The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma ("moderately" and "poorly" differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop "de novo" from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.     

Anti-inflammation effects of naloxone involve phosphoinositide 3-kinase delta and gamma

Background

Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110δ and p110γ isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kδ and PI3Kγ in mediating the anti-inflammation effects of naloxone.

Materials and methods

Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kδ inhibitor IC87114, the PI3Kγ inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-κB (NF-κB) activation and Akt activation (indicator of PI3K activity) among these groups were compared.

Results

The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2/prostaglandin E₂) and the levels of NF-κB activation (p-NF-κB p65 and p-inhibitor-κB concentrations and NF-κB-DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kδ and PI3Kγ, as the concentrations of inflammatory molecules and the levels of NF-κB activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05).

Conclusions

PI3Kδ and PI3Kγ play crucial roles in mediating the anti-inflammation effects of naloxone.     

A novel rat full‐thickness hemi‐abdominal wall/hindlimb osteomyocutaneous combined flap: influence of allograft mass and vascularized bone marrow content on vascularized composite allograft survival

Vascularized bone marrow transplantation (VBMT) appears to promote tolerance for vascularized composite allotransplantation (VCA). However, it is unclear whether VBMT is critical for tolerance induction and, if so, whether there is a finite amount of VCA that VBMT can support. We investigated this with a novel VCA combined flap model incorporating full‐thickness hemiabdominal wall and hindlimb osteomyocutaneous (HAW/HLOMC) flaps. Effects of allograft mass (AM) and VBMT on VCA outcome were studied by comparing HAW/HLOMC VCAs with fully MHC‐mismatched BN donors and Lewis recipients. Control groups did not receive treatments following transplantation. Treatment groups received a short course of cyclosporine A (CsA), antilymphocyte serum, and three doses of adipocyte‐derived stem cells (POD 1, 8, and 15). The results showed that all flaps in control allogeneic groups rejected soon after VCAs. Treatment significantly prolonged allograft survival. Three of eight recipients in HLOMC treatment group had allografts survive long‐term and developed donor‐specific tolerance. Significantly higher peripheral chimerism was observed in HLOMC than other groups. It is concluded that the relative amount of AM to VBMT is a critical factor influencing long‐term allograft survival. Accordingly, VBMT content compared with VCA mass may be an important consideration for VCA in humans.     

Treatment of early cut-out of a lag screw using a trochanter supporting plate: 11 consecutive patients with unstable intertrochanteric fractures

Introduction Superior cut-out of a lag screw remains a serious complication in the treatment of intertrochanteric fractures. It is related to the stability of fracture reduction. We describe the application of a trochanter supporting plate (TSP) to restore the fracture stability after early cut-out of a lag screw in unstable intertrochanteric fractures.Materials and methods A total of 11 consecutive patients with superior cut-out of the lag screw of a dynamic hip screw (DHS) or a gamma nail in an unstable intertrochanteric fracture occurring within 6 months after surgery were included in the present study. They underwent repeat surgery for placement of a DHS and a laterally mounted TSP of our design. All patients were monitored for at least 6 months (median 15 months; range 6–28 months).Results There was no repeated cut-out of a lag screw, and 10 patients (91%) achieved bony union within 5 months. At the last follow-up, all patients could walk with or without aids.Conclusion It reveals that a TSP, as an adjuvant to a lag screw placed inferiorly, is an easy and safe solution for the treatment of early cut-out of a lag screw in unstable intertrochanteric fractures.     

Scale‐up of MSC under hypoxic conditions for allogeneic transplantation and enhancing bony regeneration in a rabbit calvarial defect model

To realize the therapeutic potential of mesenchymal stem cells (MSCs), we aimed to develop a method for isolating and expanding New Zealand rabbit MSCs in a great scale. Rabbit MSCs expanded under hypoxic and normoxic conditions were compared in terms of replication capacity, differentiation potential, and the capacity for allogeneic transplantation in a calvarial defect model. The cells from all tested rabbits were expanded more rapidly when plated at low‐density under hypoxic conditions compared to under normoxic conditions. Moreover, cells expanded under hypoxic conditions increased in the potential of osteoblastic, adipocytic, and chondrocytic differentiation. More importantly, radiographic analysis and micro‐CT measurement of bone volume revealed the hypoxic cells when transplanted in the calvarial defects of another rabbit increased in the ability to repair bone defect compared to the normoxic cells. Six weeks after allogeneic transplantation of hypoxic MSCs, histological analysis revealed a callus spanned the length of the defect, and several bone tissues spotted in the implant. At 12 weeks, new bone had formed throughout the implant. Using BrdU labeling to track the transplanted cells, the hypoxic cells were more detected in the newly formed bone compared to the normoxic cells. For defects treated with allogeneic MSCs, no adverse host response could be detected at any time‐point. In conclusion, we have developed a robust method for isolation and expansion of rabbit MSCs by combining low‐density with hypoxic culture, which can be applied for the design of clinical trials in allogeneic transplantation of MSCs for bone healing. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1213–1220, 2012     

Oral bisphosphonate use in the elderly is not associated with acute kidney injury

Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60?ml/min per 1.73?m(2)). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury.     

Multislice computed tomography angiography in pediatric liver transplantation

BACKGROUND: Preoperative delineation of any vascular anomalies offers planning for possible alteration of surgical procedures, especially in pediatric recipients undergoing living-related liver transplantation. PURPOSE: We assess the efficacy of three-dimensional (3D) multislice computed tomography (CT) angiography in the hope of replacing conventional angiography as the pretransplant evaluation of the hepatic vascular system for potential recipients of liver transplantation. METHODS: 3D CT angiography was performed in 38 children with biliary atresia. Conventional angiography was also performed in the first 15 patients. Twelve patients underwent living-related liver transplantation. The findings on 3D CT angiography were compared with conventional angiography and operative findings. RESULTS: 3D CT angiography was successfully performed in 37 pediatric patients. All findings of 3D CT angiography on hepatic artery, portal vein, and inferior vena cava paralleled those of catheter angiography and operative findings. Four patients were unsuitable to receive living grafts because of pathologic insults of the hepatic artery (one patient) and the portal vein (three patients). Three patients were advised to undergo a venous graft for portal anastomoses. Eight patients demonstrated portosystemic shunts that may require closure. CONCLUSION: 3D CT angiography proves to be a better tool in the demonstration of the vascular system and identification of pathologic insults in pediatric patients. It is superior to conventional angiography because it is less invasive, more convenient, and more efficient in providing thorough preoperative information that would have a major impact on patient selection and surgical planning.     

Periacetabular osteotomy through a modified ollier transtrochanteric approach for treatment of painful dysplastic hips

BACKGROUND: Elimination of abnormally high joint-loading resulting in excessive contact stresses may prevent or reduce the onset of osteoarthrosis in a dysplastic hip. A number of periacetabular osteotomies have been shown to be effective in restoring normal hip-joint mechanics. We treat acetabular dysplasia with a periacetabular osteotomy performed through a modified Ollier transtrochanteric approach. In this report, we describe the operative technique and the clinical and radiographic results. METHODS: Thirty-six patients (thirty-eight hips) in whom a painful dysplastic hip had been treated with a periacetabular osteotomy between March 1991 and June 1999 were included in the study. There were thirty-five female patients and one male patient with a mean age (and standard deviation) at the operation of 29.42 +/- 9.1 years. The technique utilizes a u-shaped skin incision, and a routine osteotomy of the greater trochanter with distal transfer if needed, and allows excellent visualization enabling the surgeon to perform the periacetabular osteotomy without penetrating the joint. RESULTS: At a mean of five years and six months postoperatively, the mean modified Harris hip score had improved from 59.1 +/- 15.8 points preoperatively to 87.97 +/- 14.3 points. Radiographically, the degree of osteoarthrosis had decreased in eleven hips, remained unchanged in twenty-four, and worsened in three. The mean anterior center-edge angle had increased from 22.0 degrees +/- 12.9 degrees to 36.1 degrees +/- 12.3 degrees, the mean lateral center-edge angle had increased from -2.7 degrees +/- 14.4 degrees to 26.6 degrees +/- 14.1 degrees, the mean acetabular index angle had improved from 23.4 degrees +/- 6.6 degrees to 12.7 degrees +/- 4.6 degrees, and the mean acetabular head index had increased from 48.2% +/- 12.7% to 73.1% +/- 16.0%. The Shenton line was restored in eleven hips. Thirty patients (thirty-two hips; 84%) had a satisfactory result. A poor preoperative functional score was associated with an unsatisfactory outcome (p = 0.00191). Complications included prolonged limping (eleven hips); numbness in the distribution of the lateral femoral cutaneous nerve (four); osteonecrosis of the rotated acetabular fragment (two); and acetabulofemoral impingement, heterotopic ossification, and a defect on the rotated ilium (one hip each). CONCLUSIONS: Painful dysplastic hips should be treated before function becomes seriously impaired. We believe that periacetabular osteotomy through a modified Ollier approach, which allows osseous cuts to be made under direct vision, can be learned readily. It provides improved femoral head coverage and relief of symptoms in most painful dysplastic hips in adolescents and young adults.     

Gamma knife radiosurgery for intracranial mature teratoma--long-term results and review of literature

BACKGROUND: The purpose of this report is to present long-term outcomes of gamma knife radiosurgery for intracranial mature teratoma after debulking surgery. METHODS: Three patients with intracranial mature teratoma had initial target volumes of 5.4, 18.7, and 5.1 cm(3), respectively, and were treated by gamma knife radiosurgery between 1993 and 2004. Marginal doses of 17, 12.5, and 13.5 Gy, respectively, were delivered to the tumors at isodose levels of 50%, 50%, and 62%, respectively. The first patient received radiosurgery after surgical removal and conventional radiotherapy. The second patient received similar management, including surgery and radiotherapy, with tumor recurrence. Two additional operations and subsequent radiosurgery were performed on this patient. Based on the favorable results of the first 2 patients, we performed radiosurgery instead of conventional radiotherapy after subtotal surgical removal in the last patient. By reviewing literatures concerning the therapeutic modalities and the long-term results of our 3 patients, we discuss the role of radiosurgery in treating intracranial mature teratoma. RESULTS: A follow-up period of 121, 89, and 31 months, respectively, demonstrated tumor volume reduction rates of 70%, 89%, and 48%, respectively. No evidence of further tumor progression and no radiosurgery-related complication or morbidity was noted. The school performances of the affected children are all above average. CONCLUSIONS: Gamma knife radiosurgery provides a safe and effective alternative as the adjuvant treatment of intracranial mature teratoma after surgical debulking. Previous conventional radiotherapy does not alter final tumor control. Radiosurgery should be considered when residual tumor growth continues with no related symptoms or evaluations of tumor markers during follow-up.     

Emergency airway management with fiberoptic intubation in the prone position with a fixed flexed neck

We describe emergency airway management with fiberoptic intubation in a patient in the prone position with her neck flexed by a head pin holder during a neurosurgical procedure. Laryngeal mask airway is suggested in emergency difficult airway algorithms; however, this was not feasible in this patient because of her edematous upper airway and limited mouth opening resulting from extreme neck flexion by a head pin holder. The case illustrates the role of fiberoptic intubation in emergency airway management in this critical situation. Maneuvers to facilitate fiberoptic technique are also described.