinion: Interplay of multiple factors, such as interpatient variability in AI metabolism, possibly related to pharmacogenetic factors, the sudden decline of estrogen synthesis, vitamin D status, as well as upregulation of cytokines and inflammation pathways may precipitate or exacerbate muscle and joint pain are linked during AI therapy. However, much more research is needed in this area given the frequency and severity of AI-associated arthralgia.

Phase I study of pre-operative continuous 5-FU and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma.

PURPOSE: The standard of care in locally advanced rectal cancer is preoperative treatment with fluoropyrimidine-based chemoradiotherapy. Sorafenib works synergistically with radiation and inhibits Ras/Raf, PDFGR, and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-fluorouracil (5-FU) and radiation in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level, with an expansion cohort at the maximum tolerated dose. A 3+3 dose escalation design was used. Radiation was given in 28 fractions at 1.8 Gy (50.4 Gy) day 1-5 at all dose levels. Initial dose of sorafenib was 200mg qd and titrated up to 400mg BID to determine the MTD. Standard dose of infusional 5-FU was used (225 mg/m(2)/24h). Patients underwent surgery 6-10 weeks after neoadjuvant therapy. RESULTS: Between August 2011 and August 2014, 17 patients (median age of 54 years) were enrolled. After toxicities requiring dose interruptions were observed in cohort 1 (2 patients with grade 2 (G2) and grade 3 (G3) hand foot skin reaction and 1 patient with G2 mucositis), the protocol was amended, changing administration of chemotherapy and sorafenib from daily to days 1-5 only. With the amended protocol, the primary G3 toxicity was hypertension in 2 patients at the 200-mg adjusted dose level (day1-5) and 1 patient at the 400-mg twice daily dose level. One patient had G3 ALT elevation at 400mg, and no grade IV toxicities were observed. G1 and G2 toxicities included hand-foot skin reaction, diarrhea, mucositis, nausea, fatigue, and proctitis. No perioperative complications were seen. Two patients refused to undergo surgery. The pathological complete remission (pCR) rate was 33%, and downstaging was observed in 85.7% of patients. Median neoadjuvant rectal cancer score was 8.7. CONCLUSIONS: With the changed dosing schedule, this regimen was very well tolerated. The tumor pCR and downstaging rates are encouraging and support further clinical investigation of this regimen.

Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban.

Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing.

Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation.

INTRODUCTION: Recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) carries a poor prognosis. The aim of our study was to assess the safety and efficacy of sorafenib in patients with recurrent HCC following LT. METHODS: A prospectively maintained LT database was retrospectively analyzed for patients with recurrent HCC following LT between 2001 and 2011-34 patients. Patients were divided into two groups based on whether they were prescribed sorafenib (n = 17) or not prescribed sorafenib (n = 17). The primary endpoint was overall survival. RESULTS: There were no significant differences between the two groups analyzed. Seventeen patients were on sorafenib for recurrent HCC, with a mean daily dose of ~444 mg. Mean duration of treatment was ~10 months. Side effects included: thrombocytopenia, diarrhea, rising transaminases, fatigue, hand-foot skin reaction, and nausea. Survival in the sorafenib vs. non-sorafenib group was greater at three-, six-, nine-, and 12-month intervals and overall survival. CONCLUSION: Sorafenib can be well tolerated and safe in patients with recurrent HCC following LT and may be associated with a modest survival benefit. To our knowledge, this is the largest single-center retrospective analysis of patients prescribed sorafenib for recurrent HCC after LT.

CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge.

The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The U.S. Food and Drug Administration (FDA) authorized use of sorafenib for "unresectable HCC", an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC.

Safe use of sorafenib in a patient undergoing salvage liver transplantation for recurrent hepatocellular carcinoma after hepatic resection.

Sorafenib, a multikinase inhibitor targeting angiogenesis, cell survival, and proliferation in hepatocellular carcinoma (HCC) is a standard therapy for advanced stage disease. However, its utilization as neoadjuvant therapy is under investigation and remains an off label indication. The use of sorafenib in pre-liver transplant setting raises caveats associated with risk of bleeding, wound healing deficiencies, and hepatic decompensation. Herein, we report the case of a patient who after exhibiting HCC relapse post-hepatic resection underwent sorafenib therapy and subsequent transplantation. Sorafenib was well tolerated, and no adverse events were noticed. The use of sorafenib as neoadjuvant therapy in pre-transplant patients is feasible and deserves investigation in large clinical settings.

Radiologic complete response with sirolimus and sorafenib in a hepatocellular carcinoma patient who relapsed after orthotopic liver transplantation.

BACKGROUND: No standard therapies have been established for the treatment of recurrent hepatocellular carcinoma (HCC) after liver transplantation. DISCUSSION: Sirolimus is a mTOR inhibitor which has been used as an immunosuppressive medication in patients who are at high risk of tumor reoccurrence after liver transplantation. Sorafenib is a multikinase inhibitor approved for the treatment of advanced HCC. However the role of sorafenib in patients with HCC reoccurrence after liver transplantation is unclear. RESULTS: Combination of sirolimus and sorafenib appears to have synergistic effect when treating HCC in preclinical settings. We report a case of a post-liver transplant patient treated with sorafenib and sirolimus for hepatic HCC recurrence who exhibited complete radiologic response after 5A months of therapy.