The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment.

Bone marrow-derived mesenchymal stem cells (BMSC) modulate inflammatory/immune responses and promote motor functional recovery after spinal cord injury (SCI). However, the effects of BMSC transplantation on central neuropathic pain and neuronal hyperexcitability after SCI remain elusive. This is of importance because BMSC-based therapies have been proposed for clinical treatment. We investigated the effects of BMSC transplantation on pain hypersensitivity in green fluorescent protein (GFP)-positive bone marrow-chimeric mice subjected to a contusion SCI, and the mechanisms of such effects. BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. The pain improvements were mediated by suppression of protein kinase C-γ and phosphocyclic AMP response element binding protein expression in dorsal horn neurons. BMSC transplants significantly reduced levels of p-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (p-ERK1/2) in both hematogenous macrophages and resident microglia and significantly reduced the infiltration of CD11b and GFP double-positive hematogenous macrophages without decreasing the CD11b-positive and GFP-negative activated spinal-microglia population. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB), which was associated with decreased levels of (a) inflammatory cytokines (tumor necrosis factor-α, interleukin-6); (b) mediators of early secondary vascular pathogenesis (matrix metallopeptidase 9); (c) macrophage recruiting factors (CCL2, CCL5, and CXCL10), but increased levels of a microglial stimulating factor (granulocyte-macrophage colony-stimulating factor). These findings support the use of BMSC transplants for SCI treatment. Furthermore, they suggest that BMSC reduce neuropathic pain through a variety of related mechanisms that include neuronal sparing and restoration of the disturbed BSCB, mediated through modulation of the activity of spinal-resident microglia and the activity and recruitment of hematogenous macrophages.

Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor.

OBJECTIVE: This study was conducted to expand the sunitinib safety database in Japanese imatinib-resistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. METHODS: Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. RESULTS: No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16-24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7-24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88-94). Higher relative dose intensity (≥70 vs. <70%) during the first 6 weeks and better Eastern Cooperative Oncology Group performance status (0 vs. ≥1) were associated with longer progression-free survival (24.0 vs. 20.1 weeks; P = 0.011; and 24.1 vs. 16.9 weeks; P < 0.001) and higher 24-week overall survival rate (94 vs. 83%; P < 0.001; and 96 vs. 83%; P < 0.001). Increased progression-free survival and overall survival rates were associated with specific adverse events. Cox proportional hazard modeling adjusted for relative dose intensity and performance status established hand-foot syndrome (hazard ratio = 0.636; 95% confidence interval, 0.456-0.888) and leukopenia (hazard ratio = 0.683; 95% confidence interval, 0.492-0.948) occurring within 12 weeks were significantly correlated with increased progression-free survival. CONCLUSION: Sunitinib showed good efficacy and tolerable safety. Factors associated with greater efficacy were relative dose intensity, performance status and specific early adverse events.

[Ossification of the posterior longitudinal ligament (OPLL) and the ligamentum flavum (OLF)].

The adult population is frequently sustained with ossification of the posterior longitudinal ligament (OPLL) and/or the ligamentum flavum (OLF) of the spine and the diseases may subsequently result is serious spinal cord insult with profound paralysis of the extremities. These pathologies are genetically denoted metaplasia of the elastic fibers of the ligament with consequent ectopic ossification process. The spinal cord is chronically compressed and will result in profound motor paralysis with sensory deficit. Both diseases are well imaged on CT and MRI, showing a various magnitude of spinal cord compression.

A case of non-esophageal eosinophilic gastrointestinal disease diagnosed by mucosal incision-assisted biopsy.

A 46-year-old woman presented at our hospital with anorexia, vomiting, and diarrhea. Blood tests indicated markedly increased eosinophil counts, and esophagogastroduodenoscopy revealed slight erythema in the gastric body. Computed tomography showed edematous thickening of the stomach and small intestinal walls and peritonitis. Thus, eosinophilic gastrointestinal disease was suspected. Endoscopic biopsies from the esophagus, stomach, and duodenum were collected, but no significant increases in eosinophil counts were observed. Little ascites effusion was detected and puncture cytology was difficult to perform. Thus, a sample of the muscularis propria layer was obtained by mucosal incision-assisted biopsy. Histopathological examination of the biopsy revealed significant eosinophilic infiltration within the muscularis propria layer of the stomach, confirming the diagnosis of non-eosinophilic esophagitis eosinophilic gastrointestinal disease. The patient was treated with a leukotriene receptor antagonist and prednisolone, and her clinical symptoms and gastrointestinal wall thickening rapidly improved. The Japanese diagnostic guideline for non-eosinophilic esophagitis eosinophilic gastrointestinal disease requires endoscopic biopsy or eosinophilic infiltration of ascites fluid. When diagnosis is difficult using conventional methods, as in this case, mucosal incision-assisted biopsy is useful as a next step.

Knee laxity after staircase exercise predicts radiographic disease progression in medial compartment knee osteoarthritis.

OBJECTIVE: To evaluate whether increased laxity of the knee during daily physical activities such as stair climbing is associated with progression of knee joint osteoarthritis (OA). METHODS: During the years 2001-2003, 136 patients with bilateral primary medial compartment knee joint OA were enrolled in this prospective study. Baseline data collected were body mass index (BMI), muscle power, radiographic joint space width, mechanical axis on standing radiography, and anteroposterior (AP) knee laxity before and after physical exercise. After 8 years of followup, 84 patients were reexamined to assess radiographic changes. Radiographic disease progression was defined as progression of >1 grade on the Kellgren/Lawrence scale. RESULTS: AP knee laxity increased significantly after stair climbing. Patients with OA progression and those without progression did not differ significantly in age, sex, baseline quadriceps muscle strength, mechanical axis, joint space width, and AP knee laxity before exercise. The 2 groups of patients did, however, differ significantly in baseline BMI and change in AP knee laxity due to exercise. The risk of progression of knee OA increased 4.15-fold with each millimeter of increase in the change in AP knee laxity due to exercise and 1.24-fold with each point increase in the BMI. CONCLUSION: Our results indicate that patients with OA progression have significantly greater changes in knee joint laxity during physical activities and a higher BMI than patients without OA progression. These findings suggest that larger changes in knee laxity during repetitive physical activities and a higher BMI play significant roles in the progression of knee OA.

Modified metaphyseal-loading anterolaterally flared anatomic femoral stem: five- to nine-year prospective follow-up evaluation and results of three-dimensional finite element analysis.

We have designed a proximal-fitting, anterolaterally flared, arc-deposit hydroxyapatite-coated anatomical femoral stem (FMS-anatomic stem; KYOCERA Medical, Osaka, Japan) for cementless total hip arthroplasty (THA) for Japanese patients with dysplastic hip osteoarthritis, using a nonlinear three-dimensional finite element analysis simulating loading conditions. The Anatomic Fit stem was modified in the region of the arc-sprayed surface, to allow more proximal appearance of spot welds. The aim of the present study was to analyze the clinical and radiographic outcomes of patients who underwent THA using this stem. We reviewed 73 consecutive patients (79 hips; 13 men 16 hips; 60 women 63 hips; age at surgery, 57.6 years, range, 35-78) who underwent cementless THA using the Anatomic Fit stem, at a follow-up period of 7.1 years (range, 5.1-9.4). Harris Hip score improved from 40.7 ± 17.1 before surgery to 91.0 ± 5.2 points at follow-up. The 7.1-year stem survival rate was 100%. Radiographs at follow-up confirmed the stability of the femoral stems within the femoral canal in all cases, with sufficient bone ingrowth. None of the patients had subsidence of the stem exceeding 2.0 mm within the femoral canal or changes in varus or valgus position of more than 2.0°. The Anatomic Fit stem provided excellent results. The nonlinear three-dimensional finite element analysis demonstrated that the stem-bone relative motion was 10 µm at the proximal end of the stem and proximal load transfer. Our analysis confirmed reduced radiolucency around the stem, minimal subsidence, appropriate stress shielding, and promising medium-term stability within the femoral canal.

Dislocated intra-articular femoral head fracture associated with fracture-dislocation of the hip and acetabulum: report of 12 cases and technical notes on surgical intervention.

This report describes case series of the femoral head fractures associated with fracture-dislocation of the hip joint to evaluate the mid- and long-term outcomes and to highlight the surgical technique of fixation of the femoral head from the posterior trochanteric flip osteotomy approach. Twelve patients (6 men and 6 women) with dislocated femoral head fractures (mean age at the time of injury, 56 years; range, 23-80) were followed up for mean period of 9.7 years (range, 5-20). All dislocations were reduced within less than 6 h after the injury. The type of femoral head fracture was classified according to the Pipkin classification on radiographs and CT. Five patients were classified as type I, 2 as type II, 2 as type III, and 3 as type IV. The clinical and radiological outcomes were assessed by Thompson and Epstein's regimen. Excluding 2 patients with Pipkin type III, the outcome of 9 patients was excellent/good, and poor in 1. The latter patient sustained Pipkin type IV and developed osteoarthritis 1 year after surgery and consequently required total hip arthroplasty. We conclude that small fragment of the femoral head less than 1 cm can be removed, while larger fragments should be fixed by bioabsorbable screws or pins in all types of femoral head fractures. In Pipkin type IV fractures, surgeons should always take anatomical reduction in the acetabulum into consideration during surgery.

Fracture of the acetabulum: a retrospective review of ninety-one patients treated at a single institution.

Acetabular fracture result in fairly good outcome after the anatomic reduction in the displaced fracture fragments and damaged joint structure, but some patients will inevitably suffer from hip joint problems during their courses after the insult. We retrospectively reviewed 91 patients with acetabular fractures to investigate the causes of clinical failure and relationship among the fracture types, selected treatment options and their courses. Ninety-one patients (73 men and 18 women) with an average age of 49 years (range 18-80) at the time of injury were followed up for an average of 8.6 years (range 2-18). Judet-Letournel classification of fracture type and Matta's rating regimen of functional and radiographic patient' assessment were conducted. Conservative treatment was provided in 20 patients, in which 19 attained excellent/good, and one fair clinical results. All achieved excellent/good radiographic outcome. Surgically treated patients (n = 71) with critical dislodgement of the fracture fragment showed that 64 (90%) attained excellent/good and 7 (10%) fair/poor clinical outcomes. Sixty-three (89%) attained excellent/good and 8 (11%) fair/poor postoperative radiographic outcome. Five patients with poor radiographic outcome after surgery subsequently required total hip arthroplasty, due to the development of hip joint osteoarthritis in 3 and femoral head avascular necrosis in 2. We conclude that displacement of the joint surface should be reduced to less than 3 mm in accordance with the selection of the most appropriate surgical approach for open reduction/fixation in each fracture type; however, comminuted fracture and avascular necrosis of the femoral head may be the cause of poor clinical results.

The Plastic Larval Body Color of the Pale Grass Blue Butterfly Zizeeria maha (Lepidoptera: Lycaenidae) in Response to the Host Plant Color: The Maternal Effect on Crypsis.

Many lepidopteran larvae show body color polyphenism, and their colors may be cryptic on the host plant leaves. To elucidate the effect of the host plant color on the plastic larval body color, we focused on the lycaenid butterfly Zizeeria maha, which shows various larval body colors ranging from green to red, even within a sibling group. We showed that oviposition was normally performed on both green and red leaves, despite a green preference and the fact that the larvae grew equally by consuming either green or red leaves. The number of red larvae decreased from the second instar stage to the fourth instar stage, demonstrating a stage-dependent variation. When the larvae were fed either green or red leaves across multiple generations of the lineages, the red larvae were significantly more abundant in the red leaf lineage than in the green leaf lineage. Moreover, the red-fed siblings showed a significantly higher red larval frequency than the green-fed siblings in the red-leaf lineage but not in the green-leaf lineage. These results suggest that, in this butterfly species, the plastic larval body color for crypsis may be affected not only by the color of the leaves that the larvae consume (single-generation effect) but also by the color of the leaves that their mothers consume (maternal effect), in addition to a stage-dependent color variation.

Postmarketing surveillance of nivolumab plus ipilimumab combination therapy in Japanese patients with unresectable malignant melanoma.

Although malignant melanoma is relatively rare in Japan, it is often diagnosed at a later stage than in Western countries. Nivolumab and ipilimumab are immune checkpoint inhibitors targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein 4, respectively. Owing to their complementary anticancer effects, nivolumab and ipilimumab combination therapy (N + I) has been studied and approved for treating malignant melanoma in various countries including Japan. Real-world postmarketing surveillance was implemented to record treatment-related adverse events (TRAEs) in patients treated with N + I following its approval in Japan. Patients were eligible for registration if they had unresectable malignant melanoma and started N + I between September 2018 and August 2019. The observation period was 13 weeks from starting N + I. Only safety information was collected and evaluated. The final case report form lock was March 2021. Overall, 173 patients (median age, 66.0 years; performance status 0-1, 88.4%; skin: 53.2%; mucosal: 32.4%) were eligible for the analyses. Overall, 34.1% of patients completed 4 doses of N + I. N + I was discontinued by 63.0% (due to adverse events in 67.9% and disease progression/death in 22.9%). Any grade and grade ≥3 TRAEs were reported in 73.41% and 52.02%, respectively. TRAEs in ≥10 patients were hepatic function abnormal (any grade/grade ≥3: 23.12%/13.29%), pyrexia (10.40%/0.58%), diarrhea (9.25%/2.89%), rash (8.67%/0.58%), hypophysitis (5.78%/5.20%), interstitial lung disease (5.78%/2.89%), and liver disorder (5.78%/4.62%). TRAEs were classified as recovered (36.99% of patients), recovering (44.51%), unrecovered (13.29%), recovered with sequelae (2.31%), and death (1.73%). Overall, 24 of 34 patients (70.59%) with gastrointestinal-related and 53 of 65 (81.54%) liver-related TRAEs received treatment, such as a steroid with/without an immunosuppressant; most patients recovered within 1 to 2 months. In conclusion, this postmarketing surveillance of N + I in patients with unresectable malignant melanoma revealed no new safety concerns compared with results of prior studies. Immune-related TRAEs were generally manageable by appropriate treatment including a steroid.

Clinical significance of MRI/(18)F-FDG PET fusion imaging of the spinal cord in patients with cervical compressive myelopathy.

PURPOSE: (18)F-FDG PET is used to investigate the metabolic activity of neural tissue. MRI is used to visualize morphological changes, but the relationship between intramedullary signal changes and clinical outcome remains controversial. The present study was designed to evaluate the use of 3-D MRI/(18)F-FDG PET fusion imaging for defining intramedullary signal changes on MRI scans and local glucose metabolic rate measured on (18)F-FDG PET scans in relation to clinical outcome and prognosis. METHODS: We studied 24 patients undergoing decompressive surgery for cervical compressive myelopathy. All patients underwent 3-D MRI and (18)F-FDG PET before surgery. Quantitative analysis of intramedullary signal changes on MRI scans included calculation of the signal intensity ratio (SIR) as the ratio between the increased lesional signal intensity and the signal intensity at the level of the C7/T1 disc. Using an Advantage workstation, the same slices of cervical 3-D MRI and (18)F-FDG PET images were fused. On the fused images, the maximal count of the lesion was adopted as the standardized uptake value (SUV(max)). In a similar manner to SIR, the SUV ratio (SUVR) was also calculated. Neurological assessment was conducted using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy. RESULTS: The SIR on T1-weighted (T1-W) images, but not SIR on T2-W images, was significantly correlated with preoperative JOA score and postoperative neurological improvement. Lesion SUV(max) was significantly correlated with SIR on T1-W images, but not with SIR on T2-W images, and also with postoperative neurological outcome. The SUVR correlated better than SIR on T1-W images and lesion SUV(max) with neurological improvement. Longer symptom duration was correlated negatively with SIR on T1-W images, positively with SIR on T2-W images, and negatively with SUV(max). CONCLUSION: Our results suggest that low-intensity signal on T1-W images, but not on T2-W images, is correlated with a poor postoperative neurological outcome. SUV(max) of lesions showing increased signal intensity and SUVR measured on fusion MRI/PET scans are more sensitive parameters for predicting clinical outcome than signal intensity on the MRI scan.

Changes in gait pattern and hip muscle strength after open reduction and internal fixation of acetabular fracture.

OBJECTIVES: To characterize changes in the gait pattern at 3 and 12 months after surgery for acetabular fracture, to assess the relationship between various gait parameters and hip muscle strength, and to determine the factors associated with gait disorders that correlate with gait parameters measured at 12 months after surgery. DESIGN: Prospective cohort study. SETTING: University hospital. PARTICIPANTS: Patients (N=19) with acetabular fractures were treated by open reduction and internal fixation (ORIF) and examined at 3 and 12 months postoperatively. The study also included a similar number of sex- and age-matched control subjects. INTERVENTIONS: Postoperative rehabilitation program. MAIN OUTCOME MEASURES: Spatiotemporal, kinematic, and kinetic variables of gait and strength of hip flexor, adductor, and abductor muscles at 3 and 12 months after ORIF. RESULTS: Walking velocity at 3 months after ORIF was slower in the patients than in the control subjects; however, walking velocity at 12 months was similar in the 2 groups. Although most of the kinematic and kinetic variables showed recovery to control levels at 3 and 12 months after ORIF, recovery was incomplete for pelvic forward tilt and hip abduction moment even at 12 months after ORIF. The greatest loss of muscle strength was noted in the hip abductors, where the average deficit was 35.4% at 3 months and 24.6% at 12 months. There was a significant relationship between hip abductor muscle strength and hip abduction moment at 3 months (R(2)=.63); however, this relationship diminished at 12 months (R(2)=.14). The presence of associated injuries correlated with lack of recovery of the peak hip abduction moment. CONCLUSIONS: Pelvic forward tilt and peak hip abduction moment showed incomplete recovery at 12 months after ORIF with subsequent conventional and home exercise rehabilitation programs. Our results suggest that improvement of hip abductor muscle strength in the early postoperative period could improve the peak hip abduction moment.

Infiltrative Erythemas and Nodules on a Unilateral Cheek Following Inappropriate Use of a Topical Steroid.

A 50-year-old Japanese woman referred to us with erythematous nodules on her left cheek. She had been treated with topical corticosteroids on her left cheek at a previous local clinic for 4 years. A skin biopsy specimen from a nodule showed perifolliculitis and folliculitis with a destruction of hair follicle without epidermal involvement. Based on the patient's history of the long-term topical corticosteroids and physical examination, we finally diagnosed this case as unilateral steroid-induced rosacea-like dermatitis (SIRD). She stopped topical steroid and was treated with topical application of benzoyl peroxide. One and a half year after starting the treatment, the nodules were flattened. Use of long-term and only unilateral application of topical corticosteroids probably resulted in unique clinical findings in our case. Given the broad clinical differential diagnosis, our case highlights the importance of appropriate application of topical steroids as well as histopathological analysis on any facial erythematous nodules.

NMR analysis of the fibronectin cell-adhesive sequence, Arg-Gly-Asp, in a recombinant silk-like protein and a model peptide.

It is well established that by introducing the cell-adhesive sequence Arg-Gly-Asp (RGD) from fibronectin into Bombyx mori silk fibroin by covalent coupling or bioengineering techniques, excellent biomaterials have been developed with the modified silk fibroin. However, there is no report about the structure and dynamics of the RGD moiety in the silk fibroin. To clarify the origin of such a high cell adhesion character and to design new recombinant silk protein with higher cell adhesion ability, it is necessary to characterize the structure and dynamics of the RGD moiety introduced into silk fibroin. In this study, the structure and dynamics of the RGD moiety in a recombinant silk-like protein, SLPF(10), consisting of the repeated silk fibroin sequence (AGSGAG)(3) and the sequence ASTGRGDSPA including the RGD moiety, were studied using solution NMR. The (1)H, (15)N, and (13)C chemical shifts indicate that the RGD moiety, as well as the silk fibroin sequence, takes a random coil form with high mobility in aqueous solution. Next, a (13)C solid-state NMR study was performed on a (13)C selectively labeled model peptide, AGSGAG[3-(13)C]A(7)GSGAGAGSGGT[2-(13)C]G(19)R[1-(13)C]G(21)DSPAGGGAGAGSGAG. After formic acid treatment, an increase in the ß-sheet fraction for the AGSGAG sequence and peak narrowing of the residues around the RGD moiety were observed in the dry state. The latter indicates a decrease in the chemical shift distribution although the RGD moiety is still in random coil. A decrease in the peak intensities of the RGD moiety in the swollen state after immersing it in distilled water was observed, indicating high mobility of the RGD sequence in the peptide in the swollen state. Thus, the random coil state of the RGD moiety in the recombinant silk-like protein is maintained in aqueous solution and also in both dry and swollen state. This is similar to the case of the RGD moiety in fibronectin. The presence of the linker ASTG at the N-terminus and SPAGG at the C-terminus seems important to maintain the random coil form and the flexible state of the RGD sequence in order to permit access for binding to various integrins.