A New Technique for Harvesting Limbal Stem Cell Tissue for Transplantation Using an Automated Microkeratome and a Novel Globe-Fixation System.

PURPOSE: To introduce an unprecedented technique, instrumentation, and setup for the superficial limbus harvest from the human cadaver donor whole globe. METHODS: We studied several superficial limbus harvest alternatives, developed a preferred approach with our available instruments, and optimized it on a handful of (seropositive) cadaver donors of whole globes. RESULTS/TECHNIQUE: The globe was pressurized to about normal intraocular pressure by viscoelastic injection through the optic nerve stump. The globe was then mounted on a dynamic globe fixator that maintained a negative pressure in its stabilizing socket. Exertion of the negative pressure effectively elevated globe intraocular pressure (to over 40 mm Hg) and made the corneoscleral wall tight. The socket was then held tilted to the left side for about 35 to 40 degrees to put the limbal zone horizontally and mildly "chin-up." Next, the microkeratome was put on the uppermost and exposed limbus of the globe and activated, and the socket was rotated clockwise under the microkeratome head and its oscillating blade, allowing an effective 360-degree revolution of the microkeratome head around the limbal belt (for a right-handed operator and a counterclockwise cut). CONCLUSIONS: We consistently succeeded in peeling intact 360-degree strips of the smooth superficial limbus by using blades with varying depths. Our method can be further equipped and optimized and be used by the eye banks and the surgeons for keratolimbal grafting as a more efficient limbal stem cell tissue harvest technique.

Triamcinolone-loaded self nano-emulsifying drug delivery systems for ocular use: An alternative to invasive ocular surgeries and injections.

Inflammation of the posterior segment of the eye is a severe condition and hard to cure as delivery of drugs to the inflammation site is inefficient. Currently, the primary treatment approach is ocular surgery or invasive ocular injections. Herein, we designed and developed a topically self nano-emulsifying drug delivery system (SNEDDs) to deliver triamcinolone acetonide (TCA) to the posterior segment of the eye. A screening based on TCA solubility was conducted on each excipient followed by preparation of various formulations using different ratios of the selected excipients. Vesicles of optimized SNEDDs had less than 100 nm size and spherical morphology. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay showed self-emulsified vesicles have relatively high safety on retinal pigment epithelium (RPE) cell line. Furthermore, efficient cellular uptake of coumarin 6-loaded SNEDDs in RPE using confocal laser scanning microscopy (CLSM) was confirmed. In addition, an in-vivo study using hematoxylin and eosin (H&E) staining revealed that 14 days of topical treatment of albino rabbit eyes with TCA-loaded SNEDDs was safe and no sign of tissue destruction and inflammation was detected in different parts of the eye sections including cornea, sclera, retina, and optic nerve. Also, the CLSM images from topically treated eyes with coumarin 6 (a hydrophobic, fluorescent drug model) loaded SNEDDs, showed that the optimized SNEDDs could properly penetrate toward the posterior segments of the eye especially the retina, posterior parts of the choroid, and sclera. Considering the outstanding results obtained by ocular tissue penetration and low toxicity, prepared SNEDDs, have the potential to be used as a topical administration for treating posterior segment disorders of the eye through an utterly non-invasive route and TCA-loaded SNEDDs could be an alternative for TCA intravitreal and intra conjunctival injections.

Machine learning for classification of cutaneous sebaceous neoplasms: implementing decision tree model using cytological and architectural features.

BACKGROUND: This observational study aims to describe and compare histopathological, architectural, and nuclear characteristics of sebaceous lesions and utilized these characteristics to develop a predictive classification approach using machine learning algorithms. METHODS: This cross-sectional study was conducted on Iranian patients with sebaceous tumors from two hospitals between March 2015 and March 2019. Pathology slides were reviewed by two pathologists and the architectural and cytological attributes were recorded. Multiple decision tree models were trained using 5-fold cross validation to determine the most important predictor variables and to develop a simple prediction model. RESULTS: This study assessed the characteristics of 123 sebaceous tumors. Histopathological findings, including pagetoid appearance, neurovascular invasion, atypical mitosis, extensive necrotic area, poor cell differentiation, and non-lobular tumor growth pattern, as well as nuclear features, including highly irregular nuclear contour, and large nuclear size were exclusively observed in carcinomatous tumors. Among non-carcinomatous lesions, some sebaceoma and sebaceous adenoma cases had features like high mitotic activity, which can be misleading and complicate diagnosis. Based on multiple decision tree models, the five most critical variables for lesion categorization were identified as: basaloid cell count, peripheral basaloid cell layers, tumor margin, nuclear size, and chromatin. CONCLUSIONS: This study implemented a machine learning modeling approach to help optimally categorize sebaceous lesions based on architectural and nuclear features. However, studies of larger sample sizes are needed to ensure the accuracy of our suggested predictive model.

The Antitumor Effect of Topotecan Loaded Thiolated Chitosan-Dextran Nanoparticles for Intravitreal Chemotherapy: A Xenograft Retinoblastoma Model.

Purpose: This research intended to fabricate the thiolated chitosan-dextran nanoparticles (NPs) containing topotecan (TPH-CMD-TCS-NPs) to assess the ability of NPs in improving the efficacy of intravitreal chemotherapy of retinoblastoma in a rabbit xenograft model. Methods: The coacervation process was used to produce the NPs. The cellular uptake of Cyanine-3 (CY3)-labeled NPs were investigated in human retinoblastoma Y79 cells using confocal microscopy. Also, the prepared TPH-CMD-TCS-NPs were tested in vitro by the tetrazolium dyes II (XTT) and flow cytometry in order to assess their cytotoxicity. In addition, a rabbit xenograft model of retinoblastoma was developed to test the antitumor effectiveness of TPH-CMD-TCS-NPs through intravitreal administration. Results: NPs had a mean diameter, polydispersity index, and zeta potential of 30 ± 4 nm, 0.24 ± 0.03 and +10 ± 3 mV, respectively. NPs (IC50s 40.40 compared to 126.20 nM, P = 0.022) were more effective than free topotecan as a dose-based feature. The tumor reaction to intravitreal chemotherapy with NPs was measured by evaluating the percentage of necrosis in the tumor tissue (91 ± 2%) and vitreous seeds (89 ± 9%) through hematoxylin and eosin (H&E) staining. In comparison with the control group, the TPH-CMD-TCs-NPs treated group showed a significant decrease in tumor volume seven days after the intravitreal injection (P = 0.039). No significant changes were found in the ERG parameters after the intravitreal injection of TPH-CMD-TCs-NPs or TPH (P > 0.05). Conclusion: This investigation revealed definitive antitumor efficacy of TPH-CMD-TCS-NPs by intravitreal administration in the rabbit xenograft retinoblastoma model.

Histopathology Study of Patients with Delayed Mustard Gas Keratopathy 30 Years After Exposure.

Background & Objective: Delayed mustard gas keratopathy (DMGK) is the main chronic outcome in eye-chemical injured patients. The aim of this study was the histopathological evaluation of mustard-exposed cornea after more than 30 years. Methods: Fourteen corneas after Lamellar keratoplasty were evaluated in this study. Corneal tissues were prepared by histologic methods and stained by H&E. Results: The main histopathological findings in these cases were the presence of severe stromal edema and corneal scar. In the sections with visible superficial epithelium, subepithelial bullae formation was observed. Focal or diffuse disruption of Bowman's membrane and replacement with fibrosis were also seen. There was no evidence of stromal vascularization and inflammation in all specimens. Conclusion: After more than 30 years, an extensive corneal scar is seen in sulfur mustard exposed patients. Scar tissue without vascularization and fibroblastic proliferation is the main finding in the sulfur mustard exposed cornea. This pathology result is different from other scars. No evidence of inflammation or immune cell infiltration should be considered in managing DMGK.

Intracameral Injection of Methotrexate for Treatment of Epithelial Ingrowth.

Purpose: To report a case of intracameral injection of methotrexate (MTX) to treat the epithelial ingrowth that occurred following glaucoma surgery. Methods: A case report of a 40-year-old male with epithelial ingrowth after implantation of Ahmed glaucoma valve. Results: The patient was treated with 11 doses of weekly intracameral MTX (400 mg/0.1 ml). Clinical evidence of recurrence was not observed after 11 months of follow-up. Discussion: Intracameral MTX can be used as an alternative for the treatment of epithelial ingrowth.

Orbital Dirofilariasis Masquerading As Orbital Rhabdomyosarcoma.

Purpose: To report a 12-year-old patient with a rapid growing orbital mass and imaging findings suggestive of rhabdomyosarcoma that was found to be dirofilariasis after mass resection. Case Report: We describe a 12-year-old patient with a rapid growing orbital mass involving medial part of orbit and medial rectus muscle and imaging findings suggestive of rhabdomyosarcoma. Histopathologic examination showed the mass to be composed of granulomatous inflammation and the thread-like object to be Dirofilaria repens. The patient was well post-operation without morbidity. In this paper, we describe distinct clinical features and imaging findings of this interesting case. Conclusion: Deep orbital lesions due to dirofilariasis, as in our case, is extremely rare. It is important to add dirofilariasis to the differential diagnosis of orbital mass lesions. Attention to the imaging clues, as provided in this report, can be helpful.

Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

To evaluate the ocular safety of intravitreal carboplatin and digoxin injections as a new intravitreal chemotherapy option for retinoblastoma tumor vitreous seeds. Eighteen rabbits were divided randomly into three groups to receive intravitreal injection of Digoxin (6 rabbits), Carboplatin (7 rabbits), or Saline (5 rabbits). In every group, one eye randomly treated with 10 µg Digoxin in 0.1 cc or 1 µg Carboplatin or Saline, and the contralateral eye was considered as the control. All groups underwent three consecutive injections of the drugs with 1-week intervals. Baseline electroretinography (ERG) was recorded from both eyes of all the animals prior to injection and was repeated 1st day, 1st week, and 1st month after the last injection. All rabbits were sacrificed 1 month after the last injection, and histological studies were done. Mean a and b wave amplitudes decreased significantly at 1st day, 1st week, and 1st month after the last intravitreal injection of 10 µg Digoxin in comparison with other groups (p-value: .02). Contradictory, 1 µg Carboplatin injected eyes had minimal ERG changes. There were some nonspecific ERG changes with unclear clinical significance in non-injected contralateral control eyes of Digoxin and Carboplatin groups in comparison with the control eyes of the Saline group. Histological studies revealed considerable neural retinal atrophy in injected eyes of the Digoxin group. Intravitreal 10 µg Digoxin might have more local ocular toxicity in comparison with intravitreal Carboplatin in albino rabbit eyes. Future studies should assess the induced toxicity of intravitreal injection of these drugs on the non-injected contralateral eye.

Comparison of Topical Pigment Epithelium-Derived Factor (PEDF) with Topical Bevacizumab for Accelerating the Regression of Corneal Neovascularization in an Experimental Model of Rabbit Corneal Angiogenesis.

Purpose: To evaluate the anti-angiogenic effect of topical administration of Pigment epithelium-derived factor (PEDF) on the reduction of corneal neovascularization (NV) in comparison to topical Bevacizumab.Methods: 18 eyes of 18 New Zealand rabbits were enrolled. Corneal NV was induced by a 7-0 silk suture. After suture removal, rabbits were randomly divided into three groups. In every group, one eye randomly treated with topical bevacizumab or topical PEDF or saline for 14 days. The area and length of neovascularization were measured by Image J. Histological studies were done in three groups.Results: After 14 days, the mean decrease of corneal NV length was 1.84 ± 0.17 mm (P < .001) in PEDF group and 1.6 ± 0.07 mm (P < .001) in bevacizumab group which was significantly more than the saline group (P = .001 and P < .001, respectively). There was no significant difference between PEDF and bevacizumab group in the reduction of corneal NV length (P = .85). The mean decrease of corneal NV area was 4.94 ± 0.55 mm2 (P < .001) in PEDF group and 4.23 ± 0.29 mm2 in the bevacizumab group (P < .001). PEDF and bevacizumab significantly decreased corneal NV area in comparison to the saline group (p = .017, p = .001, respectively). The mean decrease of corneal NV area did not show a significant difference between PEDF and bevacizumab groups (P = .72).Conclusion: Topical PEDF might be an effective and safe treatment option as bevacizumab in a short-term use, indicating that it is as good as the standard. However, long-term effect is required to be investigated.

Increasing the efficiency of the retinoblastoma brachytherapy protocol with ultrasonic hyperthermia and gold nanoparticles: a rabbit model.

PURPOSE: This study purposed to evaluate the efficacy of brachytherapy with the modality of ultrasonic hyperthermia in the presence of gold nanoparticles (GNPs) on an ocular retinoblastoma tumor in an animal model of the rabbit. MATERIALS AND METHODS: A retinoblastoma tumor was induced by the injection of the human cell line of Y79 in rabbit eyes (n = 41). After two weeks, tumor size reached a diameter of about 5-7 mm. Seven groups were involved: control, GNPs injection, hyperthermia, hyperthermia with GNPs injection, brachytherapy with I-125, a combination of hyperthermia and brachytherapy, and a combination of brachytherapy, hyperthermia and, GNPs. The tumor area was measured using B-mode ultrasound images on the zero-day and at the end of the third week. The groups were evaluated for a histopathological study of tumor necrosis. RESULTS: There was a significant difference between the relative area changes of tumor in the combination group with the other study groups (p < .05). The results of histopathologic studies confirmed the necrosis of living retinoblastoma cells. CONCLUSION: Combination therapy of brachytherapy and hyperthermia with GNPs reduces the relative size of the tumor. This method increases the necrosis percentage of retinoblastoma and significantly reduces the retinoblastoma mass in the rabbit eyes.

Solitary neurofibroma of the orbit with intracerebral extension associated with ocular surface melanocytoma: a case report.

Solitary or isolated neurofibroma is uncommonly observed in the orbit. Neurofibromas typically involve peripheral nerves and occasionally the cranial nerves. A 29-year-old man presented with recent onset left eye proptosis and exotropia. Physical examination was positive for hyperpigmented lesions of the ipsilateral ocular surface and hard palate. Imaging revealed an infiltrative orbital mass with extension through superior orbital fissure into the brain. There was also bone defect of greater sphenoid wing. Medial orbitotomy was performed to obtain biopsies of the orbital mass and the pigmented ocular surface lesions. Histopathologic diagnosis of neurofibroma was confirmed for the former and melanocytoma for the latter. His symptoms and examinations remained stable during the follow up. This case is unique due to several features, including extensive intracerebral spread of orbital neurofibroma in a patient without definite diagnosis of neurofibromatosis type 1 and association with ipsilateral ocular surface melanocytoma and palatal pigmented lesions. ABBREVIATIONS: CT: computed tomography; GFAP: glial fibrillary acid protein; MRI: magnetic resonance imaging; NF-1: neurofibromatosis type 1.

Safety and Bioavailability of Complete and Half-Dose Intravitreal Ziv-Aflibercept in an Experimental Model: Contralateral Eye Study.

BACKGROUND AND OBJECTIVE: To evaluate the safety and bioavailability of complete and half-dose of intravitreal ziv-aflibercept (IVZ) in an experimental model. MATERIALS AND METHODS: Thirty-two eyes of 16 male rabbits received one IVZ injection under anesthesia and the operating microscope. All right and left eyes received 1,250 µg/0.05 mL and 625 µg/0.05 mL of ziv-aflibercept, respectively. Then, rabbits were randomly allocated to four groups (four rabbits in each group). The rabbits were euthanized at predesignated intervals (at 24, 168, 336, and 720 hours), and the eyes were enucleated. Indirect ophthalmoscopy, vitreous sampling, and electrophysiological recordings were obtained before euthanization. Histological examination was performed after enucleation. Vitreous samples were evaluated by enzyme-linked immunosorbent assay to measure the concentration of aflibercept. RESULTS: No serious drug-related ocular inflammation and toxicity or systemic adverse events were identified. Electroretinogram findings showed no significant difference to the baseline measurements. Remaining vitreal concentrations of ziv-aflibercept injection for the 625 µg/mL group were 416 µg/mL, 349 µg/mL, 124 µg/mL, 41.2 µg/mL, and 18.1 µg/mL (± 10 µg/mL) and for the 1,250 µg/mL group were 833 µg/mL, 737 µg/mL, 284 µg/mL, 87.3 µg/mL, and 38.2 µg/mL (± 10 µg/mL), at zero, 24, 168, 336, and 720 hours after injection, respectively. The vitreous concentration of aflibercept was analyzed by one-compartment model. The area under curve from time 0 to the end point (AUC last) was 147,637 hours × µg/mL for the complete dose group (1,250 µg/0.05mL) and 68,498 hours × µg/mL for the half-dose group (625 µg/0.05 mL). The assessed vitreous half-life of ziv-aflibercept was 113 hours in both groups. CONCLUSIONS: IVZ proved to be safe and well tolerated, even in the complete dose group. It seems to be a cost-effective therapeutic option for the treatment of retinal vascular diseases. However, the long-term safety and efficacy of intravitreal ziv-aflibercept remain unknown. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:785-790.].

A Rare Case of Congenital Orbital Cystic Neuroblastoma in an Infant.

Neuroblastoma, a relatively common tumor in infants, is rarely present at birth. A solid mass is the typical appearance of this neoplasm, while cystic formation is uncommon. Congenital cystic neuroblastoma is extremely rare and no previous report exists of its occurrence in the orbit. A newborn girl was referred with an extremely large mass on the right side of her face on the third day of her life. Prenatal ultrasonography had revealed a large mass (80 × 80 mm) in the frontal area. MRI revealed a heterogeneous mass composed of cystic and solid, contrast-enhancing components. Excisional biopsy was successfully performed and histopathologic diagnosis of neuroblastoma was confirmed. Systemic workup was negative for involvement of other organs and levels of catecholamine metabolites of serum and urine (homovanillic acid and vanillylmandelic acid) were normal. Postoperative course was uneventful with complete healing of the anophthalmic socket and normal physical and mental growth and development of the infant. To our knowledge, this is the first report of congenital cystic neuroblastoma primarily arising in the orbit.

Case Report: Scleral Metastasis of Esophageal Squamous Cell Carcinoma.

In this report, a case of ocular scleral metastasis was reported in a patient with a past history of esophageal squamous cell carcinoma. The patient was a 58-year-old male who was admitted to Urmia Imam Khomeini Hospital, Urmia, Iran, 8 years ago with progressive dysphasia. Seven years after initial diagnosis and treatment of esophageal cancer, the patient had no signs or symptoms of the disease. But 2 months ago, he was referred to the hospital due to ocular swelling, redness and watering. Pathologic examination of the excised lesion at Farabi Hospital reported metastasis of squamous cell carcinoma to the connective tissue of the sclera.

Spontaneous Rupture of Lacrimal Gland Pleomorphic Adenoma: Pivotal Role in Masquerading Orbital Cellulitis.

The authors aim to report a 68-year-old patient presenting with acute swelling and redness of orbital area diagnosed initially as orbital cellulitis. Surgical excision was decided based on clinical and imaging findings with the diagnosis of pleomorphic adenoma of the lacrimal gland. Lacrimal gland pleomorphic adenoma usually presents with painless gradual swelling of upper eyelid. In an exceptionally rare circumstance, this case showed acute orbital inflammation, and imaging findings of orbital inflammation mostly focused around the cystic space of the lacrimal gland tumor. Histologic evaluation confirmed a ruptured cystic space of pleomorphic adenoma with foreign body-type inflammatory reaction. The authors propose spontaneous rupture of cystic space in the lacrimal gland pleomorphic adenoma as underlying mechanism for acute presentation of this tumor. Imaging and clinical characteristics and also prognostic implication of this phenomenon are discussed.

Orbital basal cell adenoma: A case report.

Basal cell adenomas are uncommon benign epithelial tumors of the salivary gland. Orbital basal cell adenoma of the orbit has not been described before. The authors report an unusual case of basal cell adenoma that presented in the orbit. Immunohistochemical findings for the tumor are also described.

Evaluation of Nanocarrier Targeted Drug Delivery of Capecitabine-PAMAM Dendrimer Complex in a Mice Colorectal Cancer Model.

Capecitabine, an effective anticancer drug in colorectal cancer chemotherapy, may create adverse side effects on healthy tissues. In the present study, we first induced colon adenocarcinoma with azoxymethane, a carcinogen agent, and then investigated the potentiality of polyamidoamine (PAMAM) dendrimer to improve capecitabine therapeutic index and decrease its adverse side effects on healthy tissues like liver and bone marrow. Other variables such as nanoparticle concentrations have also been investigated. Drug loading concentration (DLC) and encapsulation efficiency (EE) were calculated for capecitabine/dendrimer complex. Experimental results showed an increase in DLC percentage resulted from elevated capecitabine/dendrimer ratio. Capecitabine/dendrimer complex could reduce tumor size and adverse side effects in comparison with free capecitabine form.

Clinicopathologic Assessment of Ocular Adnexal Lymphoproliferative Lesions at a Tertiary Eye Hospital in Iran.

BACKGROUND: The most common type of ocular lymphoma is non-Hodgkin lymphoma (NHL), categorized into two groups: indolent (slow growing) and aggressive (rapid growing). Differentiating benign reactive lymphoid hyperplasia (RLH) from malignant ocular adnexal lymphoma (OAL) is challenging. Histopathology, immunohistochemistry (IHC) and ow cytometry have been used as diagnostic tools in such cases. MATERIALS AND METHODS: In this retrospective case series, from 2002 to 2013 at Farabi Eye Center, 110 patients with ocular lymphoproliferative disease were enrolled. Prevalence, anatomical locations, mean age at diagnosis and the nal diagnosis of the disease with IHC were assessed. Comparison between previous pathologic diagnoses and results of IHC was made. Immunoglobulin light chains and B-cell and T-cell markers and other immuno-phenotyping markers including CD20, CD3, CD5, CD23, CD10, CYCLIND1 and BCL2 were evaluated to determine the most accurate diagnosis. The lymphomas were categorized based on revised European-American lymphoma (REAL) classi cation. RESULTS: Mean age±SD (years) of the patients was 55.6 ±19.3 and 61% were male. Patients with follicular lymphoma, large B-cell lymphoma or chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) tended to be older. Nine patients with previous diagnoses of low grade B-cell lymphoma were re-evaluated by IHC and the new diagnoses were as follows: extranodal marginal zone lymphoma(EMZL) (n=1), SLL(n=1), mantle cell lymphoma (MCL) (n=3), reactive lymphoid hyperplasia RLH (n=2). Two cases were excluded due to poor blocks. Flow cytometry reports in these seven patients revealed SLL with positive CD5 and CD23, MCL with positive CD5 and CyclinD1 and negative CD23, EMZL with negative CD5,CD23 and CD10. One RLH patient was negative for Kappa/Lambda and positive for CD3 and CD20 and the other was positive for all of the light chains, CD3 and CD20. Orbit (49.1%), conjunctiva (16.1%) and lacrimal glands (16.1%) were the most common sites of involvement. CONCLUSIONS: Accurate pathological classi cation of lesions is crucial to determine proper therapeutic approaches. This can be achieved through precise histologic and IHC analyses by expert pathologists.

Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1ß were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.