Safety and effectiveness of pembrolizumab monotherapy in Japanese patients with unresectable urothelial carcinoma: a nation-wide post-marketing surveillance.

BACKGROUND: This study was conducted to identify factors associated with the safety and effectiveness of pembrolizumab in Japanese patients with unresectable urothelial carcinoma and to confirm the real-world safety and effectiveness of pembrolizumab in Japanese patients. METHODS: This multicenter, observational, post-marketing surveillance was conducted over a 1-year observation period starting at pembrolizumab initiation (200-mg pembrolizumab every 3 weeks); data were collected from case report forms (3 months and 1 year). Safety measures included treatment-related adverse events and adverse events of special interest (AEOSI). Effectiveness assessments included tumor response, objective response rate (ORR), and disease control rate (DCR). RESULTS: Overall, 1293 patients were evaluated for safety and 1136 for effectiveness. At 12 months, the treatment-related adverse event incidence was 53.8% (n = 696) and that of AEOSI was 25.0% (n = 323). The most frequent AEOSI of any grade were endocrinological disorder (10.4%, n = 134), interstitial lung disease (ILD) (7.2%, n = 93), and hepatic function disorder (4.9%, n = 64). Multivariate analysis demonstrated that the risk of developing ILD was almost seven times greater (odds ratio 6.60) in patients with a comorbidity of ILD, and approximately twice as high in patients aged ≥ 65 years (odds ratio 2.24) and with smoking history (odds ratio 1.79). The ORR was 26.1% and the DCR was 50.7%. The ORR was 46.4% in patients with a Bellmunt risk score of 0 and decreased as the Bellmunt risk score increased. CONCLUSIONS: This post-marketing surveillance confirmed the safety and effectiveness of pembrolizumab in Japanese patients with unresectable urothelial carcinoma in the real-world setting.

Real-world outcomes of pembrolizumab monotherapy in non-small cell lung cancer in Japan: A post-marketing surveillance.

This post-marketing surveillance (PMS) was initiated in Japan to identify factors affecting the safety and effectiveness of pembrolizumab monotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) expression. This PMS was conducted from December 2016 to June 2019 at 717 centers across Japan. Patients with unresectable advanced/recurrent NSCLC who received pembrolizumab monotherapy as first-line (1L) treatment for PD-L1-expressing tumors (Tumor Proportion Score [TPS] ≥ 50%) or second-line or later (2L+) treatment for tumors with PD-L1 TPS ≥ 1% were enrolled and followed up for 1 year. Of 2805 registered patients, 2740 and 2400 comprised the safety and effectiveness analysis sets, respectively. The median age (range) was 69 (27-92) years; 55.7% and 29.2% of patients experienced treatment-related adverse events and adverse events of special interest (AEOSIs), respectively. More common AEOSIs included interstitial lung disease, endocrine disorders, liver dysfunction, colitis/severe diarrhea, infusion reactions, and severe skin disorders. The frequency of experiencing ≥2 AEOSIs was low (1L, 6.5%; 2L+, 2.8%). Most AEOSIs occurred within 150 days after initiation of pembrolizumab monotherapy. At 1-year follow-up, the objective response rate was 39.2% (1L, 51.5%; 2L+, 30.0%). In conclusion, the 1-year safety and effectiveness of pembrolizumab monotherapy in patients with unresectable advanced/recurrent NSCLC as 1L treatment for tumors with PD-L1 TPS ≥ 50% and 2L+ treatment for tumors with PD-L1 TPS ≥ 1% were similar to those reported in phase 2/3 trials.

Surface Modification of Layered Perovskite Nanosheets with a Phosphorus Coupling Reagent in a Biphasic System.

Oleyl phosphate-modified HLaNb2O7· xH2O nanosheets (OP_HLaNb nanosheets) were prepared via phase transfer from an aqueous phase, comprising a dispersion of HLaNb2O7· xH2O (HLaNb) nanosheets, formed through the intercalation of tetrabutylammonium ion (TBA+) in the interlayer space of HLaNb and subsequent delamination, to a cyclohexane phase containing oleyl phosphate (OP, a mixture of monoester and diester). The modification of HLaNb nanosheets with OP was essentially completed within 3 days at a pH value of 2 or 4. Both infrared and solid-state 13C cross-polarization and magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectra of the OP_HLaNb nanosheets showed the presence of OP and/or related species and TBA+ on the HLaNb nanosheet surface. The solid-state 31P MAS NMR spectra of OP_HLaNb nanosheets exhibited new signals at -2 and 0 ppm, the former of which indicates the formation of Nb-O-P bonds. These whole data set obtained by complementary techniques clearly point out the modification of the HLaNb nanosheet surface by OP moieties causing a phase transfer. OP_HLaNb nanosheets showed higher dispersibility in cyclohexane than the OP_HLaNb_interlayer nanosheets, which were prepared via stepwise substitution reactions in the interlayers of HLaNb to achieve surface modification with OP and subsequent exfoliation in cyclohexane. The presence of TBA+ on the HLaNb nanosheets and the use of a liquid-liquid biphasic system were likely to improve the dispersibility. These results show that the preparation of OP-modified HLaNb nanosheets which could be well-dispersed in the cyclohexane phase was successful because of the use of a liquid-liquid biphasic system.

Angiosarcoma of the gallbladder with hemobilia: a case report.

A 61-year-old woman presented to our hospital with epigastric pain. She underwent abdominal contrast-enhanced computed tomography, which showed signal enhancement in the gallbladder fundus. As biliary obstruction was suspected, endoscopic nasobiliary drainage was performed, which revealed hemobilia. Based on this finding, gallbladder tumor was suspected, and open cholecystectomy was performed. Immunohistological staining of the resected tissue was positive for factor VIII that led to the diagnosis of gallbladder angiosarcoma. Hepatectomy and biliary reconstruction were performed for disease control; however, the patient died due to multiple liver metastases 4 months after the surgery.

Multiple recurrent sinus of valsalva aneurysms.

We report a case of multiple unruptured sinus of Valsalva aneurysms in an adult patient over nine years.

Renal Vein Thrombosis Occurring in Association with Oral Contraceptives: A Case Report.

Peripheral venous thromboembolism is a well-known complication of hormonal contraception, but reports on its association with visceral vein thrombosis is limited. We report the case of left renal vein thrombosis (RVT) associated with oral contraceptives (OCs) and concurrent smoking. The clinical presentation of this patient was acute left flank pain. Computed tomography revealed left RVT. The OC was discontinued, and we initiated anticoagulation with heparin and switched to edoxaban. Computed tomography 6 months later showed complete resolution of the thrombosis. This report alerts us regarding the importance of OCs as a risk factor for RVT.

Cardiac surgery for a right atrial myxoma with traumatic intracranial hemorrhage: a case report.

BACKGROUND: The timing of cardiac surgery with cardiopulmonary bypass (CPB) for intracranial hemorrhage is controversial. CASE PRESENTATION: We report the case of an 82-year-old woman who was transferred to our hospital because of a head injury. Brain computed tomography (CT) revealed traumatic intracranial hemorrhage, and transthoracic echocardiography revealed a giant right atrial myxoma. After confirming the disappearance of intracranial hemorrhage on brain CT, cardiac surgery with CPB was performed, which was uneventful. CONCLUSIONS: For an uneventful surgery, the optimal timing of cardiac surgery with CPB in patients with giant right atrial myxoma and intracranial hemorrhage should be based on brain CT.

[A case of small intestinal stage IV gastrointestinal stromal tumor in which long-term disease control was maintained for more than 10 Years through a multidisciplinary team approach].

The prognosis of metastatic or recurrent gastrointestinal stromal tumors (GISTs) accompanied by multiple hepatic metastases and peritoneal dissemination is very poor. We encountered a case of stage IV small intestinal GIST with multiple hepatic metastases and peritoneal dissemination that were observed after resection of the primary lesion. Multidisciplinary treatments were performed over time, including hepatic resection, radiotherapy, imatinib therapy, sunitinib therapy, and transcatheter arterial chemoembolization, and the disease had been brought under control following resection of a primary lesion 14 years ago. The patient was a 49-year-old woman diagnosed with hemorrhagic stool in July 1998, when a computed tomography scan revealed an 8-cm-diameter tumor in her small bowel. Partial resection of her small bowel was performed and the pathological diagnosis was a high-risk GIST showing 15 mitoses per 50 high power fields. Several metastases developed in the S4 and S5 segments of the patient's liver 3 years after resection of the primary lesion, and a central two-segmental resection of the liver was performed. Furthermore, 1 year after this procedure, peritoneal dissemination developed near the pancreas, for which radiotherapy was performed. Four months later, the patient again developed multiple liver metastases and was started on treatment with 400 mg imatinib per day, achieving a partial response(PR). Five years and 6 months after imatinib initiation, resistance emerged in one of the liver metastases. The patient was switched to sunitinib(50 mg per day), but was diagnosed with progressive disease at the end of the second course and the procedure was discontinued. Treatment with 400 mg of imatinib per day was resumed, and transcatheter arterial chemoembolization was performed twice over a 17-month period for the resistant hepatic region and a PR was achieved each time. We were able to maintain a PR in this patient; other metastases indicated the effectiveness of imatinib therapy. Therefore, a multidisciplinary team approach can be effective in achieving long-term disease control in patients with metastatic or recurrent GIST.

Real-world safety and effectiveness of pembrolizumab in Japanese patients with radically unresectable melanoma: An all-case postmarketing surveillance in Japan.

This all-case postmarketing surveillance (PMS) survey (101 centers; February 15, 2017, to March 3, 2020) captured factors that impact the safety and effectiveness of newly initiated pembrolizumab monotherapy for the treatment of radically unresectable melanoma in Japan. Eligible patients were enrolled both retrospectively and prospectively, and followed up at 1, 3, 6, and 12 months. Safety assessments included treatment-related adverse events (TRAEs), adverse events of special interest (AEOSIs) from the Japanese Risk Management Plan (J-AEOSIs), and J-AEOSIs related to pembrolizumab. Effectiveness assessments included objective response rate (ORR; complete response/partial response) and disease control rate (DCR) according to the RECIST criteria. Overall, 294 and 236 patients comprised the safety and effectiveness (RECIST) assessment sets, respectively. Median (range) age of the patients was 70 (22-94) years, and the majority (60.4%) received pembrolizumab as first-line therapy. The most common type of melanoma was cutaneous (41.5%), followed by mucosal (29.3%), acral (24.8%), and unknown (4.4%). Overall, 45.2% and 24.8% of patients experienced TRAEs and AEOSIs, respectively. In total, 24.8% and 9.2% of patients experienced any-grade and grade ≥3 pembrolizumab-related AEOSIs, respectively. The most common grade ≥3 pembrolizumab-related AEOSIs were endocrine disorders and liver dysfunction (2.4% each), followed by colitis/severe diarrhea (2.0%), interstitial lung disease (1%), and type 1 diabetes (0.7%). No grade 5 J-AEOSIs were observed. ORR was 16.5% at the 1-year follow-up: mucosal melanoma (20%), acral melanoma (10%), and cutaneous melanoma (17.5%). ORR was higher among patients who did not receive versus those who did receive previous systemic therapy across all three melanoma types. DCR was 52.1% at the 1-year follow-up: cutaneous melanoma (57.3%), acral melanoma (51.7%), and mucosal melanoma (43.1%). This all-case PMS survey confirmed the real-world safety and effectiveness of pembrolizumab monotherapy for the treatment of radically unresectable melanoma in Japan.

Fatal pulmonary thromboembolism caused by idiopathic ovarian vein thrombosis.

Ovarian vein thrombosis (OVT) is observed in the field of obstetrics and gynaecology. It is occasionally diagnosed during the postpartum period or in patients with ovarian malignancy. Few cases of pulmonary thromboembolism (PTE) caused by OVT have been reported previously. We report the case of a 67-year-old woman who presented with fatal PTE due to left OVT during hospitalization for cerebral infarction. The left ovary of the postmenopausal elderly patient showed no tumorous appearance. This case of OVT is extremely rare because of its idiopathic nature and fatal result.

A case of plastic bronchitis after mitral valve surgery in an adult.

Plastic bronchitis is a rare and fatal disease that is characterized by the presence of long dendritic bronchial casts in the airway. It is encountered most frequently in children with congenital heart disease after correction surgery. We reported a case of plastic bronchitis after mitral valve surgery in a 70-year-old woman.

[A case of primary hepatic actinomycosis].

Primary hepatic actinomycosis is relatively rare, but it should be remembered in the differential diagnosis of liver masses. A 66-year-old woman with right hypochondralgia was admitted and for detailed examination and treatment of a liver tumor. Abdominal ultrasonography revealed a hypoechoic lesion 55 mm in diameter in the anterior segment. Enhanced CT showed a deep-stained tumor in the early phase and a low density area in the late phase. The feeding arteries were the right hepatic artery and right inferior phrenic artery on abdominal angiography. The patient was given a diagnosis of hepatocellular carcinoma with invasion of the inferior lobe of the right lung. We performed a central bisegmentectomy of the liver and partial resection of the inferior lobe of the right lung. Microscopic findings of the resected specimen revealed sulfur granules and the tumor was diagnosed as primary hepatic actinomycosis.

Comparative pharmacological profiles of morphine and oxycodone under a neuropathic pain-like state in mice: evidence for less sensitivity to morphine.

The present study was undertaken to investigate pharmacological actions induced by morphine and oxycodone under a neuropathic pain-like state. In the mu-opioid receptor (MOR) binding study and G-protein activation, we confirmed that both morphine and oxycodone showed MOR agonistic activities. Mice with sciatic nerve ligation exhibited the marked neuropathic pain-like behavior. Under these conditions, antinociception induced by subcutaneously (s.c.) injected morphine was significantly decreased by sciatic nerve ligation, whereas s.c. injection of oxycodone produced a profound antinociception in sciatic nerve-ligated mice. There were no significant differences in spinal or supraspinal antinociception of morphine and oxycodone between sham operation and nerve ligation. Moreover, either morphine- or oxycodone-induced increase in guanosine-5'-o-(3-thio) triphosphate ([(35)S]GTPgammaS) binding in the spinal cord, periaqueductal gray matter and thalamus in sciatic nerve-ligated mice was similar to that in sham-operated mice. Antinociception induced by s.c., intrathecal, or intracerebroventricular injection of the morphine metabolite morphine-6-glucuronide (M-6-G) was significantly decreased by sciatic nerve ligation. Furthermore, the increase in the G-protein activation induced by M-6-G was eliminated in sciatic nerve ligation. In addition, either morphine- or oxycodone-induced rewarding effect was dramatically suppressed under a neuropathic pain-like state. The increased [(35)S]GTPgammaS binding by morphine or oxycodone was significantly lower in the lower midbrain of mice with sciatic nerve ligation compared with that in control mice. These findings provide further evidence that oxycodone shows a profound antinociceptive effect under a neuropathic pain-like state with less of a rewarding effect. Furthermore, the reduction in G-protein activation induced by M-6-G may, at least in part, contribute to the suppression of the antinociceptive effect produced by morphine under a neuropathic pain-like state.

Efficacy of Preoperative Antibiotic Therapy for the Treatment of Vascular Graft Infection.

Objective: We aimed to assess the efficacy of preoperative antibiotic therapy for the treatment of prosthetic graft infection. Materials and Methods: We retrospectively analyzed the treatment strategies used for managing patients with prosthetic vascular graft infections between 2000 and 2016. The patients were divided into two groups: early antibiotic (EA) group, those who were administered with antibiotics ≥2 weeks preoperatively and late antibiotic (LA) group, those who were administered with antibiotics <2 weeks preoperatively. We evaluated the outcomes including surgical procedures, length of hospital stay, and surgical revision. Results: All the surgical procedures performed in the EA group were elective surgeries. Three of the 11 surgeries performed in the LA group were emergency surgeries (P=0.16). No significant differences were observed in the operative procedure (P=0.64), operation time (P=0.37), and blood loss (P=0.63) of the two groups. Although the length of postoperative hospital stay did not significantly differ (P=0.61), the total length of hospital stay was longer in the EA group (P=0.02). Surgical revisions were performed for five patients in the LA group and for none in the EA group (P=0.04). Conclusion: Preoperative antibiotic therapy provided excellent outcomes in terms of avoiding surgical revisions in the treatment of vascular graft infection.

Off-pump coronary artery bypass grafting for a patient with anomalous origin of the right coronary artery from the pulmonary artery.

We report on a case of a 70-year-old chronic hemodialysis patient. He presented with anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) and severe left anterior descending coronary artery (LAD) stenosis, which supplied collateral flow to the right coronary artery (RCA). The patient complained of myocardial ischemic symptoms during routine hemodialysis. We performed off-pump coronary artery bypass grafting (OPCABG) surgery and ligation of the origin of the ARCAPA. Previous reports described that the myocardial ischemia was a rare complication with the ARCAPA patients. However, this case required coronary revascularization because of the atherosclerotic LAD stenosis as a collateral source of the RCA.

Effect of a selective GABA(B) receptor agonist baclofen on the mu-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects.

The management of excessive adverse effects of opioids is a major clinical problem. The present study was undertaken to investigate the effect of a selective gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen on the mu-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects. Either morphine or fentanyl produced a dose-dependent antinociceptive effect in both ferrets using Randall-Selitto test and mice using tail-flick test. Under these conditions, pretreatment of baclofen produced an additive antinociception induced by morphine or fentanyl. Furthermore, the augmentation of antinociception induced by systemic administration of baclofen with morphine or fentanyl was completely abolished by either i.c.v. or i.t. pretreatment with the selective GABA(B) receptor antagonist CGP 35348 in mice. We next investigated the emetic response induced by mu-opioid receptor agonist in ferrets. Morphine at lower doses than that used for antinociceptive assay produced both retching and vomiting, whereas fentanyl failed to produce the retching and vomiting in ferrets. Here we reported for the first time that baclofen significantly suppressed the retching and vomiting induced by morphine, indicating the involvement of GABA(B) receptor in emetic control pathway. Furthermore, baclofen also inhibited place preference elicited morphine or fentanyl in rats. Taken together, these results suggest that co-administration of baclofen with mu-opioid receptor agonist produced a potentiation of antinociceptive effect, whereas an untoward effect was completely blocked.

[Basic studies on cancer pain control].

According to the World Health Organization (WHO) guidelines for patients with moderate or severe pain, morphine has been used as a "gold standard" treatment for cancer pain. Recent clinical experiences have demonstrated that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern. However, undue anxiety about psychological dependence on morphine in cancer patients has caused physicians and patients to use inadequate doses of opioids. In basic research, we reported that the morphine-induced rewarding effects can be dramatically suppressed under a neuropathic pain-like state induced by sciatic nerve ligation and an inflammatory pain-like state produced by intraplantar injection of formalin or carrageenan in rodents. The use of morphine for the treatment of pain is sometimes accompanied with side effects such as emesis, constipation and drowsiness. We show that the lower doses of morphine produce emesis, whereas antinociceptive doses of morphine show no emetic responses in ferrets. These findings provide further evidence that an adequate dose of morphine is useful and safe in a clinical setting.

[Infective endocarditis caused by methicillin resistant Staphylococcus aureus following corticosteroid pulse therapy; report of a case].

A 51-year-old man, with a history of corticosteroid pulse therapy 3 weeks previously, developed infective endocarditis of the mitral valve due to methicillin resistant Staphylococcus aureus, and underwent mitral valve replacement. Since the second postoperative day, clinical course was seriously complicated because of recurrent abdominal pain corresponding with commencement of oral intake, unremitting spike fever, and renal and hepatic dysfunction. Various examinations except angiography failed to demonstrate the etiology. Two months later, the patient developed panperitonitis due to perforation of ischemic ulcer of the cecum and underwent ileo-cecal resection. After this operation, he convalesced very quickly. Ischemia is one of the main causes of abdominal complication following cardiac surgery. Angiography should be positively considered in cases like the present one.