Opioid-induced respiratory depression suspected of drug interaction in a prostate cancer patient: a case report.

BACKGROUND: Many of the drugs used for the treatment and alleviation of symptoms in cancer patients are known to inhibit or induce cytochrome P450 (CYP). Therefore, it is important to pay attention to the drug interactions of opioid analgesics that are metabolized by CYPs, because for example when using oxycodone metabolized by CYP3A4, it is possible that the effect will be attenuated or enhanced by the concomitant use of drugs that induce or inhibit CYP3A4. Aprepitant, an antiemetic drug used in many patients receiving anticancer drugs, is known as a moderate competitive inhibitor of CYP3A4. We experienced a case of respiratory depression caused by opioids, which was suspected to be caused by a drug interaction with antiemetics especially aprepitant. CASE DESCRIPTION: The patient was a 72-year-old man. He had been treated with continuous oxycodone infusion for perianal pain associated with the rectal invasion of prostate cancer. No comorbidities other than renal dysfunction were observed. Oxycodone treatment was started at 48 mg/day, and was increased to 108 mg/day, and then the pain decreased. Once the pain was controlled, chemotherapy was planned. Antiemetics (dexamethasone, palonosetron, and aprepitant) were administered before anticancer drug administration. Approximately 3 hours after antiemetics administration and before the administration of the anticancer drugs, a ward nurse noticed that oversedation and respiratory depression had occurred. When the patient was called, he immediately woke up and was able to talk normally, so the anticancer drugs were administered as scheduled. About 2 hours after the nurse noticed oversedation, the attending physician reduced the dose of oxycodone infusion to 48 mg/day. After that, his drowsiness persisted, but his respiratory condition improved. Despite reducing the dose of oxycodone to less than half, the pain remained stable at numeric rating scale (NRS) 0-1, without the use of a rescue dose. The patient was discharged from the hospital 36 days after the administration of anticancer drugs, without any problems. CONCLUSIONS: The cause of respiratory depression in this case was thought to be a combination of factors, including drug interactions between oxycodone and antiemetics, and oxycodone accumulation due to renal dysfunction.

Investigation of Parotid Cancer Cases Diagnosed as Bell's Palsy at Initial Presentation: The 23 Year Experience of a Single Institution.

Objective: Facial nerve paralysis due to parotid carcinoma is sometimes misdiagnosed as Bell's palsy. This study aimed to compare patients with parotid carcinoma with and without accompanying facial nerve paralysis and to capture the features of patients misdiagnosed with Bell's palsy. Methods: Among 209 patients, 42 (20%) had facial nerve paralysis. Of these 42 patients, 14 had received treatment for facial nerve paralysis without being diagnosed with parotid carcinoma (pretreatment group); the remaining 28 patients had not received any pretreatment and were diagnosed with parotid carcinoma at the initial visit to our hospital (no pretreatment group). This study compared patients with and without facial nerve paralysis and the pretreatment and no pretreatment groups. Results: The 42 patients with facial nerve paralysis had a significantly higher frequency of pain/tenderness and adhesion with surrounding tissues, significantly higher proportions of deep lobe tumors, and a significantly higher proportion of high-grade malignancy. In addition, the disease-specific and disease-free 5 year survival rates were significantly poorer in patients with than in those without facial nerve paralysis. The comparison between the pretreatment and no pretreatment groups revealed no significant differences in any factors nor survival rate. Five patients in the pretreatment group complained of palpable masses or pain/tenderness at the time of their initial treatment for paralysis. Conclusion: Patients with parotid carcinoma who present with facial nerve paralysis at the initial visit have a significantly poorer prognosis. The number of cases in the pretreatment group can be reduced by performing a detailed examination, which can potentially improve the prognosis.

The Efficacy and Safety of EUS-Guided Gallbladder Drainage as a Bridge to Surgery for Patients with Acute Cholecystitis.

BACKGROUND AND AIM: This study aimed to compare the efficacy and safety of endoscopic ultrasound-guided gallbladder drainage and percutaneous transhepatic gallbladder drainage as a bridge to surgery in patients with acute cholecystitis unfit for urgent cholecystectomy. METHODS: This retrospective study included 46 patients who underwent cholecystectomy following endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) or percutaneous transhepatic gallbladder drainage (PTGBD) for acute cholecystitis in NTT Tokyo Medical Center. We surveyed 35 patients as the EUS-GBD group and 11 patients as the PTGBD group, and compared the rate of technical success of the cholecystectomy and periprocedural adverse events. A 7-F, 10-cm double pigtail plastic stent was used for ultrasound-guided gallbladder drainage. RESULTS: The rate of technical success of cholecystectomy was 100% in both groups. Regarding postsurgical adverse events, no significant difference was noted between the two groups (EUS-GBD group, 11.4%, vs. PTGBD group, 9.0%; p = 0.472). CONCLUSIONS: EUS-GBD as a BTS seems to be an alternative for patients with AC because it can ensure lower adverse events. On the other hand, there are two major limitations in this study--the sample size is small and there is a risk of selection bias.

Clinical outcomes of permanent stenting with endoscopic ultrasound gallbladder drainage.

BACKGROUND/AIMS: Endoscopic ultrasound gallbladder drainage (EUS-GBD) is gaining attention as a treatment method for cholecystitis. However, only a few studies have assessed the outcomes of permanent stenting with EUS-GBD. Therefore, we evaluated the clinical outcomes of permanent stenting using EUS-GBD. METHODS: This was a retrospective, single-center cohort study. The criteria for EUS-GBD at our institution are a high risk for surgery, inability to perform surgery owing to poor performance status, and inability to obtain consent for emergency surgery. EUS-GBD was performed using a 7-Fr double-pigtail plastic stent with a dilating device. The primary outcomes were the recurrence-free rate of cholecystitis and the late-stage complication-avoidance rate. Secondary outcomes were technical success, clinical success, and procedural adverse events. RESULTS: A total of 41 patients were included in the analysis. The median follow-up period was 168 (range, 10-1,238) days. The recurrence-free and late-stage complication-avoidance rates during the follow-up period were 95% (38 cases) and 90% (36 cases), respectively. There were only two cases of cholecystitis recurrence during the study period. CONCLUSION: EUS-GBD using double-pigtail plastic stent was safe and effective with few complications, even in the long term, in patients with acute cholecystitis.

Pigmentation and TYRP1 expression are mediated by zinc through the early secretory pathway-resident ZNT proteins.

Tyrosinase (TYR) and tyrosinase-related proteins 1 and 2 (TYRP1 and TYRP2) are essential for pigmentation. They are generally classified as type-3 copper proteins, with binuclear copper active sites. Although there is experimental evidence for a copper cofactor in TYR, delivered via the copper transporter, ATP7A, the presence of copper in TYRP1 and TYRP2 has not been demonstrated. Here, we report that the expression and function of TYRP1 requires zinc, mediated by ZNT5-ZNT6 heterodimers (ZNT5-6) or ZNT7-ZNT7 homodimers (ZNT7). Loss of ZNT5-6 and ZNT7 function results in hypopigmentation in medaka fish and human melanoma cells, and is accompanied by immature melanosomes and reduced melanin content, as observed in TYRP1 dysfunction. The requirement of ZNT5-6 and ZNT7 for TYRP1 expression is conserved in human, mouse, and chicken orthologs. Our results provide novel insights into the pigmentation process and address questions regarding metalation in tyrosinase protein family.

Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation.

Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5-ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments. However, this process remains incompletely understood. Here, using genetically-engineered chicken DT40 cells, we first determined that Zrt/Irt-like protein (ZIP) transporters that are localized to the compartments of the early secretory pathway play only a minor role in the ALP activation process. These transporters included ZIP7, ZIP9, and ZIP13, performing pivotal functions in maintaining cellular homeostasis by effluxing zinc out of the compartments. Next, using purified ALP proteins, we showed that zinc metalation on ALP produced in DT40 cells lacking ZNT5-ZNT6 heterodimers and ZNT7 homodimers is impaired. Finally, by genetically disrupting both ZNT5 and ZNT7 in human HAP1 cells, we directly demonstrated that the tissue-nonspecific ALP-activating functions of both ZNT complexes are conserved in human cells. Furthermore, using mutant HAP1 cells, we uncovered a previously-unrecognized and unique spatial regulation of ZNT5-ZNT6 heterodimer formation, wherein ZNT5 recruits ZNT6 to the Golgi apparatus to form the heterodimeric complex. These findings fill in major gaps in our understanding of the molecular mechanisms underlying zinc ectoenzyme activation in the compartments of the early secretory pathway.

Ependymal cyst in the lumbar spine associated with cauda equina compression.

There are many reports of extradural ependymal cysts in the literature; however, reports of intradural ependymal cysts are very rare and there has been no prior mention of an ependymal cyst originating from the filum terminale. In this report we present the case of a 31-year-old woman with an ependymal cyst that caused cauda equina compression, and discuss the clinical profile of the case in terms of symptoms, diagnostic images, pathohistological findings, and surgical procedures. To our knowledge, this is the first report of an ependymal cyst that caused cauda equina compression. The cyst was successfully treated by excision of the cyst during careful intraoperative monitoring to prevent neurological damage to the conus medullaris and cauda equina.

Objective assessment of reduced invasiveness in MED. Compared with conventional one-level laminotomy.

Microendoscopic discectomy (MED) has been accepted as a minimally invasive procedure for lumbar discectomy because of the small skin incision and short hospital stay required for this surgery. However, there are few objective laboratory data to confirm the reduced systemic responses in the early phase after this procedure. In order to substantiate the reduced invasiveness of MED compared to microdiscectomy (MD) or procedures involved in one-level unilateral laminotomy, the invasiveness of each surgical procedure was evaluated by measuring serum levels of biochemical parameters reflective of a post-operative inflammatory reaction and damage to the paravertebral muscles. Thirty-three patients who underwent lumbar discectomy or one-level unilateral laminotomy (MED in 15 cases, MD in 11 cases and one-level unilateral laminotomy in 7 cases with lumbar spinal canal stenosis) were included in this study. The serum levels of C-reactive protein (CRP) and creatine phosphokinase (CPK) were measured at 24 h after operation. Interleukin-6 (IL-6) and Interleukin-10 (IL-10) were measured at 2, 4, 8 and -24 h following the surgery to monitor the inflammatory response to the respective surgery. The post-operative serum CRP levels from both the MD and MED groups were significantly lower than those from the open laminotomy group. However, there was no significant difference in these serum levels between the MED and MD groups. The levels of IL-6 and IL-10 in the MED group during the first post-operative day were also significantly lower than those in the laminotomy group. When the MED and MD groups were compared, the IL-6 levels in the MED group were lower than in MD group at 2, 4 and 8 h after surgery, but the differences were not statistically significant. However, the level was significantly lower in the MED group at 24 h after surgery. In terms of IL-10, no significant difference was noted between the MED and MD groups over the study period. The changes in serum levels of post-operative inflammatory: markers (CRP, IL-6 and IL-10) in the early phase indicated reduced inflammatory reactions in MED as well as in MD when compared with classical open unilateral laminotomy. These data draw a direct link between the lower level of the inflammatory response and reduced invasiveness of MED. However, an indicator for muscle damage (CPK) appeared not to be affected by the type of surgical procedure used to correct disc herniation.

Experimental spinal fusion with recombinant human bone morphogenetic protein-2 delivered by a synthetic polymer and beta-tricalcium phosphate in a rabbit model.

STUDY DESIGN: An experimental animal study to achieve posterolateral intertransverse process spine fusion with recombinant bone morphogenetic protein in combination with a new delivery system. OBJECTIVE: To evaluate the efficacy of a new synthetic biodegradable bone-inducing material containing recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone-graft substitute for posterolateral intertransverse process fusion in a rabbit model. SUMMARY OF BACKGROUND DATA: rhBMP-2, a powerful bone-inducing cytokine, has been used as a bone graft substitute in combination with animal-derived collagen to achieve spinal fusion in animal models. However, the minimum dose of rhBMP-2 required to obtain solid posterolateral intertransverse process fusion was high on the basis of previous reports (>100 microg in rabbit models). To improve the efficacy, performance of rhBMP-2, and the safety of the delivery system for this protein, a more sophisticated system is required. METHODS: To fabricate one implant for one-side L4-L5 intertransverse process fusion, beta-tricalcium phosphate (beta-TCP) powder (300 microg), a polymer gel (PLA-DX-PEG block copolymer; 300 microg) and rhBMP-2 (7.5, 15, or 30 microg) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, two implants were placed on both sides (1 per side) by surgery so as to bridge the transverse processes of adult New Zealand white rabbits (n = 27). In control animals, implants without rhBMP or autogenous cortico-cancellous bone chips from the iliaccrest were placed in a similar location. The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology. RESULTS: Rabbits that received 15 or 30 microg of rhBMP-2 showed consistent fusion. However, solid fusion was seen in 2 of 5 rabbits with autografting and rabbits that received 7.5 microg of rhBMP-2. Fusion was not observed in the rabbits that did not receive rhBMP-2. CONCLUSIONS: Consistent spinal fusion was obtained by implanting a biodegradable bone-inducing implant composed of beta-TCP, PLA-DX-PEG, and rhBMP-2 within a period of 6 weeks. The rhBMP-2 doses required for the spinal fusion were significantly lower than those reported previously.

Palsy of the C5 nerve root after midsagittal-splitting laminoplasty of the cervical spine.

STUDY DESIGN: The imaging characteristics of postoperative C5 nerve root palsy after midsagittal-splitting laminoplasty for cervical myelopathy, including those observed on plain radiography, computed tomography, and magnetic resonance imaging, were analyzed. OBJECTIVE: To investigate the imaging findings that predict occurrence of C5 nerve root palsy after midsagittal-splitting laminoplasty. SUMMARY OF BACKGROUND DATA: There have been several reports on imaging findings for postoperative nerve root palsy after open-door laminoplasty. However, there have been no detailed reports on imaging characteristics that predict the occurrence of nerve root palsy after midsagittal-splitting laminoplasty. METHODS: The study included 45 consecutive patients undergoing midsagittal-splitting laminoplasty with sufficient pre- and postoperative imaging examinations: 27 patients with cervical spondylotic myelopathy (CSM), 14 patients with ossification of the posterior longitudinal ligament (OPLL), and 4 patients with cervical disc herniation. Characteristics of pre- and postoperative plain radiographs, computed tomography scans, and magnetic resonance images were compared between the patients with and those without C5 nerve root palsy. RESULTS: Palsy of the C5 nerve root developed in 4 patients, and did not develop in 41 patients. Of the four patients with C5 nerve root palsy, one had CSM and the other three had OPLL. The incidence of C5 nerve root palsy involved 3 of 14 patients with OPLL patients (21.4%) and 1 of 31 patients without OPLL (3.2%) (P = 0.08). For both diseases, the patients with palsy tended to have increased postoperative cervical lordosis (P = 0.21). As for anterior compression on the spinal cord at C3, the P value for the comparison between the group with and the group without palsy was 0.07 for preoperative compression and 0.01 for postoperative compression. CONCLUSIONS: The preliminary data suggest that patients who have OPLL with marked anterior compression on spinal cord at C3 can be at risk for postoperative C5 nerve root palsy after midsagittal-splitting laminoplasty. Also, a postoperative increase in cervical lordosis may be the cause of postoperative nerve root palsy.

Analysis of the spastic gait caused by cervical compression myelopathy.

We evaluated the spastic gait of patients with cervical myelopathy with a three-dimensional gait analysis system. Fifteen patients with cervical myelopathy (S group) were investigated. The results obtained were compared with those of normal volunteers (N group). The S group exhibited significant reduction of gait velocity and step length (p < 0.01). In the knee flexion-extension curve, two peaks were observed in the N group. In the S1 group (symptomatic period <1 year), the anterior peak was not smooth, whereas in the S2 group (symptomatic period >1 year), no peak was observed. The pelvis tilted to the side of the standing leg in the N group. However, in the S1 group, this tilting was much less pronounced, and in some patients tilting toward the nonsupporting leg was observed. In the S2 group, the pelvis again tilting toward the supporting side was observed.