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.

Dermatomyositis Identified During Palliative Care Management for Chemotherapy-Associated Pain: A Case Report.

Background: Skin disorders and neuropathy often occur as side effects of chemotherapy. We encountered a patient who was treated for drug-induced skin symptoms, but the symptoms did not improve, and he was eventually diagnosed as having dermatomyositis. Case presentation: A 71-year-old man underwent chemotherapy with regorafenib in February 2020 for the postoperative recurrence of sigmoid colon cancer, but treatment was discontinued after about 2 months owing to the appearance of skin symptoms, which were thought to be side effects of regorafenib. Subsequently, his symptoms further worsened, and he was hospitalized 3 weeks after the appearance of the initial skin symptoms, and a palliative care team was asked to relieve his back pain caused by the drug-induced skin symptoms. Erythema was widely observed on the lower back and limbs, and he experienced needle stick-like pain. Furthermore, the patient demonstrated difficulty in lifting both upper limbs. As acetaminophen was effective for his pain, the dose was slowly increased with careful observation. The cause of the patient's muscle weakness was unclear, and after careful discussion of the possible causes among specialists in dermatology, neurology, and rheumatoid arthritis, a diagnosis of dermatomyositis associated with the malignant tumor was made about 10 days after his admission. The patient's symptoms gradually improved with steroid pulse treatment (methylprednisolone 1 g/day for 3 days) followed by high-dose gamma globulin treatment (2.5 g/day for 5 days), and the patient was discharged 48 days after admission. Discussion: Because this patient was referred to a palliative care team for the purpose of relieving pain caused by skin symptoms associated with chemotherapy, a crucial point is the symptoms were treated as side effects of the chemotherapy from the beginning. As neuropathy can occur as a result of chemotherapy, the pain and muscle weakness could be explained at the time; however, the symptoms continued to worsen even after the chemotherapy was stopped. Because the symptoms were not typical of polymyositis/dermatomyositis, diagnosis of the patient was delayed, even though he was treated in each specialized department. Our present case indicates that paraneoplastic syndrome should always be kept in mind when treating cancer patients.

[A case of UFT-induced complete response against multiple lung metastases of hepatocarcinoma].

There are still no effective treatments against advanced hepatocarcinoma. One case of advanced hepatocarcinoma with multiple lung metastases, successfully treated with UFT, is reported here. After TAE in another hospital, the patient was refered to our hospital for treatment of multiple lung metastases. PIVKA-II and AFP decreased to normal levels after UFT was administered, and the multiple lung metastases disappeared as well. There are 13 cases including this one in which UFT was effective for hepatocarcinoma with multiple lung metastases. UFT is a possible home treatment because it is an orally administered anti-cancer drug that improves the patient's QOL. As UFT is one of the effective treatments for advanced hepatocarcinoma, it will be necessary to accumulate more data concerning its use, to apply it in the future.

Plasma proteomics of pancreatic cancer patients by multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis (2D-DIGE): up-regulation of leucine-rich alpha-2-glycoprotein in pancreatic cancer.

We investigated the aberrant expression of plasma proteins in patients with pancreatic cancer. High-abundance plasma proteins (albumin, transferrin, haptoglobin, alpha-1-antitrypsin, IgG and IgA) were depleted by use of an immuno-affinity column, and low-abundance ones were separated into five fractions by anion-exchange chromatography. The fractionated plasma proteins were subjected to 2D-DIGE with highly sensitive fluorescent dyes. The quantitative protein expression profiles obtained by 2D-DIGE were compared between two plasma protein mixtures: one from five non-cancer bearing healthy donors and the other from five patients with pancreatic cancer. Among 1200 protein spots, we found that 33 protein spots were differently expressed between the two mixtures; 27 of these were up-regulated and six were down-regulated in cancer. Mass spectrometry and database searching allowed the identification of the proteins corresponding to the gel spots. Up-regulation of leucine-rich alpha-2-glycoprotein (LRG), which has not previously been implicated in pancreatic cancer, was observed. Western blotting with an anti-LRG antibody validated the up-regulation of LRG in an independent series of plasma samples from healthy controls, patients with chronic pancreatitis, and patients with pancreatic cancer. Our results demonstrate the application of a combination of multi-dimensional liquid chromatography with 2D-DIGE for plasma proteomics and suggest the clinical utility of LRG plasma level measurement.

Possible detection of pancreatic cancer by plasma protein profiling.

The survival rate of pancreatic cancer patients is the lowest among those with common solid tumors, and early detection is one of the most feasible means of improving outcomes. We compared plasma proteomes between pancreatic cancer patients and sex- and age-matched healthy controls using surface-enhanced laser desorption/ionization coupled with hybrid quadrupole time-of-flight mass spectrometry. Proteomic spectra were generated from a total of 245 plasma samples obtained from two institutes. A discriminating proteomic pattern was extracted from a training cohort (71 pancreatic cancer patients and 71 healthy controls) using a support vector machine learning algorithm and was applied to two validation cohorts. We recognized a set of four mass peaks at 8,766, 17,272, 28,080, and 14,779 m/z, whose mean intensities differed significantly (Mann-Whitney U test, P < 0.01), as most accurately discriminating cancer patients from healthy controls in the training cohort [sensitivity of 97.2% (69 of 71), specificity of 94.4% (67 of 71), and area under the curve value of 0.978]. This set discriminated cancer patients in the first validation cohort with a sensitivity of 90.9% (30 of 33) and a specificity of 91.1% (41 of 45), and its discriminating capacity was further validated in an independent cohort at a second institution. When combined with CA19-9, 100% (29 of 29 patients) of pancreatic cancers, including early-stage (stages I and II) tumors, were detected. Although a multi-institutional large-scale study will be necessary to confirm clinical significance, the biomarker set identified in this study may be applicable to using plasma samples to diagnose pancreatic cancer.

Inhibitory effect of meloxicam, a cyclooxygenase-2 inhibitor, on N-nitrosobis (2-oxopropyl) amine induced biliary carcinogenesis in Syrian hamsters.

Pancreaticobiliary maljunction (PBM) is a high risk factor in biliary tract carcinoma. The chemopreventive action of a cyclooxygenase (COX)-2 inhibitor (meloxicam) on N-nitrosobis (2-oxopropyl) amine (BOP)-induced gallbladder cancer in hamster PBM models was investigated. In 7-week-old female Syrian golden hamsters, the extrahepatic bile duct at the distal end of the common duct was ligated and cholecystoduodenostomy was performed (group I). In group II, the same surgery was performed and from week 4 after surgery, 10 mg/kg of BOP was injected subcutaneously once a week with a 1-week interval. In group III, in addition to the measures employed in group II, 5 mg/kg/day of meloxicam was administered once a day, every weekday. Pathological findings in the gallbladder in week 20 after surgery were as follows. In group I, proper epithelium (PE) was predominant and there was no cancer. In group II, PE was predominant, but there was also hyperplasia and atypical epithelium (AE) recognized in 8 of 11 cases (72.7%); the area of AE was more extensive than that in group I. Carcinoma in situ (CIS) was recognized in 4 of 11 cases (36.4%) in group II. Group III showed the same pathological findings as group I. However, compared with group II, the incidence of AE decreased to 27.3% and no cancerous lesion was observed. In week 20 after surgery, the proliferative cell nuclear antigen labeling index in group III was statistically significantly lower than in group II (P = 0.045). No statistically significant differences were noted among the groups in terms of apoptosis labeling index in week 20 after surgery. In conclusion, it was confirmed that meloxicam suppresses carcinogenesis in hamster PBM models and its mechanism may be based on the suppression of cell growth.

Pathological features and surgical outcome of pancreaticobiliary maljunction without dilatation of the extrahepatic bile duct.

In cases of pancreaticobiliary maljunction without dilatation of the extrahepatic bile duct (undilated PBM), preventive cholecystectomy is performed because there is a high incidence of gallbladder cancer as compared to cases of PBM with dilatation of the extrahepatic bile duct (dilated PBM). However, it is still controversial whether resection of the extrahepatic bile duct should also be performed in patients with undilated PBM. Accordingly, we analyzed pathological findings, postoperative complications and a long-term prognosis in 19 patients with undilated PBM to clarify the possibility of the bile duct cancer. In undilated PBM, hyperplasia was significantly recognized in the gallbladder as compared to the bile duct (p=0.0238), while no significant differences were found in other epithelium. Atypical epithelium and hyperplasia in gallbladder mucosa of undilated PBM were significantly recognized as compared to cases of pancreas or biliary tract cancer without PBM (p=0.0035, p=0.0019, respectively), while no significant differences were recognized in any kind of epithelium of the bile duct. In 14 cases of undilated PBM with preservation of the extrahepatic bile duct, the postoperative observation period was from 1 year and 5 months to 18 years and 10 months (mean: 8.3 years). One of the 5 patients with gallbladder cancer died 2 years and 6 months after surgery due to the cancer recurrence, while the remaining 13 patients had no complications such as liver dysfunction, cholangitis or remnant bile duct cancer, and the patients have survived in good health. These findings indicate that preventive bile duct resection is not necessary in patients with undilated PBM.

High risk of bile duct carcinogenesis after primary resection of a congenital biliary dilatation.

Congenital biliary dilatation (CBD) is a relatively rare disease and highly associated with hepatobiliary malignancies due to pancreaticobiliary maljunction. For the treatment of CBD, the standard surgical method is the excision of the entire extrahepatic duct with a hepaticoenterostomy. However, in recent years, there has been an increase in reports of cancer developing in the biliary or pancreatic duct after hepaticoenterostomy. In this report, we describe the postoperative complications and carcinogenesis in 50 CBD patients according to the method of reconstruction of the bile duct. Hepaticojejunostomy (HJ) was performed in 34 patients and hepaticoduodenostomy (HD) in 16. In the HJ group, there were 7 cases of ascending cholangitis (20.6%), 3 cases of choledocholithiasis (8.8%), 4 cases of anastomotic stricture (11.8%) and 1 case of cholangiocarcinoma (2.9%). In the patient with cholangiocarcinoma, all complications including ascending cholangitis, choledocholithiasis, and anastomotic stricture were present. In the HD group, however, 2 cases of ascending cholangitis (5.9%) were recognized although choledocholithiasis, anastomotic stricture or cholangiocarcinoma were not observed. No significant differences were found in incidences of these complications between HJ and HD. It is unclear which method of reconstruction has a higher risk of carcinogenesis, however, it can be stated that hepaticoenterostomy itself is indeed one of the risk factors for biliary tract carcinoma. In any event, as several researchers have pointed out, since the incidence of bile duct carcinoma after the resection of the extrahepatic bile duct in CBD patients is very high compared to natural control, a long-term follow-up of the patient is necessary.

Immunohistochemical analysis of cyclooxygenase-2 and vascular endothelial growth factor in pancreaticobiliary maljunction.

Recent studies have elucidated that cyclooxygenase (COX)-2 is strongly related to cancer progression or development by means of its anti-apoptotic effect, enhancement of angiogenesis or decrease of cell-to-cell adhesive activity. However, there is no report on the relationship between COX-2 expression and angiogenesis in pancreaticobiliary maljunction (PBM). We examined the correlation between the overexpression of COX-2 and vascular endothelial growth factor (VEGF) in 65 lesions from 30 patients with PBM immunohistochemically. The positive expression of COX-2 was found in 20% of regenerative epithelium, 11.1% of hyperplasia without atypia, 86.4% of hyperplasia with mild atypia, 75% of dysplasia, and 75% of cancerous lesions. VEGF was highly expressed in 80% of regenerative epithelium, 27.8% of hyperplasia without atypia, 86.4% of hyperplasia with mild atypia, 66.7% of dysplasia, and 75% of cancerous lesions. The positive rate of both COX-2 and VEFG expression was significantly higher in hyperplasia with atypia, dysplasia and cancerous lesions than that in hyperplasia without atypia. In addition, there was a statistically significant correlation between COX-2 and VEGF overexpression among all lesions. In 6 of 8 patients of various histological types, both COX-2 and VEGF were stained in almost exactly the same locations. In addition, there were no significant differences between the degree of inflammatory cell infiltration in the surrounding stroma and the expression of COX-2 and VEGF, respectively. These results demonstrated a strong relationship between COX-2 and VEGF overexpression in PBM. Therefore, chemoprevention via the suppression of angiogenesis by means of COX-2 inhibitor may be effective in PBM.

Artificial mimicking of physiological active transport by a membrane co-cultured with two different cells: hepatic origin HepG2 and renal origin PCTL-MDR.

We designed a membrane culture unit on which 2 different cell lines were co-cultured to achieve selective and active transport of toxins. Hepatic origin HepG2 and renal origin multidrug-resistant gene-transduced proximal convoluted tubular cell line (PCTL-MDR) were cultured on the opposite sides of an expanded polytetrafluoroethylene membrane. The activity of testosterone hydroxylation by original HepG2 was very low; however, the cytochrome p450 (CYP) 3A4-transduced recombinant HepG2 metabolized the substrate efficiently. Testosterone added into the outer medium was hydrolyzed by HepG2, and the metabolites were preferentially transported to the inner medium by PCTL-MDR. [3H]-digoxin and [14C]-inulin were added to the outer medium; the digoxin was transported from the outer to inner space through the cell monolayer but the inulin was not, suggesting that the membrane actively transported only the substrate of the channel protein, MDR. The cells were irradiated (10 Gy) to prevent a membrane leak due to overgrowth. The irradiation did not induce apoptosis but resulted in long-lasting membrane function without leakage. The membrane co-cultured with hepatic and renal origin cells will enable a novel hemofiltration system with selective and active transport activities.