A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING: National Institutes of Health and National Cancer Institute.

Osteolytic Sarcoidosis of the Orbital Roof Masquerading as a Malignant Orbital Lesion.

A 51-year-old man without a significant past medical history presented with 4 weeks of progressive swelling and drooping of his left upper eyelid. A CT of the left orbit revealed an osteolytic mass lesion in the area of the lacrimal gland. A left orbitotomy with excisional biopsy was performed. The excised tissue was sent for infectious workup and histopathological examination, which revealed osteolytic sarcoidosis. The patient was treated with systemic and local injection corticosteroids, and followed over 10 months without evidence of recurrence. Systemic workup with CT of his chest, abdomen, and pelvis revealed no further evidence of sarcoidosis. To the best of the authors knowledge, this is the first report of an otherwise healthy patient presenting with isolated osteolytic sarcoidosis of the orbit and a negative systemic workup.

Systemic Allergic Response in the Setting of a Metallic Intraorbital Foreign Body With Intraoperative Magnet-Assisted Retrieval.

A 12-year-old boy with a past medical history of nickel allergy was referred to our service after sustaining an air rifle injury with a retained BB in his left inferior orbit. On examination, he had a palpable orbital mass and systemic urticaria. Plain films demonstrated a spherical metallic foreign body adjacent to the left inferior orbital rim. Given his worsening systemic reaction despite oral antihistamine therapy, decision was made to remove the foreign body. In the operating room, the Allergan Magna Finder-a prepackaged, sterile device normally used for retrieval of a port used in tissue expansion surgery-was placed over the inferior conjunctiva of the lower eyelid. With the magnet holding gentle anterior traction on the foreign body, it was easily dissected and removed. The patient tolerated the procedure well, and had rapid resolution of his systemic allergic response following removal of the BB.

Thymic Origin Neuroendocrine Carcinoma Metastasizing to the Orbit in an Otherwise Asymptomatic Patient.

A 39-year-old man without a significant medical history developed headaches, OS swelling, and limited left-sided ocular motility. An ultrasound of the left orbit and head MRI revealed a retro-orbital mass. A partial left anterior orbitotomy with partial resection was performed, and histopathologic examination of the resected tumor portion was suggestive of a neuroendocrine carcinoma. A large, anterior mediastinal mass was found on chest imaging, and the patient was diagnosed with a primary thymic neuroendocrine tumor. To the authors' knowledge, this is the first report of an otherwise healthy patient presenting with the mass effects of a thymic neuroendocrine carcinoma metastasis to the orbital tissues before detection of the primary thymic malignancy.

Evaluation of uveal and capsule biocompatibility of a single-piece hydrophobic acrylic intraocular lens with ultraviolet-ozone treatment on the posterior surface.

PURPOSE: To evaluate a single-piece hydrophobic acrylic intraocular lens (IOL) with ultraviolet-ozone (UV-O3) treatment on the posterior surface and compare it with an identical untreated IOL in a rabbit model. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Study IOLs were implanted in the right eyes and control IOLs in the left eyes of 10 New Zealand rabbits. Slitlamp examinations were performed 1 to 6 weeks postoperatively. Neodymium:YAG (Nd:YAG) posterior capsulotomy was performed in both eyes of 5 rabbits after the 4-week slitlamp examination. At 6 weeks, the rabbits were killed humanely and their globes were enucleated. Capsular bag opacification was scored from the posterior aspect (Miyake-Apple view), and the eyes were processed for histopathology. RESULTS: At 4 weeks, the mean posterior capsule opacification (PCO) scores were 0.88 ± 0.33 (SD) in the study eyes and 2.55 ± 1.13 in the control eyes (P=.003, 2-tailed paired t test). Performance of Nd:YAG posterior capsulotomy was similar in both groups. Gross postmortem examination also showed statistically less peripheral PCO in eyes with the study IOLs than in control eyes. There was no difference in histopathologic findings between study eyes and control eyes and no signs of untoward inflammation or toxicity in any eye evaluated. CONCLUSIONS: Treatment of the posterior surface of a single-piece hydrophobic acrylic IOL with UV-O3 appears to prevent PCO, likely by increasing adhesion between the posterior capsule and the IOL while retaining uveal biocompatibility. Performance of Nd:YAG posterior capsulotomy was similar between treated IOLs and untreated IOLs.

Pathologic evidence of pseudoexfoliation in cases of in-the-bag intraocular lens subluxation or dislocation.

PURPOSE: To provide complete histopathologic evaluation of explanted capsular bags that spontaneously dislocated in the late postoperative period, with the main objective being to assess the presence of pseudoexfoliation (PXF) material. SETTING: Goethe-University Frankfurt, Frankfurt, Germany, and John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Retrospective case series. METHODS: Standard gross and light microscopy and complete histopathology were performed on explanted subluxated and dislocated capsular bags containing an intraocular lens (IOL) or a capsular tension ring (CTR) and an IOL. Questionnaires were sent to explanting surgeons, and a patient chart review was performed, when available. RESULTS: The specimens were represented by capsular bags containing an IOL (n = 37) or an IOL-CTR (n = 3). The IOLs included 3-piece hydrophobic acrylic (n = 13), 1-piece hydrophobic acrylic (n = 7), 3-piece silicone (n = 6), 1-piece hydrophilic acrylic (n = 6), 3-piece hydrophilic acrylic (n = 2), and 1-piece poly(methyl methacrylate) (PMMA) (n = 6) designs; all CTRs were PMMA. Soemmering ring formation was mild in 8 specimens, moderate in 18 specimens, and severe in 14 specimens. Excessive contraction of the capsular bag with capsulorhexis phimosis was observed in 24 specimens. Twenty-six specimens had histopathologic evidence of PXF; 13 had a clinical history or evidence of PXF. CONCLUSIONS: Pseudoexfoliation might be implicated in a larger proportion of late in-the-bag IOL subluxations and dislocations than previously thought as a result of significant clinical underdiagnosis. This might indicate a need for new considerations during the preoperative and postoperative cataract surgery assessments and follow-up.

Long-term uveal and capsular biocompatibility of a new accommodating intraocular lens.

PURPOSE: To evaluate long-term uveal and capsular biocompatibility of a new accommodating intraocular lens (IOL). SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Bilateral phacoemulsification was performed in 14 rabbits; 1 eye received the accommodating IOL (Fluidvision) and the other received a hydrophobic acrylic control IOL. Slitlamp examinations were performed at postoperative weeks 1 to 4 and months 2, 3, 4, and 6. Six rabbits were humanely killed at 2 months and 8 rabbits at 6 months. After gross examination with the Miyake-Apple view, selected IOLs were removed for implant cytology. All globes were then sectioned and processed for histopathologic examination. RESULTS: Uveal biocompatibility of study and control IOLs was similar in clinical and pathologic examinations up to 6 months postoperatively. In the study group, anterior capsule opacification appeared absent and posterior capsule opacification (PCO) was significantly less than in the control group. At the gross examination at 6 months, central PCO was 0.8 ± 0.5 (SD) in the study IOLs and 3.7 ± 0.4 in the control IOLs (P < .0001, 2-tailed paired t test). Histopathologic examination confirmed the relative lack of capsule opacification in study eyes compared with controls and the absence of untoward inflammatory reaction or toxicity in all eyes. CONCLUSIONS: The accommodating IOL maintained an expanded capsular bag secondary to the large size of the haptic elements without significant contact with the anterior capsule. This appeared to prevent overall capsular bag opacification and to retain uveal and capsular biocompatibility.

Visual aberrations in a multifocal intraocular lens with injection-related scratches.

UNLABELLED: We describe the case of a 70-year-old woman who had phacoemulsification and implantation of a single-piece hydrophobic acrylic multifocal intraocular lens (IOL). Following surgery, the patient experienced blurring, positive dysphotopsia, impaired night vision, and glare. After 2 years, optic damage likely related to the IOL injection procedure was noted. The IOL was successfully exchanged. The uncorrected distance visual acuity was 20/20, and the patient reported no further visual aberrations. Gross and microscopic examination revealed large linear scratches on the central part of the optic. Scheimpflug photography with densitometry analysis of the area of the anterior scratches revealed extremely high levels of surface backlight scattering (227 computer-compatible tape units). Modulation transfer function and Badal images of the explanted IOL and of a control IOL did not differ significantly. This report suggests that severe defects/damage such as those described would likely be clinically significant in IOLs with specialized optics and warrant immediate removal/exchange of a damaged multifocal IOL. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Electron transfer dissociation (ETD) of peptides containing intrachain disulfide bonds.

The fragmentation chemistry of peptides containing intrachain disulfide bonds was investigated under electron transfer dissociation (ETD) conditions. Fragments within the cyclic region of the peptide backbone due to intrachain disulfide bond formation were observed, including: c (odd electron), z (even electron), c-33 Da, z+33 Da, c+32 Da, and z-32 Da types of ions. The presence of these ions indicated cleavages both at the disulfide bond and the N-Cα backbone from a single electron transfer event. Mechanistic studies supported a mechanism whereby the N-Cα bond was cleaved first, and radical-driven reactions caused cleavage at either an S-S bond or an S-C bond within cysteinyl residues. Direct ETD at the disulfide linkage was also observed, correlating with signature loss of 33 Da (SH) from the charge-reduced peptide ions. Initial ETD cleavage at the disulfide bond was found to be promoted amongst peptides ions of lower charge states, while backbone fragmentation was more abundant for higher charge states. The capability of inducing both backbone and disulfide bond cleavages from ETD could be particularly useful for sequencing peptides containing intact intrachain disulfide bonds. ETD of the 13 peptides studied herein all showed substantial sequence coverage, accounting for 75%-100% of possible backbone fragmentation.

Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality.

The pharmacokinetics of cyclophosphamide (CY) and its metabolites hydroxycyclophosphamide and carboxyethylphosphoramide mustard were determined in 75 patients receiving targeted oral busulfan followed by i.v. CY ((T)BU/CY) and in 147 patients receiving i.v. CY followed by total body irradiation (CY/TBI) in preparation for hematopoietic cell transplantation (HCT). In the (T)BU/CY patients only, the association of the pharmacokinetic data with liver toxicity, relapse, and survival was evaluated. CY was infused at 60 mg/kg/day over 1 or 2 hours on 2 consecutive days; the majority of patients had BU levels targeted to a steady state plasma concentration (Css) of 800-900 ng/mL. Systemic exposure (i.e., area under the concentration-time curve [AUC]) of CY, hydroxycyclophosphamide, and carboxyethylphosphoramide mustard was measured. Liver toxicity was assessed as the development of hepatic sinusoidal obstruction syndrome (SOS). CY metabolism was highly variable and age dependent. (T)BU/CY-treated patients had lower AUC(CY) (P < .0001), higher AUC(HCY) (P < .0001), and higher AUC(CEPM) (P = .15) than CY/TBI-conditioned patients. Among patients receiving (T)BU/CY, 17 (23%) developed SOS, and there were no statistically significant associations between the AUC of CY or its metabolites and SOS, nonrelapse mortality, relapse, or survival (all P >.15). In conclusion, CY exhibits conditioning-regimen dependent pharmacokinetics and pharmacodynamics, suggesting that lowering CY doses is unlikely to improve outcomes to (T)BU/CY. Alternative strategies, such as administering i.v. busulfan or CY before BU, should be explored.

Rapid quantitation of cyclophosphamide metabolites in plasma by liquid chromatography-mass spectrometry.

A method is described for the quantification of two metabolites of cyclophosphamide, specifically 4-hydroxycyclophosphamide (HCy), and carboxyethylphosphoramide mustard (CEPM). Plasma HCy is derivatized to the phenylhydrazone which is quantitated by LC-MS monitoring the chloride adduct of the derivative. The LLOQ based on material applied to the system is approximately 20 fmol. Plasma CEPM concentration is determined using LC-MS with a deuterated internal standard. Both assays have 50-fold dynamic range and require less than 4h to complete. The development of this rapid analytical method makes it feasible to adjust the dose of cyclophosphamide based on the pharmacokinetic disposition of HCy and CEPM in hopes of decreasing nonrelapse mortality in cancer patients.

Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant.

When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54-120 mg/kg). The mean AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment.

Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation.

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.

Diminishing the risk of nonrelapse mortality in hematopoietic stem cell transplantation: Prediction of exposure to the cyclophosphamide metabolite carboxyethylphosphoramide mustard.

OBJECTIVES: Our objectives were (1) to develop a population pharmacokinetic model for cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide mustard (a reporter for nonrelapse mortality) in hematopoietic stem cell transplantation patients and (2) to validate a Bayesian approach to dosing. METHODS: In this study 147 patients received intravenous infusions of 60 mg. kg -1. d -1 cyclophosphamide for 2 days, followed by 12 to 14.4 Gy total body irradiation. A population model was developed to fit concentration-time data of cyclophosphamide and metabolites. Bayesian prediction of the area under the curve (AUC) was validated by dividing the data set into an index set (98 patients) and validation set (49 patients). Parameters from the index data set were used as priors. RESULTS: Cyclophosphamide elimination was best described by noninducible and inducible routes producing 4-hydroxycyclophosphamide. Induction was described by a zero-order maximum fold of induction-type increase in enzyme level. The prediction of the AUC of carboxyethylphosphoramide mustard was clinically accurate and precise (mean prediction error = -3.5% and root mean squared prediction error = 12.2%) with data limited to 5 to 6 points obtained in the first 16 hours. However, the AUC of 4-hydroxycyclophosphamide was overestimated (mean prediction error = 16.9%-23.6%). Several alternative models did not improve the result. CONCLUSION: The integrated mechanism-based model describes the pharmacokinetics of cyclophosphamide and carboxyethylphosphoramide mustard. Accurate modeling of 4-hydroxycyclophosphamide is limited by its chemical instability. Exposure to carboxyethylphosphoramide mustard could be accurately and precisely predicted with minimal data obtained over a 16-hour period after the first dose, offering the potential of pharmacokinetically guided dosing to reduce the nonrelapse mortality rate.